Kirsty’s Stage 4 Squamous Cell Kidney Cancer Story
Interviewed by: Taylor Scheib Edited by: Katrina Villareal
Kirsty, a single mother of two from East Yorkshire, England, was diagnosed with a rare and aggressive form of kidney cancer. Reflecting on her journey, she realized that she had been experiencing symptoms for years. During a 2021 check-up for endometriosis, fluid was discovered in her left kidney, but no further investigation was done. For two years, traces of blood in her urine were dismissed as part of her endometriosis.
In May 2023, Kirsty experienced constant flank pain on her left side after a bicycle fall. She also suffered from backache, fatigue, and significant weight loss. Persistent pain led to repeated visits to her general practitioner. In October, an ultrasound showed significantly more fluid in her kidney and a CT scan with contrast revealed the spread of cancer.
On December 1, 2023, Kirsty was diagnosed with stage 4 squamous cell kidney cancer that had spread to some lymph nodes. Though surgery was not a possibility, she began chemotherapy, which significantly reduced the tumor but came with severe side effects such as fatigue, nausea, and nerve pain. Despite the initial plan to do six cycles, she stopped after five due to the intensity of the treatment.
Kirsty was open with her children about her diagnosis, providing emotional support and encouraging them to express their feelings. Inspired by her mother’s battle with cancer, she focused on creating lasting memories with her children. Her approach to life shifted to prioritize meaningful experiences.
She advises others to listen to their bodies and seek medical attention when symptoms persist. She stressed not taking loved ones for granted and valuing time spent with family over work. Through her journey, Kirsty aims to inspire others to cherish every moment and prioritize what truly matters.
Symptoms: None; found the cancers during CAT scans for internal bleeding due to ulcers Treatment: Chemotherapy (capecitabine + temozolomide), surgery (distal pancreatectomy, to be scheduled)
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Cancer details: Also known as urothelial (invasive), 5-10% of kidney cancers 1st Symptoms: Blood in urine Treatment: Nephrectomy (surgical removal of kidney and ureter)
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Symptoms: Persistent left flank pain, backache, fatigue, weight loss, traces of blood in urine, fluid in left kidney Treatment: Chemotherapy (gemcitabine & carboplatin)
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Cancer genetics: hereditary leiomyomatosis and renal cell cancer (HLRCC) (Reed’s Syndrome) 1st symptoms: profound fatigue, hypertension, high red blood cell count, severe back pain, badly swollen legs Treatment: Cabometyx (cabozantinib) assigned under S1500 PAPMET clinical trial
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Margie shares her journey with stage 1B, grade 3 endometrial cancer. Initially attributing her symptoms to menopause, she experienced persistent irregular bleeding for years. After consulting her OB-GYN and undergoing a biopsy and ultrasound, she was diagnosed with cancer, leading to a swift progression from diagnosis to surgery, which confirmed the cancer had not spread beyond the uterine walls.
Margie’s treatment included surgery, chemotherapy, and brachytherapy radiation. Despite facing challenges with healthcare providers and navigating the medical system, she sought multiple opinions to ensure the best care. She managed side effects with essential oils and naturopathic remedies, emphasizing self-care and symptom documentation. Margie’s story highlights the importance of patient advocacy, thorough medical documentation, and compassionate healthcare providers, serving as an inspiration for others facing similar battles and advocating for awareness and proactive health management.
For more support in endometrial cancer, visit our friends at ECANA.
Thank you to Karyopharm for its support of our patient education program! The Patient Story retains full editorial control over all content.
This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
I live in Seattle, Washington. I’m single and have two adult girls and five grandchildren. I work with my oldest daughter at home as a grandma nanny. I do a lot of driving, preparing meals, laundry, and help around the house.
I’m the program director of ECANA: Endometrial Cancer Action Network for African-Americans. I facilitate one program twice a month. Right now, it’s chair yoga and conversations where we meet with Black women who have been affected by endometrial cancer. We provide a space to talk, share, and ask questions, and then spend 15 to 20 minutes doing some physical exercises to help people get back on their feet after their cancer treatments. That is one of my passions as well. I’m a fitness instructor, so I teach classes when I can.
I didn’t do anything about the bleeding because I thought it was part of menopause.
Pre-diagnosis
Initial Symptoms
I first started questioning that something might be going on with me when I was in the middle of menopause. When you’re going through menopause, you have all these different symptoms, like hot flashes and mood swings. You could have a cycle for two months and then not have one for three, and then have one for four months and not have it again, but you have to go one whole year without having any signs of blood.
I didn’t pay attention to my cycles, so I don’t know if I ever went a whole year without seeing any blood. I didn’t document it, so my strong suggestion is to document when you start your cycle and when it starts being weird, document how it was. When you’ve gone 12 months with no blood and then now there’s blood, go to your doctor.
I didn’t do anything about the bleeding because I thought it was part of menopause. I felt like I had a cycle every day. Nothing for two days and then I’ll have bleeding for a week, then nothing for 2 or 3 days and then bleeding again for three weeks. It went on for 2 to 3 years, but I was quiet about it.
The spotting and bleeding became heavier. I had no pain, but I just got tired of it and thought, This has to stop. I need to do something about this. On one of my visits, I mentioned it to my OB-GYN. I said, “Shouldn’t I be done? I feel like I’m spotting or I’m bleeding still. Should I still be bleeding?” She said, “Yeah, you should be done.”
Biopsy
My OB-GYN requested an ultrasound. Before I went, she took a biopsy sample in her office. She said, “It’s not going to hurt. It’ll be fine. I need to pull out a piece so I can send it to the lab because I feel like there’s something going on in here, but I’m not sure.”
It lasted only 10 minutes, but I asked her, “Am I going to be able to walk to my car when you’re done?” She was digging in my vaginal area, trying to pull something out. It was so painful. There wasn’t any pain after, but the whole process was horrible. I hope that procedure is better today than it was before. She sent me home with antibiotics.
‘They’re sending you to an oncologist? … Mom, they think you have cancer.’
Ultrasound
When I went for an ultrasound, the tech said, “The lining of your uterus is thick. We need to check that out. I’m going to set you up for an appointment with an OB-GYN oncologist. Make sure you bring somebody with you to that appointment.”
When I got home, I told my daughter. She dropped what she was doing, stared at me, and asked, “They’re sending you to an oncologist?” I said, “I think that’s what she said. OB-GYN oncologist.” She said, “Mom, they think you have cancer.” I said, “How do you know that?” She said, “Because you’re going to see an oncologist.”
She then asked, “Who’s going with you?” I said, “My friend Holly’s going to come with me.” She said, “Okay. Make sure you take good notes and find out what’s going on.” That was my introduction to the possibility of having cancer. Even after hearing that, I thought, I don’t have cancer. Calm down, people.
Diagnosis
Getting the Diagnosis
When I went to see the OB-GYN oncologist, he saw my ultrasound and I thought that he had the biopsy results. He was fast talking and had no bedside manners at all. It was so bad. I’m still like a deer in headlights and you’re telling me something’s wrong with me.
He said, “You might have cancer, you might not have cancer. You might have a carcinoma or you might not have one. You’re 58. You don’t really need all those parts. We’ll take everything out. We’ll have a complete hysterectomy. If we see any signs of cancer in there — we might or we might not — then we’re taking everything out.”
My friend who was with me said, “Excuse me. Can you slow down? Can you tell her what that means? She doesn’t know what you’re talking about.” In 15 minutes, I was on the table getting checked then I was over in the other room, making an appointment for a surgery.
He said, “We’ll know for sure after surgery. It might be, but it might not be,” and then he started naming off different kinds of cancers that it could or could not be. That’s the part I thought was weird. My friend was totally put off by him and said, “She needs her female organs. What do you mean she doesn’t need them anymore?” After making the appointment, she said, “You know you can cancel this if you need to.”
The surgery was supposed to take 2.5 hours but it ended up taking 4 hours… the tumor was too big.
Reaction to the Diagnosis
I was in shock and couldn’t believe it. It all happened so quickly. I was numb for about two months. Everything was a blur.
My youngest daughter, who lives in Chicago, said, “Let’s get the email strings going. Let’s find out what we need for care.” My friends started mobilizing. Then I realized that everybody was talking about me. It was me who’s going through this. I couldn’t see myself at that moment.
I was diagnosed with stage 1B, grade 3 endometrial cancer. The tumor stayed inside the uterine walls, but it was already 80% of it, so 20% more and it would have been out. I got my lymph nodes checked including all the surrounding areas to make sure. All of that came back clear. Thank you, Jesus. I was happy about that.
Treatment
Surgery
The surgery was supposed to take 2.5 hours but it ended up taking 4 hours. They went in laparoscopically and saw that the tumor was too big. They couldn’t get it out, so they ended up having to cut me a little to get it out, which extended the length of time that I was in surgery.
When I woke up, my daughter and some friends were in my room. I was still pretty groggy when the doctor came in. He said, “It stayed inside the uterine wall. We feel like we got it all. We did take some lymph nodes and stuff all around to double-check. We’ll get that back from pathology in about a week.” He said it was like everything dissolved in their hands when they were taken out. It was a relief to hear that he felt like he got it all. When I came in for my 10-day appointment, we received good news: everything was clear. I healed well from the surgery.
He was very calm, kept eye contact, and talked to me like I was a person instead of a number.
Discussing Chemotherapy & Radiation
I didn’t get a second or third opinion until after the surgery because my doctor said, “Let’s get it done and we’ll research as we go.” After surgery, they talked about treatments. At that appointment, he started throwing out information about chemotherapy and radiation. My insurance did not cover the chemo with that hospital, so I had to go to another hospital. He was saying I needed 6 to 8 rounds of chemo and 6 to 7 weeks of radiation to make sure because uterine cancers tend to hide.
Getting a Second Opinion
I was referred to the Fred Hutchinson Cancer Center in Seattle, Washington, for radiation. When I talked to the doctor, who was my second opinion about chemotherapy and radiation, he said, “I’ve looked at all your files and it looks like we’re going to probably do 4 or 5 rounds of chemotherapy and maybe 4 or 5 weeks of radiation after.”
He was the complete opposite of the other doctor. I was in his office for probably an hour. I had people with me who were taking notes. He was very calm, kept eye contact, and talked to me like I was a person instead of a number.
I met Dr. Kemi Doll, who was my third opinion and became my chemo doctor. She asked me questions and gave me time to answer. She went back to repeat what she already said to make sure I understood everything.
Getting a Third Opinion
My daughter, who lives in Chicago, was working and doing research as a professor at the University of Washington and UW Medicine. She met a doctor who knows the doctor who was going to be my chemo doctor. She’s emailing and texting me, “Mom, I just talked to so and so who’s going to hook you up with so and so. They’re going to call the office and then call you. You’re going to go see them because she’s an expert in this area.” That’s how I met Dr. Kemi Doll, who was my third opinion and became my chemo doctor.
She asked me questions and gave me time to answer. She went back to repeat what she already said to make sure I understood everything. She drew pictures. “This is this, this is this. If you don’t do chemo at all, here are the percentages that your cancer may or may not come back. If you do this much chemo, this is the percentage.”
She said, “We’re not going to do pelvic radiation. We’re going to do brachytherapy.” She explained what brachytherapy was and why. She said, “At your stage and from looking at all your records, this is preventative. Your chemo and radiation is all preventative. We want to make sure it doesn’t come back.”
I finally agreed to do four rounds of chemo and then brachytherapy. Dr. Doll said, “You’re way too anxious about the chemo, so we’re going to get it started as soon as possible.”
She said, ‘I have a feeling you’re going to do great. This is not going to be what you think it’s going to be.’ I was grateful to hear that.
Chemotherapy
At my first session, I didn’t have my port yet so I did it through the arm. My daughter from Chicago flew in. Dr. Doll showed up too. She said, “I have a feeling you’re going to do great. This is not going to be what you think it’s going to be.” I was grateful to hear that. Then she said, “I think you’re going to handle it well, but if you don’t, then we’re done. We’ll do brachytherapy and we can be done with the chemo.”
You have to get blood work done two days before a chemotherapy session to make sure that your platelets and your blood count are up. Otherwise, they can’t give you chemo. Before my last session, mine were low. They called me and told me to come in so they can give me a shot to boost the cells up and have my last chemo the following week. Then she said, “By the way, your insurance doesn’t cover it and it’s about $2,000.”
I said, “I’m good.” She said, “Are you sure? We’ll show you how to do it and then you go home and do it over the weekend.” I said, “No, thank you.” She wasn’t happy. She said, “If your temperature goes up, go to emergency. You’re very vulnerable right now because your immune system is low.”
I wore a mask for a week and that was in 2017. I immediately went to my list of foods because there are foods that help boost your immune system. I looked like I’m already eating lots of them, so I made sure to eat more, like twice a day. I protected myself and made sure that in the environment I was going in, nobody was infected with anything. I didn’t ignore what she said.
The next day, my doctor called me and said, “I talked to the nurse. She told me about her conversation with you and she told me your decision. I want you to know that this is your body. You make decisions for you. When you come for your last chemotherapy, they’ll do blood work right before to check and make sure that it’s at the level it needs to be. But if not, then we’ll skip it and wait another week. Or we could be done. It’s totally up to you. You decide whether you want to do that last chemo or not, or we can just call it. Let me know. Keep doing the stuff that you like to do for your own health. If you have any questions, call me or text me.”
I didn’t have one bout of nausea. I dealt with neuropathy and brain fog, not being able to focus on something for long periods of time.
When I went in for my last chemo, my girlfriend who went with me and I had two plans. We said, “If I don’t do chemo, we’re going shopping. If we do chemo, we’re going to high five and say, ‘This is the last one.’” After you check in, you sit in this little room and either they call your name or they walk over to you. They called my name, so I went right back and did my last chemo.
The nurse heard us talking and she said, “You mean you didn’t get the shots?” I said no. She asked, “What did you do?” The whole time, she was talking about my diet. I believe that the body is made to heal itself. Not that I don’t believe in all the other stuff, but I believe that and I was just done. I couldn’t give anymore.
Managing the Side Effects of Chemotherapy
I use essential oils, so I immediately checked to see which oils help with nausea. Nausea is one of the possible major side effects you could have from chemotherapy. And you know what? I didn’t have one bout of nausea.
I dealt with neuropathy and brain fog, not being able to focus on something for long periods of time. It takes away from who you know yourself to be. For the neuropathy, I soaked my feet, rubbed my feet, and wore good, comfortable shoes.
I also saw a naturopath once a month. Acupuncture helped with the nausea too, so I was grateful to have different avenues.
Because I felt good, I was pretty okay, but in the back of my mind, it’s always there.
Brachytherapy
The radiation was scheduled 6 to 8 weeks after surgery because complete healing time is about eight weeks.
Brachytherapy is internal radiation. They take a tube and put it right in your vagina.
When I went to my first brachytherapy appointment, they got me ready and put my legs up in the stirrup. They had everybody in the room to look: the interns, the specialists, and all that. I sat mortified. I’m glad I took a pill to keep me calm. Then he said, “I still see some blood up here. You are not completely healed.”
My first appointment was a wash. He kept apologizing and asked, “Where do you live?” I said, “Just down the street.” He said, “Oh, good because some people have to travel. Let’s give this two more weeks because this needs to be completely closed before we do any radiation.”
I came back two weeks later and by the end of February, I was done. I didn’t have any major side effects from brachytherapy.
Follow-up Protocol
I ended my chemo in February 2017. I saw Dr. Doll every three months. In 2018, I saw her twice a year. I went in every six months for blood work and checkups. In 2019, I saw her once and then I was good.
Because I felt good, I was pretty okay, but in the back of my mind, it’s always there. A month or two before the appointment, if I knew I was going to see her again, I would have to do a lot of deep breathing and checking myself physically, thinking, You know the signs, you know what to look for, and being aware of my own body. If I hear from her within the next 24 or 48 hours after my appointment, I wonder why. Each year got better.
The work that I do with ECANA helps, but sometimes it doesn’t because I feel like I’m constantly reliving that hard season of my life.
The only thing that still happens that’s annoying me are the sharp pains that I sometimes get in my wrist, my hands, or my feet, which I believe are side effects from neuropathy. They say it doesn’t really go away, but that’s about it.
Don’t let a doctor dismiss you or tell you that what you’re experiencing is all in your head. If they don’t have an answer, find someone who does.
Words of Advice
If you start going through menopause and your cycle starts going crazy, document everything. If you have not had your menstrual cycle in more than 12 months and then all of a sudden, you have a cycle or see blood, go see your doctor. That is the strongest message from my journey that I speak loudly about because I didn’t know to do that. I didn’t keep a journal. I didn’t pay attention. I figured I was in menopause so when it’s done, it’s done.
Find a doctor who you like, who’s going to listen to you, and who’s not going to dismiss you. It’s not okay for a doctor to presume what you’re feeling and what you’re going through. They’re supposed to listen to you.
As the patient, you are the most important person in the room. When I was at the 2024 SGO Annual Meeting in San Diego, I saw a black and white picture on a screen that said: as a doctor, if you listen long enough to your patient, they’ll tell you what’s wrong with them. Make sure the doctor listens to what you have to say. You’re not just another number.
For years, I’ve thought that the doctor knows everything. No, the doctor doesn’t. All the doctor knows is the book. You know you. Don’t let a doctor dismiss you or tell you that what you’re experiencing is all in your head. If they don’t have an answer, find someone who does. If the doctor doesn’t have your respect, leave and find one you can. That’s so important. It’s you that you’re talking about, it’s your health. You have to be able to communicate in a way that’s clear and where you feel like you’re being heard.
Special thanks again to Karyopharm for its support of our independent patient education content. The Patient Story retains full editorial control.
Navigating the Latest Metastatic Colorectal Cancer Treatments and Clinical Trials
Edited by: Katrina Villareal
Please watch the above video replay then take our program survey.
Allison Rosen, a colorectal cancer patient advocate, talks with leading oncologist Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center. Gain valuable insights into the latest advancements in the treatment of metastatic colorectal cancer and a deeper understanding of the current treatment landscape, including the most recent FDA-approved therapies that are making a difference.
Learn how biomarkers are revolutionizing the approach to treating metastatic colorectal cancer, potentially leading to more personalized and effective treatment plans. Discover emerging therapies and the most promising clinical trials available, offering new hope and options for patients. Equip yourself with the knowledge to collaborate effectively with your medical team, ensuring the best possible outcomes and quality of life.
We’d like to thank our promotional partners for their continued support of our programs. Please visit the Colon Cancer Coalition and Colontown to learn more about the important work they are doing.
Thank you to Takeda for its support of our patient education program! The Patient Story retains full editorial control over all content.
This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
Stephanie Chuang: I’m a blood cancer survivor and the founder of The Patient Story, which I started out of my own experience. I had so many questions and all I found was medical jargon and outdated statistics.
Our goal at The Patient Story is to help patients and care partners navigate life after a diagnosis. What does this mean in human terms? We do this primarily through in-depth patient stories and educational programs. We hope to help connect patients and families to information about topics like self-advocacy and the latest treatment options, which is especially important in colorectal cancer. It makes a difference how early someone can get a diagnosis, how much people know about what’s available to them, and what questions they can ask their healthcare providers.
We want to thank Takeda for its support of our independent educational program, which helps us host more of these free programs for our audience. The Patient Story retains full editorial control of the content. We also want to thank our promotional partner, the Colon Cancer Coalition.
While we hope you walk away with more knowledge, this discussion is not a substitute for medical advice so please consult with your healthcare team.
It’s my pleasure to introduce Allison Rosen, a very well-known and respected individual in the colorectal cancer advocacy space and someone I’m lucky to call a friend. Thank you so much, Allison, for joining us.
Allison Rosen, Patient Advocate
Allison Rosen: I’m a 12-year stage 2C colorectal cancer survivor and a very passionate patient advocate. My treatment consisted of surgery, radiation, chemotherapy, more surgery, and ultimately, a permanent ostomy.
I wanted to meet other young people like me who were diagnosed with colorectal cancer because I felt very alone when I was first diagnosed. When I was being treated at MD Anderson, I asked to talk to another young adult. She was very active in advocacy and introduced me to the advocacy space. Now I volunteer with a lot of national and local advocacy organizations. I get to work with amazing clinicians, researchers, and doctors to help provide the patient perspective.
Dr. Cathy Eng: You are so fortunate to be diagnosed with stage 2 because, unfortunately, most young adults are diagnosed with a much more advanced stage. Stage 2 is a very unique setting because it’s extremely early with regard to prognosis. For the majority of patients, surgical resection is curative. I’m so glad to have you here with us today.
Allison: Thank you. It’s interesting because the reason why I’m so active is because I’m alive. I have a purpose and my mission is to be a part of things like this educational program to talk about what is out there, so people who may not have access to what I had access to can get current information and the best possible treatment.
Dr. Cathy Eng, Medical Oncologist
Allison: Dr. Cathy Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology at the Vanderbilt-Ingram Cancer Center. She’s also the co-leader of the Gastrointestinal Cancer Research Program, co-director of GI Oncology at Vanderbilt, the executive director of the Young Adults Cancers Program, and co-chair of the NCI GI Steering Committee. Dr. Eng, what drew you to this field?
Dr. Eng: What drew me is individuals like yourself. I had a very, very large clinic when I used to work at MD Anderson and I was seeing patients as young as 16. These patients do not have an inherited form of colorectal carcinoma. The majority have sporadic colorectal cancer and, unfortunately, they were showing up in my clinic with very advanced diseases, stages 3 and 4. It’s hard not to be able to appreciate all the hurdles that a young adult has to go through in order to go through their treatment with success and hopefully few toxicities. It’s that communication with the patient and that lives with you as a physician.
Allison: I know many people who are part of the Young Adult Cancers Program and many people who have gone through it. I appreciate everything you’re doing for the young adults who are going through treatment and, unfortunately, the future young adults who will go through treatment. You have to treat the patient as a whole. Things like fertility and body image are so important along with chemotherapy and radiation.
Dr. Eng: Thank you. I want to thank you also for helping promote education and awareness. We don’t know the exact etiology of why this is happening, but in the interim, we can continue to promote awareness so people can be diagnosed earlier.
Allison: Awareness is key.
You don’t need to remove your primary tumor to improve overall survival. In fact, it does not improve overall survival and that’s important to keep in mind.
Dr. Cathy Eng
Latest Treatment Options for Metastatic Colorectal Cancer
Allison: As an advocate, I’ve seen that progress is being made in treating metastatic colorectal cancer, but it’s still challenging. What are the latest treatment options?
Dr. Eng: Oxaliplatin-based and irinotecan-based treatments are still commonly utilized for patients who don’t have a particular molecular marker. We have to recognize that it’s still important to be in contact with the patient because in combination with a fluorouracil-based therapy, those regimens are still the foundation of basic treatment.
Over the past two years, one thing that came out was looking at tumor-sidedness. A patient with a left-sided tumor has a better prognosis overall than a right-sided tumor for a non-inherited form of colorectal cancer. If the patient is RAS wild-type, the data shows that you would probably benefit from anti-EGFR therapy in combination if you’re considering irinotecan- or oxaliplatin-based therapy and that has been shown to improve overall survival. Not everybody loves EGFR therapy because it causes a significant rash, but there are benefits to considering that type of treatment.
A RAS mutation is very common in up to 60% of all colorectal cancer patients. We’re getting so specific that we’re asking what type of RAS mutation you have with regard to KRAS.
Patients ask if they need to have their primary tumor removed because they have metastatic disease. It’s not like breast cancer where you need to have your primary tumor removed to reduce your tumor burden. That doesn’t benefit a colorectal cancer patient with metastatic disease.
A pooled analysis came out in the Journal of Clinical Oncology. Three presentations from countries all across the world indicated that you don’t need to remove your primary tumor to improve overall survival. In fact, it does not improve overall survival and that’s important to keep in mind.
Sometimes we hear from patients that they’re told they have to remove their primary tumor. You shouldn’t have to unless you have uncontrolled bleeding, near obstruction, or a high risk of perforation. We don’t encourage that for all comers in general. For a rectal cancer patient, if you’re having symptoms, we can give short-course radiation therapy to help alleviate some of those symptoms despite having metastatic disease.
HER2-Targeted Therapy Combination
Dr. Eng: Tucatinib is the most recent drug that has been approved, which is an oral tyrosine kinase inhibitor of HER2 that prevents downstream phosphorylation and involves the EGFR pathway. These are for patients with RAS wild-type and most often have left-sided tumors.
The best part about the tucatinib study, which shows the relevance of having a rare mutation, is it got FDA-approved based on a small phase 2 study. It wasn’t a giant phase 3 study and that’s important to keep in mind. It showed that these patients, despite heavily being heavily pre-treated, had a great response rate. Progression-free survival was excellent and the overall survival was close to two years.
HER2 testing is one of the newest things to be considered. We’re very familiar with it in gastric cancer and breast carcinoma, but this is the first time looking at it in metastatic colorectal cancer and making sure that all patients get tested for HER2. It’s extremely important to look at the role of HER2. We have seen that looking at HER2 amplification, which is present in approximately 4% of our patient population, is very, very important.
Looking at HER2 amplification, which is present in approximately 4% of our patient population, is very, very important.
Dr. Cathy Eng
Fam-Trastuzumab Deruxtecan-nxki (ENHERTU)
Dr. Eng: The new drug deruxtecan is an antibody-drug conjugate. It isn’t necessarily new with regard to its presentation but in the sense that it just received tumor-agnostic approval, so it’s approved for colorectal cancer and other tumor types.
It does best in the IHC 3+ patient population, but it has a benefit with regard to progression-free survival and overall survival. What’s unique about deruxtecan is that the original study that resulted in its approval allowed patients who received prior HER2-based therapy. You could have had tucatinib, pertuzumab, or lapatinib, but you can receive deruxtecan as a single agent.
They’re moving the G12C inhibitors in combination with chemotherapy to the front-line setting.
KRAS G12C inhibitors don’t work by themselves. They were evaluated by themselves with a less than 10% response rate. In combination with anti-EGFR (epidermal growth factor receptor) therapy, the combination resulted in an improved benefit for patients. Although it’s not FDA-approved at this time, if you’ve been previously treated, you can inquire about receiving it in combination with anti-EGFR therapy.
They’re moving the G12C inhibitors in combination with chemotherapy to the front-line setting. In the HER2 setting with newly diagnosed patients, they’re also looking at tucatinib in combination with oxaliplatin-based therapy. The fact that we’ve found molecular alterations that have been positive studies in the refractory setting is exciting. We’re now moving into front-line therapy to see if that is more advantageous for our patient population.
BREAKWATER Trial
Dr. Eng: BREAKWATER is a phase 3 trial for BRAF V600E mutation tumor types, which is about 9% of all of our patients. Encorafenib and cetuximab were approved in the previously treated setting and are now being moved up to the front-line setting in combination with oxaliplatin-based therapy. I’m one of the investigators on that trial and there’s another arm that’s open, which is in combination with irinotecan-based therapy.
I hope that we will continue to move these rare molecular alteration subtypes earlier on in development because we can get greater outcomes. We hope to improve and break the barrier of overall survival, which is currently about 35 to 37 months for the majority of our patients.
For any metastatic patient, the very first thing they need to ask is their molecular sequencing. It’s critical because it helps create a treatment plan.
Dr. Cathy Eng
Trending to More Personalized Treatment
Allison: You talked about the KRAS, HER2, and BRAF mutations, and about treatment being driven by a particular mutation. Why is biomarker testing important? What would you tell a patient if their doctor hasn’t necessarily brought it up?
Dr. Eng: For any metastatic patient, the very first thing they need to ask is their molecular sequencing. It’s critical because it helps create a treatment plan. Previously, we would look at all metastatic colorectal cancer patients as the same and that’s not the case. Having a molecular marker can make a big difference because it can prevent you from receiving unnecessary toxicities and costs.
KRAS- and EGFR-Targeted Therapy
Dr. Eng: The most pivotal one was looking at KRAS and anti-EGFR therapy, such as panitumumab and cetuximab. That class of drugs causes a rash in 80 to 90% of patients and depending on where you live, you’re also at a higher risk for having an allergic hypersensitivity reaction to cetuximab.
Bevacizumab
Dr. Eng: Bevacizumab is an IV drug that’s involved in anti-angiogenic therapy. Anti-angiogenesis or anti-VEGF (vascular endothelial growth factor) therapy means it’s working on the blood supply. Our goal for this class of drugs is to reduce the development of metastatic disease because a tumor needs a blood supply to survive and thrive.
FRESCO-2 Trial
Dr. Eng: When we designed FRESCO-2, it allowed almost all comers. Patients were allowed to have received prior TAS-102 (trifluridine/tipiracil) and that was before the approval with bevacizumab in combination. They also could have received regorafenib, which has been approved for quite a while now. Patients may have been exposed to either or both of the drugs. It was a trial that allowed almost all patients to participate with the median line of four prior lines of therapy.
Fruquintinib was compared to a placebo. It was a 2-to-1 randomization. Some people criticize the fact that there was a placebo arm, but there’s no standard of care for fourth-line or fifth-line therapy, so there was nothing to compare it to. Some people say, “Can’t you go back to 5-FU (fluorouracil)?” But the reality is patients have already progressed through 5-FU, so they’re not going to be receptive to 5-FU.
The primary endpoint was met with an improvement in overall survival as well as progression-free survival.
The FDA approval allows patients to receive oral fruquintinib as a potential option for third-line therapy and beyond.
Dr. Cathy Eng
Fruquintinib (FRUZAQLA) Approved by FDA
Allison: With the recent FDA approval of fruquintinib, how can it help address an unmet need in the metastatic colorectal cancer treatment landscape?
Dr. Eng: It’s a drug that I helped bring to the United States. I was involved in the original trial as the senior investigator. This drug is an oral agent, which specifically blocks receptors 1, 2, and 3 of the VEGF pathway. It was originally approved in China in the third-line setting based on a phase 3 trial called FRESCO that was conducted overseas.
FRESCO-2 is specifically trying to address the practice patterns of what we are doing in the United States, which is continuing bevacizumab for front-line and second-line therapy but also trying to ensure the majority of patients had received anti-VEGF therapy as part of treatment, which was the case in 97-98% of patients who participated in FRESCO-2.
Based on the results of both FRESCO and FRESCO-2, the FDA approval allows patients to receive oral fruquintinib as a potential option for third-line therapy and beyond.
Overall, it was tolerated fairly well. Hypertension is an issue with this class of drugs, but it’s treatable. It got approved in November and we are very pleased to see the FDA approved it. It’s pending the European Medicines Agency’s approval as well as approval in Japan. After that, hopefully, it will be approved internationally so all patients can get access.
At the end of the day, the reality is you need to make sure you have drugs available to the patient. When you ask, “Do you prefer FOLFIRI (folinic acid, fluorouracil, and irinotecan) or FOLFOX (folinic acid, fluorouracil, and oxaliplatin)?” The reality is you’re going to get both regimens. What matters is how well you tolerate the treatment and how you derive the best benefit.
I try not to make it very competitive. I don’t think it benefits anybody. It’s important to recognize that there’s a new drug on the market, it’s available for patients, and it does not require IV therapy.
In a prior study, it was seen that if you have the RAS mutation and receive anti-EGFR therapy, it’s no better than receiving a placebo.
Dr. Cathy Eng
Biomarkers (“Molecular Markers”)
Dr. Eng: There’s a lot of interest with regard to other molecular markers, like a patient’s KRAS status and mutation. KRAS G12C inhibitors are further along in development than G12D. Granted, G12C in colorectal carcinoma is less than 5% of our patient population, but once those patients are identified, they may benefit from therapy.
Importance of Biomarkers
Dr. Eng: The KRAS mutation is in about 30 to 60% of all colorectal cancer patients. In a prior study, it was seen that if you have the RAS mutation and receive anti-EGFR therapy, it’s no better than receiving a placebo. Why would you want to subject your patient to toxicity, a potential allergic reaction, and extreme financial costs if it doesn’t benefit them?
Different Biomarkers
Dr. Eng: KRAS was just the beginning. We are now identifying all these new molecular subgroups, such as HER2, BRAF, and microsatellite instability-high (MSI-H), which is extremely important with regard to the role of immunotherapy. That’s another small patient population, less than 5% of our patients, but that’s where immunotherapy may benefit our MSI-high or mismatch repair protein deficiency (MMR-d) patient population where immunotherapy can have a significant role in potentially curing them.
Tissue molecular sequencing can look at hundreds and hundreds of various molecular alterations, mutations, or amplifications… Information from the blood can be critical in identifying a suitable clinical trial.
Dr. Cathy Eng
Tissue vs. Blood Samples in Biomarker Testing
Dr. Eng: Molecular sequencing can be obtained from tissue and blood. If you’re newly diagnosed, it’s important to send off that tissue as soon as possible before it gets sent off to some warehouse because it can’t sit in the pathology department forever.
Depending on which panel you use, tissue molecular sequencing can look at hundreds and hundreds of various molecular alterations, mutations, or amplifications. Blood sequencing is quicker. You can get it back within less than two weeks, but you’re only looking at 100 different mutations relative to the 500 or so plus potential molecular alterations.
Some places still do it in-house, but the majority of institutions send it out to a third party. Ask for tissue and blood to be sent off because the information from the blood can be critical in identifying a suitable clinical trial for the patient as well. I cannot emphasize enough the importance of participating in clinical trials.
Allison: I’m very, very passionate about access to clinical trials, education for clinical trials, not being scared, and not thinking that a clinical trial means you’re going to die.
Dr. Eng: Every single FDA-approved drug came from a clinical trial.
Allison: Exactly. It’s the point that I make as an advocate all the time.
Choosing Among Different Treatment Options
Allison: Where do you see fruquintinib fitting in with the current therapies available for metastatic colorectal cancer? Is there a potential for it to be used as a maintenance therapy?
Dr. Eng: My understanding is it’s being investigated as a maintenance therapy. It makes a lot of sense since the majority in the United States use capecitabine, bevacizumab, or 5-FU with bevacizumab for maintenance therapy, so it would make sense to consider this as a potential maintenance therapy.
When thinking about it relative to other agents, such as regorafenib and TAS-102 plus bevacizumab, I talk to the patient. I utilize TAS-102 plus bevacizumab quite a bit. However, some patients are tired of coming in every two weeks for bevacizumab. They want a break and that’s very reasonable.
With TAS-102, they’re at risk for myelosuppression, so their white blood cell count can drop. That’s a known side effect of that class of drugs, so the patient has to be compliant and not take medications incorrectly. You don’t want a neutropenic patient walking around at risk for other infections.
I don’t offer TAS-102 to certain patients. I had an elderly patient whose platelet count was never above 100,000. He had been on a lot of therapies and came to me for a second opinion. I would be hesitant to give him TAS-102 because I know that his platelet count is going to be a problem, so I chose fruquintinib for him first. Once again, I don’t try to choose one versus the other. I talk to the patient about the potential side effects and see what they’re willing to endure.
Allison: It’s all about shared decision-making. You know about what’s going on and having that conversation with your physician is very, very important.
Emerging Clinical Trials for Metastatic Colorectal Cancer Patients
Dr. Eng: For the MSI-high patient population, there should be some updates soon regarding NIVO+IPI (nivolumab and ipilimumab). They presented their data at the 2024 ASCO GI (American Society of Clinical Oncology Gastrointestinal Cancers Symposium) looking at NIVO+IPI in combination versus chemotherapy and that was superior, but it was a very rapid abstract presentation, so we don’t have further details. I think there’s going to be an update at the 2024 ASCO, so I look forward to that. Are two immunotherapies better than one for this patient population? What about toxicities? It will be interesting to see.
The CodeBreaK 301 trial is looking at the role of sotorasib, a first-generation KRAS G12C inhibitor, in the upfront setting. Sometimes the next generation may be even better, so I’m looking forward to those trials as well.
EA2222 (PUMP) Trial
Dr. Eng: The PUMP trial is a new NCI-sponsored study specific for newly diagnosed patients. They will get randomized to having the PUMP versus continuing chemotherapy.
This is an important trial that will answer that question. We know all the data from Memorial Sloan Kettering, but can we validate and replicate that data outside of that institution, especially in an earlier line setting?
ERASur Trial
Dr. Eng: The ERASur trial is another NCI-sponsored study that looks at the role of stereotactic radiation therapy, ablation, or some type of liver-directed intervention to improve overall survival.
MOUNTAINEER-03 Trial
Dr. Eng: The MOUNTAINEER-03 trial is looking at tucatinib with trastuzumab in the front-line setting.
We cannot make breakthroughs until we get trials completed. It’s very, very important to keep in mind that not all trials involve a placebo.
Dr. Cathy Eng
Importance of Participating in Clinical Trials
Allison: We touched on the importance of clinical trials, but do you have any message about the importance of participating in clinical trials?
Dr. Eng: Focusing on metastatic disease, I encourage all patients to consider participating in a clinical trial. Currently, enrollment across the United States is about 7% for non-NCI cancer centers and up to 20% for NCI-designated cancer centers. We cannot make breakthroughs until we get trials completed. It’s very, very important to keep in mind that not all trials involve a placebo.
All patients should consider getting a second opinion if they haven’t been offered a clinical trial. There are some selective settings where there is no clinical trial available, but you should have that discussion with your provider on your first or second meeting.
It doesn’t take that long to get a second opinion. You want to look at all your options and feel informed. That’s extremely important as a patient and the best way to optimize your care. As a medical oncologist, it’s very, very distressing when I meet a patient who received one cycle of chemotherapy before they walked into my office and find out they would have been a perfect candidate for a clinical trial but now they’re automatically disqualified.
Allison: Knowledge is power. There are so many amazing trials and the first step is educating yourself on clinical trials. There are a lot of advocacy groups and organizations that are trying to educate patients on what a trial is and having that conversation with their doctors. It’s so important because the last thing you want to do is disqualify yourself for a trial because you did something here versus going there.
Because of my age, I got three different opinions before I decided on where I was going to get treated. For the younger people especially, talk to as many people as you can and educate yourself as much as you possibly can. This program is an amazing start for people to better understand that there are options.
Get a second or a third opinion. I’m not telling you to delay your treatment by months, but give yourself 2 to 3 weeks to make an informed decision by getting another opinion.
Dr. Cathy Eng
Final Takeaways
Allison: What message do you have for metastatic colorectal cancer patients? I always tell them that their lives aren’t over. There are treatment options available. I know quite a few people who were stage 4 who are now in remission.
Dr. Eng: I hear time and time again that they’ve been given a poor prognosis of 6 to 8 months to live; that’s very discouraging and not the right approach. We have so many new options available. Science has advanced so much. If you hear that kind of negative attitude at your first meeting with your physician, you need to go get a second or a third opinion. I’m not telling you to delay your treatment by months but give yourself 2 to 3 weeks to make an informed decision by getting another opinion.
Allison: I agree. The relationship you have with your care team is important. It can spell the difference between a lot of different things that can happen along a journey.
Dr. Eng: It’s also important for people to keep in mind that there’s always hope.
Allison: I was originally diagnosed with stage 3 and they said it was about to break through my colon wall. There’s so much going on and so much information you’re getting when you’re first diagnosed. Talking to someone else who’s gone through it gave me hope. It differs with every stage. I know people who are 20-year stage 4 colorectal cancer survivors. That’s the hope that someone needs.
Dr. Eng: Your medical oncologist is key. Your radiation oncologist and surgical oncologist are always there, but the captain of your ship, besides your primary care doctor, is your medical oncologist.
Allison: You are an amazing captain of the ship. I know this from hearing from many people and knowing you for as long as I have. Thank you so much for your time and for sharing invaluable information.
Stephanie: Thank you so much, Dr. Eng, for what you do in terms of research, which is critical to advancing care, and the way you’re thinking about patients. Thank you also to Allison for the work you do in advocacy and leading this program, which wouldn’t be the same without the patient perspective.
Thank you to our promotional partner the Colon Cancer Coalition, which was founded by someone who lost her sister to stage 4 colorectal cancer. The Colon Cancer Coalition is celebrating its 20th Get Your Rear in Gear fundraiser in the Twin Cities in Minnesota with other rides and fundraisers happening across the country as well. These fundraisers highlight the need to screen and raise awareness of colorectal cancer. The organization gives more than $1 million every year to local community programs to help fill that need.
We hope that you walk away with a better understanding of what’s out there and something to talk to your own healthcare team about. We hope to see you at a future program.
If you read and/or watched our program, we encourage you to take our program survey to help us improve future programs and answer your questions.
Special thanks again to Takeda for its support of our independent patient education content. The Patient Story retains full editorial control.
Interviewed by: Taylor Scheib Edited by: Katrina Villareal
Ben was diagnosed with essential thrombocythemia in 2012 and myelofibrosis in 2023. His ET was discovered during a pre-employment exam that revealed high platelet counts. Initial treatment with hydroxyurea managed his condition, though he experienced kidney issues. Seeking more information, Ben educated himself about ET and later learned about the CALR mutation through a second opinion.
As his symptoms intensified, Ben’s care was transferred to a new hematologist, leading to a myelofibrosis with CALR mutation diagnosis in 2023. Despite significant scarring in his bone marrow, his treatment remained largely unchanged. With an increased symptom burden and feeling unhappy with his doctor’s response, Ben sought a second opinion. His new doctor switched him to ruxolitinib, significantly improving his quality of life.
Ben became an advocate for himself and others, emphasizing the importance of seeking second opinions and connecting with specialists. He joined the MPN Research Foundation’s Patient Impact Council, connecting with other patients and professionals. Grateful for the support from his family, medical team, and the myeloproliferative neoplasms (MPN) community, Ben continues to advocate for better patient education and support. He stresses the importance of patient advocacy and utilizing available resources for support and information.
Thank you to Sobi for its support of our patient education program! The Patient Story retains full editorial control over all content.
This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
Name: Ben H.
Diagnoses:
Essential Thrombocythemia (ET)
Myelofibrosis (MF)
Mutation:
CALR (calreticulin)
Initial Symptoms:
None; caught at a routine blood test
Treatment:
Hydroxyurea & aspirin
Ruxolitinib
I have myelofibrosis [with CALR mutation] but, other than that, I’m healthy and can enjoy things.
I’m married with two kids. My oldest is in college and my youngest recently turned 16. They certainly keep me busy along with other family activities.
I was diagnosed with essential thrombocythemia (ET) in 2012 and with myelofibrosis (MF) in 2023.
When I first was diagnosed, there wasn’t a lot of information provided. I was told I had ET and what it was. I did a lot of research on my own.
Essential Thrombocythemia
Initial Symptoms
I found out about it by chance. I had recently switched jobs and was going through pre-employment exams. My blood test results showed that my platelets were extremely high, about 1.2 million at the time. My platelet count was anywhere from 1.2 to 1.5 million. It didn’t keep me from being employed, but they recommended that I follow up on it. I had initial follow-ups with my primary care physician who recommended that I see a hematologist.
Official Diagnosis
I went to a local hematologist from where I’m from, which is a rural area. We did a bone marrow biopsy. They said I had essential thrombocythemia but at that time, they didn’t know the driver mutation.
Treatment
I began treatment with hydroxyurea. We were managing my blood counts and able to stay in the 600,000 to 800,000 range. It’s the sweet spot for me where we weren’t suppressing anything else too much. I managed with that for a number of years.
Side Effects of Hydroxyurea
It was pretty unremarkable at first, but I did have some significant side effects. Initially, I had issues with my kidneys. It was a learning experience for me. I needed to stay much more hydrated to keep everything flushed.
It didn’t feel like there was any plan. I didn’t know if there was anything I needed to watch for or if I needed to do anything differently.
Learning About ET
When I first was diagnosed, there wasn’t a lot of information provided. I was told I had ET and what it was, but I had to do a lot of my own research to figure out what it was and to explain the diagnosis and its impact to my family and friends. I was told that this would be something that I would die with not die from.
I didn’t think too much of it. I continued with the same hematologist for a period of time. There wasn’t a lot of interaction. It was mostly regular blood work and going to see the hematologist. I was kept on hydroxyurea and was told that we’ll adjust as needed. It didn’t feel like there was any plan. I didn’t know if there was anything I needed to watch for or if I needed to do anything differently.
Getting a Second Opinion
Fortunately, my dad had some contacts through his work. I talked to the head of the hematology group at the hospital that I was visiting and he said that if I wanted to get another opinion, he could hook me up with another location. This is a larger cancer institute that has people who deal more with some of these rare blood cancers.
I connected with a hematologist down there. A couple of years has transpired at this point. I met with the new doctor and went through everything. They got everything sent down, including my original bone marrow slides. They reviewed everything and re-ran some of it.
When I was doing physical activity, I would notice the fatigue and sweating more than before.
CALR Mutation
I learned about the CALR mutation. They explained what it was and its impact. It was more favorable than other mutations, so that gave me some level of comfort.
It didn’t change a whole lot, even with treatment. There was a lot of adjusting as blood counts changed. I took anywhere from 500 mg of hydroxyurea a day up to 2,500 mg plus two baby aspirin.
Symptoms Intensified
When I was doing physical activity, I would notice the fatigue and sweating more than before. It was primarily driven by the blood counts. Nobody tells you about it. Why is it completely different all of a sudden? What’s changed? I managed it pretty well by knowing my limits on different things.
Myelofibrosis with CALR Mutation
New Hematologist
My physician moved to Vanderbilt, so I had my care transferred to one of her colleagues. The transition went well. As we went along, something in the blood work made her decide that we needed to take another look.
At first, it wasn’t bad. There wasn’t a lot of impact. But all of a sudden, I started getting a lot of fatigue and night sweats.
Official Diagnosis
I had my second bone marrow biopsy in 2023 and found out that I had myelofibrosis. What’s great was getting the information in real time as the results came back from different tests, so I was able to research. My son is studying to be a pharmacist, so he was pulling up information as well and we were comparing notes. By the time I had the appointment with my physician, I had a good idea of what was going on.
On the scale of 0 to 3, the fibrosis was in the grade 3 range, so I had a significant amount of scarring in the bone marrow. The treatment wasn’t going to change. I was staying on hydroxyurea and baby aspirin. I was told, “We’ll keep monitoring it. Let us worry about the bad stuff. You keep on living your life.”
Symptom Burden
At first, it wasn’t bad. There wasn’t a lot of impact. But all of a sudden, I started getting a lot of fatigue and night sweats, a lot of the symptom burden that was coming with myelofibrosis.
When I had an appointment with my doctor, I met with the physician’s assistant and went through all the symptoms and the impact on me being able to do things. I was falling asleep by 7 to 7:30 in the evening because I was completely drained after being at work all day.
If I worked in the yard, I’d be going back inside after a couple hours to take a nap because I was physically drained and exhausted. Their response was, “Well, sometimes you just have to deal with it.” I said, “Yeah, you know what? You’re right,” so I dealt with it my way.
Getting a Second Opinion
I reached out to people who I worked with at one of the research foundations and they had contacts throughout the MPN community. I was looking for other options to get a second opinion and was given a number of different places and different physicians.
I made an appointment. My wife goes to a number of things with me. My parents asked if they could come along, so I said, absolutely, come on.
My new physician explained everything from the very beginning with the ET all the way through MF and what MF could become. They explained not just to me but to my family and made sure that there was an understanding that this is what’s going on and this is what we do to treat it.
We talked through different clinical trials and different medications that were available. We went through the symptoms and some of the things that I was dealing with. My hemoglobin was pretty low at the time; I was in the 8 to 9 range.
We were looking at one medication that was getting ready to come to market versus other ones that were available. It kept getting delayed. They said, “Let’s switch medications now and if we need to switch again, we will, no problem. But let’s get you on something different now.”
Switching to Ruxolitinib
I made the switch and started on ruxolitinib. It was amazing how quick the symptom burden was reduced. I was able to stay up in the evenings and watch movies without falling asleep. From a quality of life perspective, it was far greater than with the other treatments.
I’m not an expert, but I knew enough to know that there are other options and for those not to be part of the conversation was very, very frustrating.
Patient Advocacy
I was a strong advocate not only for myself but for other patients as well. There are people who don’t have the resources within a reasonable distance to see some of the MPN specialists or may not know who to reach out to for additional input or help.
If we look at how many people are going through something similar, how many cases do some of these hematologists see? I may have been the only one they’ve ever seen with this condition. They may have read about it, but it’s not common. It’s important to make sure that physicians have all of the information available. Personally, I wasn’t satisfied with the doctor saying that they have things covered. I want to know.
There was some frustration at times. When I hit the roadblock of being told to just deal with it, I was informed enough. I’m not an expert, but I knew enough to know that there are other options and for those not to be part of the conversation was very, very frustrating. I left that appointment feeling very unhappy and almost abandoned. You’re putting your trust in your provider and for them to tell you to just deal with it, I’m sorry, but I want something better.
Learning About MPNs
All the way back, even from the ET perspective, I was trying to figure out what it was. At the time, they didn’t even talk about it as blood cancer. It was still a neoplasm. They didn’t elaborate that this was what’s going on. We did a lot of research trying to find out things.
I was connected with some of the folks at the MPN Research Foundation. There are a number of online resources that provide factual information. It’s a balancing act. What are you seeing online and what’s correct?
As I was seeing the results come back, they listed what articles they were citing for the diagnosis, so I found the articles and read them. Because I’m not in the medical field, there are words I’ve never seen before in my life. What do these words mean? Is that good or bad? I was pulling together resources on my own.
Connecting with the MPN Community
I stumbled across and got involved with the MPNRF Patient Impact Council. It was through some of those contacts that led me to other recommendations for where to go.
It was nice being involved with other patients and having conversations. Even though a number of us have had the same diagnosis, there may be different genetic mutations so there are little differences on how it impacts everybody. Having somebody to talk to has been fantastic because you can hear about other people’s journeys, what they went through, treatment options, or things that I’m not aware of that some of my peers would be dealing with.
We have a group where we can sit back and laugh. Everybody was joking about things and having a good time. You’re with people who understand what you’ve gone through, what you’re going through, or people who have gone further through things.
Stem Cell Transplant
After my myelofibrosis diagnosis, we had conversations about stem cell transplant. Although I didn’t need it yet, we did the work to make sure we have things lined up. In the event that there’s a bone marrow failure, I progress into acute myeloid leukemia (AML), or things don’t go as well as we would like them to, we have options.
I went through the matching process and I was very fortunate to have my brother as a full match. We have multiple people on the donor registry that are full matches for me as well, so the prospect is very good in that avenue.
One of my peers who I’ve spent time with is not as fortunate. He has progressed very far through myelofibrosis and has zero matches. You see other people like him who go through struggles. If there’s anything that I can do to help advocate for people and make it easier for the next person, I’m certainly all for it.
We talk about clinical trials at every appointment. We talk about the ones that are currently out there, some that are coming, and why I would or would not be eligible for them.
Clinical Trials
Cleveland Clinic is one of the major centers that has some of the clinical trials. I’m fortunate to be fairly close and to have access to some of the experts in the field. We talk about clinical trials at every appointment. We talk about the ones that are currently out there, some that are coming, and why I would or would not be eligible for them.
It’s balancing risk versus the reward. It’s not necessarily the reward for me but to the larger community. I’m benefiting from medication that other people went through a clinical trial on. If a clinical trial is available and if it fits with what you’re looking for, advocate for that.
Follow-up Protocol
I have follow-up visits and routine blood work every three months. Where I work, we have a clinic on site that can do my blood draws, so I send the results to Cleveland Clinic and my physician for review.
I don’t need to physically go to the Cleveland Clinic every time. I’ve been able to do remote visits, which is quite a time saver. It takes me about three hours to get to the Cleveland Clinic from where I live, so it’s not overly burdensome, but it’s not the most convenient either.
The plan moving forward is to monitor the blood counts and make sure to communicate with the physician if the symptoms return. They are very responsive.
I’m in the middle of switching providers not because I’m unhappy or there were any issues, but because my current physician has taken a different role within the leukemia division and will be handling inpatient care only. I would be happy if I saw him, but I hope I don’t need to. Transitioning care is a very seamless process. They work with you right through it.
I’ve put myself out there by getting involved with different organizations. It’s through those things that I get access to people who are in the know.
Patient Education
From a broader perspective, through the work I’ve done with the MPNRF Patient Impact Council, I was fortunate to spend time with a number of physicians and researchers as they were going through and seeing some of the cutting edge treatments. It was nice hearing from their perspective but also being there to provide the patient perspective on how meaningful and impactful that is to a patient.
A lot of the treatments available improve quality of life by reducing the spleen size and symptom burden, but it’ll be fantastic when we get to the point of disease modification and change the landscape.
Through some of those interactions, I met one of the doctors that chairs a research consortium of some of the major cancer institutes. I have his personal cell phone number and he said, “If you ever need anything, call me.” I’ve put myself out there by getting involved with different organizations. It’s through those things that I get access to people who are in the know about something rare. It provides a level of comfort as you go through it.
One of the things that we were talking about recently was how to get that education into the hands of physicians, patients, and the broader community so that it’s more readily available. It was interesting because as we were talking in a group, one of the physicians said, “I’ve seen hundreds of patients with various MPNs and I’ve hit on some of the things that you, the patients, have brought up in these conversations, but it’s making me rethink my interactions and my dealings with them.” This is an MPN specialist who’s starting to think if he might have missed an opportunity or could have helped a patient in these avenues. It was fantastic. We’re at a point where it’s a conversation of what can we do better for everybody through the community.
Reach out to an MPN specialist. I would advocate for an MPN specialist over another hematologist because you need somebody who understands, studies, and specializes in MPNs.
Words of Advice
Don’t accept any answer that you’re not comfortable with. If you have questions, make sure you’re bringing them up.
Reach out to broader resources. There are a number of organizations that put on different programs. The Leukemia & Lymphoma Society puts on blood cancer meetings where they have specialists who you can interact with. People are afraid to talk to doctors sometimes. They’re normal people. They welcome the interaction. In some of the appointments, they seem very routine and very quick maybe, but if you’re not comfortable with where it is, call a timeout.
Get a second opinion. If you’re not happy with what you’re going through or with what you’re being told, there are tremendous resources available through a number of organizations. Reach out to an MPN specialist. I would advocate for an MPN specialist over another hematologist because you need somebody who understands, studies, and specializes in MPNs. You will get better traction and better information if you can get to one of the major centers that can support that.
I’m very grateful for the connections that I’ve made. It’s not just physicians and researchers but other patients too. The network keeps growing.
Feeling Grateful
I’m eternally grateful for everything that has happened. Even the bad stuff helped drive me to find something better. They say everything happens for a reason. I can’t say how grateful I am for all of the people who have been involved. There are people who are totally unaffected by MPNs personally who have dedicated their work and their time to helping others who are going through this. Pharmaceutical companies get beat up over things, but they are a very integral part in this. They help with the medications.
I’m very grateful for the connections that I’ve made. It’s not just physicians and researchers but other patients too. The network keeps growing. I’m fortunate to live in an area where I’m in fairly close proximity to a number of places with specialists that I can access if necessary.
We’ve had a group chat and there’s a group of people who will share normal, daily life things. Then one day, one of the individuals was going through treatment and said, “I could use some words of encouragement.” When you get tied into it, there are so many wonderful people who will help you through the journey. It’s that community support.
I know the impact that it’s had on my family being on ruxolitinib. It’s completely different. My son was talking about watching a movie one evening with us and he made a spot-on impression of me sleeping on the couch. We were able to laugh about it because it was so true and it’s not that way anymore. I hit my lowest compared to where I am now. Even when it’s bad, I realized that others have it much, much worse. I have myelofibrosis but, other than that, I’m healthy and can enjoy things.
Special thanks again to Sobi for its support of our independent patient education content. The Patient Story retains full editorial control.
Graft-versus-host disease is a potentially life-threatening condition affecting an estimated 50% of blood cancer patients who receive stem cell transplants from a donor. Transplant experts explain GVHD risks, how to watch for symptoms, the current treatments available, and new clinical trials aimed at prevention and treatment.
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Advances in GVHD Treatments and Clinical Trials
Hosted by The Patient Story
Graft-versus-host disease is a potentially life-threatening condition affecting an estimated 50% of blood cancer patients who receive stem cell transplants from a donor.
Patient advocate and GVHD Alliance co-founder Meredith Cowden shares her experiences with GVHD. Experts from UChicago Medicine, Roswell Park Comprehensive Cancer Center, and The Leukemia & Lymphoma Society who are on the front lines of GVHD research and treatment discuss the role clinical trials play in advancing the treatment landscape and what it could mean for you. Discover how to take steps to learn more about clinical trials from a clinical trial nurse navigator.
Stephanie Chuang: I’m a blood cancer survivor myself and started The Patient Story out of my own experience. I felt so alone. I wanted to know what it meant after diagnosis and how we could get through it. As we know, a diagnosis is just the beginning of figuring things out. Our goal at The Patient Story is to help patients and care partners navigate life after a cancer diagnosis, primarily through in-depth conversations with patients, care partners, and top cancer specialists.
We are so proud to partner with The Leukemia & Lymphoma Society, the largest nonprofit dedicated to creating a world without blood cancers. For decades, they have invested almost $2 billion in groundbreaking research and pioneering so many approaches. On top of that, they also support patients and families with programs like the Clinical Trial Support Center, which provides free one-on-one support with nurse navigators.
This program is not meant to be a substitute for medical advice, although we hope that you walk away feeling like you have more to ask your own medical team.
Satyajit Kosuri, MD
Stephanie: Dr. Satyajit Kosuri is a hematologist-oncologist with the University of Chicago Medicine. He is an expert in stem cell transplantation and leads the Graft-Versus-Host-Disease Clinic and the research in trying to improve patient access to transplants. Dr. Kosuri, what drew you to this field of medicine and specifically GVHD?
Dr. Satyajit Kosuri: When I started my oncology fellowship, I was going to be a genitourinary oncologist and I was very much set. When I did my transplant rotation, what drew me was that it spanned all fields of medicine, so you had to continue to have a pretty good breadth of knowledge. The immunology was very, very intriguing. We’re dealing with very complex diseases as well as the transplant itself, which is basically an immune system transplant.
When I tell patients, family members, fellows, and trainees about the field of transplant, I tell them, number one, I’m an immunologist, number two, I become an infectious disease doctor, and then, number three, oncology comes in as part of the triad. That’s what drew me to the field and what I find very interesting. Graft-versus-host disease is part of the entire picture that we’re trying to improve upon within the context of transplant.
Shernan Holtan, MD
Stephanie: Dr. Shernan Holtan is a hematologist-oncologist with Roswell Park Comprehensive Cancer Center in Buffalo, New York. She is the chief of the Blood and Marrow Transplantation and has led so many clinical trials in GVHD. Her research has led to the discovery of the amphiregulin (AREG) biomarker for monitoring graft-versus-host-disease. Dr. Holtan, what drew you to medicine and specifically focus on graft-versus-host disease?
Dr. Shernan Holtan: My story is a lot like Dr. Kosuri’s. In medical school, I was most interested in rheumatology, infectious disease, cancer medicine, critical care medicine, dermatology, and plastic surgery. I thought, How am I ever going to pick between these different specialties? I loved cancer reconstruction and the connection with patients going through cancer and giving them hope after a devastating diagnosis.
On a whim, I took a rotation on the BMT service, in part because it sounded cool. The other part of it is you didn’t have to work weekends and as a very tired fourth year med student, I was excited about that. I was stunned. It was every great aspect of medicine rolled in one specialty, so I was sold and never looked back.
Meredith Cowden, Patient Advocate
Stephanie: Meredith Cowden is a chronic GVHD patient advocate and co-founder of the GVHD Alliance. Why did you decide to dedicate your life to advocating for so many other people with GVHD?
Meredith Cowden: I had acute myelogenous leukemia (AML) at 19. Chemotherapy wouldn’t completely work, so I needed a bone marrow transplant. Shortly after, I developed acute graft-versus-host disease and then I developed chronic graft-versus-host disease, which I’ve had since April 2002.
Graft-versus-host disease is rare and we’re spread out all over the place, so it’s isolating and hard to find resources, information, and even the appropriate treatment team.
I originally wasn’t into the patient advocacy world. I didn’t want to deal with it anymore, but I didn’t want anyone else to have to deal with it. I got angry and frustrated, and frustration is one of the greatest motivators for me. When I would talk to other patients, there was a sense of relief and comfort they felt in talking with somebody who could understand their experience. From that point, I thought that this is where I need to be.
Ashley Giacobbi: I am a nurse navigator with The Leukemia & Lymphoma Society’s Clinical Trial Support Center. We provide individualized clinical trial searches and clinical trial resources to patients with blood cancers or patients who have had blood cancer in the past but may be managing long-term effects of their disease or treatment.
We provide one-on-one connection with patients, caregivers, and their healthcare providers. We take the time to learn about a patient’s diagnosis, past treatment, and other medical conditions that could play a role in their eligibility for clinical trials. Most importantly, we take the time to learn about patient and caregiver preferences and any unique obstacles that may hinder or support their participation in a clinical trial, so that we can target the support that we’re able to offer and give personalized resources.
When immune systems grow suspicious, they’re programmed to do one thing and that is to attack. This new immune system can attack the recipient from the inside.
Dr. Satyajit Kosuri
Understanding Graft-Versus-Host Disease (GVHD)
Stephanie: Dr. Kosuri, what is GVHD?
Dr. Kosuri: When we’re doing a stem cell transplant or bone marrow transplant, we’re doing an immune system transplant. When we’re healthy, the immune system protects us, whether it’s getting rid of bad cells or protecting us from various infections. It considers the body that it’s growing up in as its neighborhood, so it has an inherent desire to protect its neighborhood and recognizes the body that it’s in as being part of itself. When there are things that are not supposed to be there, it recognizes them and gets rid of them.
We’re taking the stem cells from a person with a healthy immune system and putting them into the transplant recipient, so this immune system is growing inside of a new neighborhood. For the most part — and this is where matching comes into play — it recognizes its new neighborhood as its own and leaves it alone. It takes up the mantle of, “I’m going to protect this body and eradicate any leukemia cells,” and that’s the graft-versus-leukemia effect.
But sometimes, there are parts of the new neighborhood that are not what it’s used to, so it starts to grow a little bit suspicious. When immune systems grow suspicious, they’re programmed to do one thing and that is to attack. This new immune system can attack the recipient from the inside, which can lead to some inflammatory physical damage to the patient or the recipient of the stem cell transplant.
Types of GVHD
Stephanie: Dr. Holtan, what are the main types of GVHD? How do they differ and what are some of the common symptoms?
Dr. Holtan: We mainly think of graft-versus-host disease in two phase although there can be some overlap between the two.
Acute graft-versus-host disease happens within weeks to the first few months post-transplant and that has a particular pattern. Most of the time, it’s a red skin rash, but sometimes it can also lead to nausea, vomiting, diarrhea, and liver abnormalities that we might see on blood tests. There’s a very clear time during which this develops and a pretty clear clinical presentation, so it’s pretty easy to determine what it is.
Chronic graft-versus-host disease typically happens later in the months to years after transplant. It can be more subtle and difficult to diagnose. As Dr. Kosuri was saying, this is primarily an inflammatory reaction at the beginning, which ultimately will gradually lead to scar tissue.
Think of a wound that is having some difficulty healing. There’s a lot of inflammation and the body tries to stop that inflammation by putting a scar on top of it. This can happen in almost any organ in the body. Usually, the skin is involved, but it can also cause dry eyes, dry mouth, mouth sores, difficulty breathing, difficulty swallowing, changes with the muscle tissue fascia, and making people feel stiff and have muscle cramps. Any organ can be involved with chronic graft-versus-host disease.
Even though we think about chronic manifestations as a later problem after transplant, we can see some of those changes even within the first few weeks.
Dr. Shernan Holtan
Stephanie: Dr. Holtan, when does it technically turn from acute to chronic? Is there an official time where now we know it’s chronic? Is there a general time frame?
Dr. Holtan: There isn’t an official rule. When Dr. Kosuri and I were in training, we were taught that acute graft-versus-host disease happens before Day 100 and chronic GVHD happens after Day 100, but that’s not really true. The biologic processes can happen at any time post-transplant. Acute GVHD usually happens in the first few weeks to months, but we have even seen acute manifestations of GVHD happen much later.
Even though we think about chronic manifestations as a later problem after transplant, we can see some of those changes even within the first few weeks. The lines are blurred now, so we describe graft-versus-host disease based on its symptoms and appearance rather than time frame post-transplant.
It took a while before my doctors said I had GVHD because they were thinking it was something else. Over the years, I’ve had a variety of different manifestations of chronic GVHD.
Meredith Cowden
Meredith’s GVHD Story
Stephanie: Meredith, what was it for you in terms of those first symptoms? At what point did you realize that this was not going away?
Meredith: In the beginning, I noticed that I had a couple of different things going on at the same time. My stomach started to bother me a lot and I got very nauseous. It was hard to find food that I could tolerate and that was appetizing. I had some gastrointestinal issues going on. I also developed a rash. I’m naturally a pasty pink person, but my skin got red and burned, so it was hard to wear clothing.
When I received treatment, the issues started to get resolved, but then it started to transition. The GI issues didn’t necessarily go away but they changed and my skin got a little bit different.
I had musculoskeletal involvement. I developed polymyositis, so there was a lot of pain. I was very weak and couldn’t move around a lot. I lost muscle mass. It took a while before my doctors said I had GVHD because they were thinking it was something else. Over the years, I’ve had a variety of different manifestations of chronic GVHD.
Dr. Kosuri: Chronic graft-versus-host disease can affect multiple sites in a way that may be difficult to initially pick up. I’ve gotten feedback from patients that what they’ve found helpful is when I describe chronic GVHD prior to the transplant.
I ask them to imagine taking all the autoimmune conditions and rolling them into one and putting them inside a human body. Those are ways that chronic GVHD can manifest, whether it’s dry eyes, a scleroderma type presentation, or pulmonary fibrosis. It’s a great mimicker.
Stephanie: It sounds like it might be hard to identify quickly if people aren’t speaking up too and share the different things that you’re experiencing and communicating openly with your doctor.
There are many different types of complications, but infection comes to the forefront.
Dr. Satyajit Kosuri
Severe Complications in GVHD
Stephanie: I don’t know if there’s difficulty in noticing what the severe complications are, but, Dr. Kosuri, are there any that you’d like to highlight?
Dr. Kosuri: There are complications of the entity itself and then there are complications that will arise from the treatment or the way we try to treat the disease. GVHD in and of itself is an immune dysregulation. The immune system that’s supposed to behave in a certain way is misbehaving or it might be turned on and can’t really control itself. What happens in this state?
There are many different types of complications, but infection comes to the forefront. We prioritize monitoring patients who have graft-versus-host disease not only from the GVHD itself but also from the medications that we use to try to quell the inflammation and calm things down. Both can lead down the pathway of bringing down the level of protection that the human body has as it’s starting or trying to recover from the stem cell transplant.
One of the things that we emphasize for patients is if they’re feeling unwell in any way, shape, or form, they have to let their transplant providers know very quickly. That way, whatever suspicion we may have, we can diagnose and take care of it very quickly. If it’s a small infection, we can treat it and it doesn’t become a big infection.
Be very proactive and very compliant with the medications. Patients take 20 different medications after a transplant and sometimes it’s hard to take all of them, especially when the pills are big. We hear that as one of the main complaints. We make sure that patients are on antiviral medications, antifungal medications, and a medication to protect them from PJP (pneumocystis jiroveci) pneumonia. These help protect and almost substitute in a way because the immune system is not online early on and when you have graft-versus-host disease, it’s not behaving the way that it’s supposed to.
Dr. Holtan: We certainly know that graft-versus-host disease can affect different organs and tissues, and that the treatment can have just as many toxicities as GVHD itself. Some of the most challenging issues we run into are malnutrition, straight-up difficulty eating, all the way to impaired organ function.
What Dr. Kosuri mentioned is key about notifying for changes in symptoms with chronic graft-versus-host disease. You want to intervene before there’s permanent damage. The longer the inflammation and scar tissue goes, the more difficult it is or it might even become impossible to reverse. Early intervention is necessary to try to avoid permanent damage.
If there’s anything that seems even a little bit wacky, ask. There’s no harm in asking. It’s one of the best ways to take care of yourself.
Meredith Cowden
Stephanie: From your own patient experience, did you know that you could bring these up to your doctor? Do you feel that patients you talk to know that they can do that? What do we need to do to make sure that this is happening?
Meredith: I was diagnosed at 19. I was young and there were things I learned over the years. This might sound naive and silly, but there were things that I thought were completely normal but were actually symptoms of GVHD.
Over time, I’ve developed strong relationships with each member of my care team, so I’m very comfortable saying, “This feels weird. I don’t know about this. Can you look at that? Check me out please.” To have that kind of conversation, you have to build that relationship so that everyone is comfortable and can have a discussion with one another even when they have differing opinions. You can get more out of that conversation than if a typical patient-doctor exchange. Oftentimes, things get missed that way.
For patients, treat your doctors like people. Be friends with them. You’re going to be with them for a long time. They want to help you. If there’s anything that seems even a little bit wacky, ask. There’s no harm in asking. It’s one of the best ways to take care of yourself. For the providers, it’s a good idea to ask patients to do a quick scan of their body to get the whole picture because it’s easy to forget stuff. Is there anything that’s going on that we haven’t touched on that you noticed?
The backbone of therapy for both acute and chronic GVHD is corticosteroids.
Dr. Satyajit Kosuri
Current GVHD Treatments
Stephanie: Dr. Kosuri, what are the current standard treatments for GVHD?
Dr. Kosuri: The keyword is current because this is something that’s changing and we hope will continue to change as we go through the years.
The backbone of therapy for both acute and chronic GVHD is corticosteroids. Many patients and their family members will have heard of the medication called prednisone or various types of the steroid.
The degree of the GVHD matters. If you have a mild, acute graft-versus-host disease, this could be potentially managed with topical corticosteroid. As it becomes more severe or involves more organ systems or more of the skin, we start graduating from topical steroids to systemic steroids.
Depending on where we are in the transplant process, our patients will already have been on another immunosuppressive agent, like tacrolimus, sirolimus, or cyclosporine. The goal is to treat with steroids plus or minus this other agent and then taper them off once we have a response.
With steroids, over a period of time, you can accumulate some of those side effects that we don’t like to see in patients, like insomnia, jitteriness, and fluid retention. Those are for people who are in the category of steroid-responsive.
Another category of patients are those who are steroid-refractory, which is where the graft-versus-host disease may be a little bit more sticky and not respond to steroids, or steroid-dependent, where patients are unable to get off steroids. In those cases, we go further down on immune suppression choices. There are other medications available. One that’s FDA-approved and works for both is ruxolitinib. There are also other various options. That becomes more of a longer term treatment.
There isn’t a blood test that can diagnose graft-versus-host disease right now, but we can use biomarkers to help us understand the severity of the immunologic reaction and how much damage has been done.
Dr. Shernan Holtan
Challenges of Existing Options for Managing GVHD
Stephanie: Dr. Holtan, what are some of the key limitations or challenges with the existing options for managing GVHD?
Dr. Holtan: The greatest challenge is understanding how much therapy to give for graft-versus-host disease. We base our treatment upon the severity of symptoms, but that isn’t adequate. There are still some patients that we are over-treating and some patients we are under-treating.
This is where the role of biomarkers can come in. There isn’t a blood test that can diagnose graft-versus-host disease right now, but we can use biomarkers to help us understand the severity of the immunologic reaction and how much damage has been done internally that we can’t detect clinically. This is a huge challenge because even though we examine patients fully and they reveal all their symptoms, we still can’t know how bad things are, so biomarkers can support us in helping to guide that therapy.
This is particularly under investigation right now using biomarkers such as ST2 (suppressor of tumorigenesis 2), REG3α (regenerating islet-derived 3-alpha) known as the MAGIC (Mount Sinai Acute GVHD International Consortium) biomarkers, and then the one that we developed at the University of Minnesota, amphiregulin or AREG. Both of these biomarkers can be used to understand how severe the graft-versus-host disease is.
I have patients who have had severe infections of the GI tract, like C. difficile colitis or viral gastroenteritis such as adenovirus gastroenteritis. An allogeneic transplant recipient might have these infections and we’ll treat the infections, but they’ll have persistent severe diarrhea so you won’t know if you’re still dealing with the infectious process and the healing that has to occur or if graft-versus-host disease developed as a result of the immune system trying to target the infections. Even a biopsy can’t always tell you this, but we can use biomarkers, especially amphiregulin, to help sort this out.
When we’re treating patients with these symptoms, it’s almost like it’s graft-versus-host disease until proven otherwise.
Dr. Satyajit Kosuri
I had a gentleman who had severe adenovirus gastroenteritis and was having 15 to 20 bowel movements a day. We used an amphiregulin test to know if this could be graft-versus-host disease. The result was normal. It was not elevated. I continued to check every week because his gastroenteritis went on for a long time, even though we treated it.
Clinically, he had weeks of diarrhea, but we followed that test every week and the number was always low, so we never gave him prednisone. If I didn’t have this reassurance, someone might say it’s GVHD. It took some time, but he made a full recovery. This is how we can use these biomarkers to help support our clinical decision-making. We need more trials along these lines because the real world is messy.
Dr. Kosuri: I can’t emphasize how important what Dr. Halton is mentioning because oftentimes in transplant medicine, we’re operating in the gray and we have to make guesses. Sometimes when we’re treating patients with these symptoms, it’s almost like it’s graft-versus-host disease until proven otherwise. When you have that type of thought process, it can be difficult and we can actually hurt the patient with the GVHD management in and of itself.
The example that Dr. Holtan mentioned, most transplant physicians would say, “This has to be GVHD and we have to give them prednisone,” and that could lead to other infections or it can worsen the infection the patient already has. We get into these situations that are difficult to manage and if we have something like these biomarkers, it can make our lives as well as the patient’s life much easier and with less toxicity than what we would say is the normal kind of approach.
We had no human data to support how we manage steroid-refractory GVHD. Out of decades worth of work, there were no studies.
Dr. Shernan Holtan
Stephanie: A lot of this is addressing the symptoms that come with GVHD. This may be a rookie question, but I’m trying to understand. Is there research going into how to address the drivers of what’s happening with GVHD?
Dr. Holtan: We know what causes graft-versus-host disease. The donor T cells are attacking tissues and organs. However, we can’t always tell when that attack is over. The whole field of steroid-refractory graft-versus-host disease has developed out of an assumption that the T cell-mediated attack is still happening, so all trials for steroid-refractory GVHD involve intensification of immunosuppression without actual knowledge that there are T cells still causing damage.
This was something that bothered me. These are things that drive you crazy about the field and want to change it. I realized that we had no human data to support how we manage steroid-refractory GVHD. Out of decades worth of work, there were no studies that justified that this is the right path.
I performed a study where we had rectal biopsies of patients with grades 3 to 4 gastrointestinal GVHD. They were steroid-refractory and received other therapy. I wanted to look at the biopsies for a sign that it was the donor immune system still doing the damage to prove what we’re doing is right and I found absolutely no evidence to support our practices. There was no increase in T cell infiltration. There was no immune signature at all that suggested that it was out of control T cell-mediated damage in the steroid-refractory patients. All we saw were signs of tissue damage.
I’m hoping that the field will evolve. Instead of intensifying immunosuppression, give something more immunomodulatory, support immune tolerance, and give something to help heal the damaged organ. Change the paradigm. That was a huge frustration that I had as a fellow and I hope more people read that paper now.
Clinical Trials for GVHD
Stephanie: We’ve talked about the current landscape of GVHD and treatments, and some gaps of need. Before we go into them, what are clinical trials?
Ashley: Clinical trials are carefully controlled research studies that may be conducted by scientists, doctors, or researchers to either test new treatments or test treatments that have been used in the past in a potentially different way. Trials can also compare new treatments to existing treatments or to various combinations of treatments to find out which treatment might work best or which would be better tolerated, all with the goal of improving care and treatment for patients.
BMT CTN 1703 Clinical Trial
Stephanie: Dr. Holtan, can we talk about one of the trials that you helped lead? What’s the potential and the excitement about that?
Dr. Holtan: An ounce of prevention is worth a pound of cure. The theme in these studies is prevention of graft-versus-host disease. Our field is in the midst of an important era. We have very effective prevention for acute and chronic graft-versus-host disease with multiple modalities that we have not had in the past.
The BMT CTN 1703 study was repurposing a chemotherapy agent called cyclophosphamide to prevent acute and chronic graft-versus-host disease by giving it after transplant in the setting of reduced-intensity transplants, so patients who are typically older. The median age of the trial was 66, going through transplant, and would receive this chemotherapy after the transplant. That initially sounds crazy to do. Why would you give chemo after the transplant?
We’re learning how this works, but it helps to deplete allo-reactive T cells. The good cells that we want to persist are completely immune to cyclophosphamide, so regulatory T cells, which are T cell peace mediators, and stem cells themselves are resistant to this chemotherapy. It eliminates the cells we don’t want and preserves the cells we do.
This modality was compared against the standard, which was a calcineurin inhibitor (CNI) plus methotrexate (MTX), and that’s been the standard since 1986. Our field hasn’t undergone a major change where we saw that the new treatment arm was superior. We haven’t had this kind of change since the mid-80s.
We did a similar study in Minnesota looking at post-transplant cyclophosphamide in the myeloablative setting. We saw remarkably low rates of acute and chronic GVHD using this platform. The rates of grade 3 to 4 acute GVHD were 5%. The rates of chronic GVHD requiring immunosuppression were also about 5%. It’s not a randomized nor a phase 3 study, so we haven’t done that comparison. I have a lot of conflicts of interest, so I don’t want to do that study because the results of phase 2 are so good. I wonder what Dr. Kosuri thinks about that.
Dr. Kosuri: Dr. Holtan’s work with 1703 is one of the more important studies that we’ve had recently in the field of stem cell transplant. When we look at our field and the studies that we conduct, having a randomized study in such a large manner is very, very rare, so this was a big deal. It’s not just the findings, but the way that the study was conducted.
The study went through other randomized trials and the two best options went into 1703. As Dr. Holtan mentioned, the results are very, very important and being adapted in a widespread manner amongst many of the transplant centers not only in the United States but even abroad, so it’s a very, very impactful piece of work.
The important thing, as she highlighted, is that these are for older patients who have had multiple lines of therapy and may be coming into transplant in a more frail physiologic manner than someone who is in their 20s, 30s, or 40s. The reduced-intensity aspect is very, very important.
I agree that the post-transplant side has had such an impact on the incidence of acute and chronic GVHD. The other thing that I’ve noticed is the nature of the graft-versus-host disease that could develop. Even if someone were to receive post-transplant cyclophosphamide as a GVHD prevention strategy or what we call T cell-depleting methods, there are other ones also.
When we’re giving higher-intensity conditioning, the amount of initial damage and inflammation that occurs is higher and the risk of developing both acute and eventually chronic GVHD can also be higher.
Dr. Satyajit Kosuri
When we compare it to the standard of care, if they were to develop graft-versus-host disease, there is the potential that it may be more responsive to current treatment modalities. You can treat it and it can potentially go away versus you trying to treat it and patients may become more steroid-refractory or steroid-dependent. Incidence is important and the incidence is much lower. My opinion is that the nature of the GVHD that may happen is also different.
As far as myeloablative conditioning, if we think it works in one setting with a group of patients who may be a little bit more sensitive to the toxicities of transplant, as a transplant physician, we want to try to apply it to the younger, fitter patient population who are receiving myeloablative transplants or the higher-intensity transplant.
The important point there also is when we’re giving higher-intensity conditioning, the amount of initial damage and inflammation that occurs is higher and the risk of developing both acute and eventually chronic GVHD can also be higher.
If we can take this modality, use it in the myeloablative setting, and decrease the incidence of both acute and chronic GVHD, that’s something I think that we’re all very supportive of. As transplant centers are changing their standard approaches, we ourselves at the University of Chicago are figuring out a way to standardize our myeloablative transplants using PTCy (post-transplantation cyclophosphamide), even though we don’t have a randomized, large randomized study.
VIC-1911 Clinical Trial
Stephanie: Speaking of higher-intensity transplant groups, that’s also for VIC-1911, right, Dr. Holtan? What’s exciting about that and who’s going to benefit from that potentially?
Dr. Holtan: This is a new clinical trial looking to improve on the post-transplant cyclophosphamide platform. Now that we’ve nearly eliminated severe acute and chronic graft-versus-host disease, our unmet need is addressing relapse.
We’re looking to see if we could do something different within the GVHD prophylaxis platform that not only keeps GVHD rates low but also directly reduces the risk of relapse. We took away one of the drugs in the platform called mycophenolate mofetil (MMF). We don’t think that MMF probably does very much to be honest. The heavy lifting is done by cyclophosphamide in combination with whatever we partner it with, tacrolimus or sirolimus.
We took MMF out and put in a drug called VIC-1911, an Aurora kinase A inhibitor (AURKA). That drug is known in preclinical testing to keep GVHD rates low, but it also has direct anti-leukemia effects. It helped to kill leukemia cells in the test tube and in mice. Mice who received this combination had better survival overall due to less graft-versus-host disease and less relapse.
We’re testing a platform to see: does it protect people from graft-versus-host disease and can it also protect from relapse? We have two primary endpoints in this study: GVHD and relapse. If we can move the needle with relapse, we will have evolved the platform even further.
This trial is ongoing right now only for the myeloablative or high-intensity conditioning regimen, but we hope to complete the study, learn the results, and, if successful, expand it to other platforms. It’s currently in phase 1. We have just found the dose that we want to test going forward.
Stephanie: That’s great context. Some trials are further along. People are always wondering, “Oh, that sounds so promising! But when are we actually going to see that in the real-world setting?” It’s great to know that the research is happening, but we’ve got a ways to go with that one.
Dr. Kosuri, you talked about PTCy and this trial is about lowering the dose. Can you talk more about that and who will benefit?
Dr. Kosuri: In Dr. Holtan’s 1703 study, we were looking at patients who have fully matched donors or what we call well-matched donors. Well-matched donors could also mean having a single-antigen mismatch. This is coming off post-transplant cyclophosphamide.
For patients who have haploidentical donors or half-matched donors, we’ve been able to successfully use that platform with very comparable and good rates of graft-versus-host disease reduction. The idea is if you can use it in a half-matched or half-mismatch, you can also use it in well-matched patients. We call that 7/8.
There are two studies. OPTIMIZE is coming after another study called ACCESS, which is looking at the same dose of post-transplant cyclophosphamide that we used in haploidentical transplants and reducing the dose a little bit.
Post-transplant cyclophosphamide is given on days 3 and 4 after a transplant at 50 mg each day. Data in the haploidentical transplant setting suggests that if we’re able to reduce the dose a little bit, a couple of things can happen along the lines of toxicity. One of the things that interests us is how quickly someone may engraft after a transplant, meaning how quickly their white blood cells come back and how quickly their hemoglobin and platelets recover.
If we reduce the dose a little bit, are we able to maintain graft-versus-host disease prevention, efficacy, or advantage? Maybe we’re able to improve a little bit with regard to the time it takes for the graft to come in. It’s a phase 2 study looking at patients who are 18 and older, who have a 7/8 donor, and both reduced-intensity as well as the myeloablative condition transplants.
We can find a list of clinical trials that will be open for consideration for a particular patient based on prior treatments and any conditions they may have.
Ashley Giacobbi
Enrolling in GVHD Clinical Trials
Finding a Clinical Trial
Stephanie: Finding clinical trials and enrolling in them is very difficult. We know ClinicalTrials.gov is available but may not be the most user-friendly. Can you walk us through the steps of how a patient could find a clinical trial that’s right for them?
Ashley: ClinicalTrials.gov is an amazing resource. It’s a database of all active and ongoing clinical trials, but it can be very challenging to use. This database contains all clinical trials for all conditions. It’s not exclusive to cancer clinical trials. Although cancer clinical trials make up a large portion of the clinical trials conducted in the United States, there are so many other clinical trials that are ongoing that it can be challenging to find one that’s right for you.
As a representative of the LLS and the Clinical Trial Support Center, we always encourage people to reach out. We hone in and find clinical trials that are most appropriate for the individual in whatever situation they are in. As opposed to having to filter through ClinicalTrials.gov, we can find a list of clinical trials that will be open for consideration for a particular patient based on prior treatments and any conditions they may have.
Types of Clinical Trials
Stephanie: We also understand that there are different kinds of trials available, like prevention, treatment, quality of life, and observational. Can you take us through what they mean in the context of GVHD?
Ashley: There are a lot of ongoing clinical trials for GVHD as this is an area of need. There’s a lot of ongoing research and that falls into different buckets.
Prevention clinical trials may look at altering the regimen prior to transplant or the medications taken after the transplant in an effort to prevent the development of acute or chronic GVHD.
Another type is treatment trials and these may include specific medications or investigational therapies that would manage acute or chronic GVHD if it’s already present.
Quality of life clinical trials are so important. There are a lot of clinical trials investigating symptoms that people with GVHD may experience. There may be behavioral interventions being investigated, such as exercise or even the use of an app to provide support. Some clinical trials offer social support or dietary recommendations in an effort to reduce symptom burden and really improve quality of life.
Finally, there are observational or natural history trials. These would be less involved as patients wouldn’t have to participate as much. These trials collect information either from the patient’s medical record or prior testing that’s been done to learn more about GVHD, who might develop GVHD, or how they might respond to specific treatments. These are important in the information gathering phase, but they might not require as much involvement from the patient perspective.
Eligibility criteria help determine the group of patients who will potentially receive the most benefit from the therapy being investigated.
Ashley Giacobbi
Qualifying for a Clinical Trial
Stephanie: You may find a trial that seems great, but there are eligibility criteria and screening processes that you may have to go through. What does that typically look like for patients?
Ashley: History, previous treatment received, and other factors play a role in the eligibility criteria, but those help determine the group of patients who will potentially receive the most benefit from the therapy being investigated. These criteria are also there to help reduce any unnecessary risk by preventing those who have underlying conditions that could be made worse by the treatment from participating in that clinical trial.
Those criteria may include things like the type of GVHD, acute versus chronic, which body systems are being affected, as well as any prior treatment received for the management of GVHD. Very often, steroids are used and some of these clinical trials will require that people have already attempted the use of steroids. Those eligibility criteria help us to find appropriate clinical trials for the individual.
Stephanie: You have touched on what you at the Clinical Trial Support Center in terms of helping people with a personalized trial list, going off of ClinicalTrials.gov and making sure it’s more tailored to them. Is there anything else you’d like to share about what they could expect?
Ashley: Patients can be referred to the Clinical Trial Support Center either by a healthcare provider or they can get in touch directly themselves. Very often, we connect with caregivers of patients.
Initially, we take the time to learn about the patient, what’s important to them, and their history. Those details are so important when looking for clinical trials and that’s usually via phone call.
Beyond that, we take the time to go through and review clinical trials. We’re very fortunate to have a unique database that looks at clinical trials in ClinicalTrials.gov but also stores information that we receive from investigators and sponsors of clinical trials so that we’re able to provide the most up-to-date information to patients when they’re considering clinical trial options.
Once we’ve generated a list, we’re able to send that to the patient, caregiver, or healthcare provider and share the clinical trials that we’ve found for that particular person. They can then take back that list to review with their healthcare team and see if any of those trials is a potential option for them to explore.
A lot of emerging data suggests that preservation of muscle mass actually helps reduce the risk of relapse, so this is not just cosmetic. It is about quality of life, but it’s also about the efficacy of the therapy itself.
Dr. Shernan Holtan
Nutrition & Exercise When You Have GVHD
Stephanie: Dr. Holtan, what specific nutritional and exercise interventions are being investigated to support muscle health during and after transplant?
Dr. Holtan: This is a substantial topic. I always tell my patients that if I could give a pill that could keep their muscles strong, I’d be the richest woman in the world. Having the ability to maintain muscle mass throughout chemotherapy of any kind is important. We need to do more in this area not just for transplant but for all cancer therapy.
There are multiple studies going on around the world that are looking at different types of nutritional supplements to maintain muscle mass and help promote intestinal healing. There’s some interesting research going on out of Italy using a nutritional supplement that has a growth factor that can help the gut heal itself.
There might be different nutritional approaches based on infection profiles. For example, we want to avoid a certain type of bacteria growing in the intestinal tract and avoid something in the diet that might help prevent that from growing. Those types of studies are important and we need to be able to expand them so that more patients can participate because, in reality, we don’t know what the best diet really is. We want people to get calories and protein in.
The same thing goes for exercise. We need to do more to facilitate exercise, especially resistance training. A lot of emerging data suggests that preservation of muscle mass actually helps reduce the risk of relapse, so this is not just cosmetic. It is about quality of life, but it’s also about the efficacy of the therapy itself. There’s a lot of work we need to keep doing in this space, so stay tuned. Obviously, this is the most important thing that we can work on besides improving the toxicities of the treatment itself. Supportive care is so important. We have a lot more work to do.
It’s on us to educate both referring providers as well as patients to understand that things have improved over time both from an access standpoint as well as supportive care standpoint.
Dr. Satyajit Kosuri
Areas Requiring More Research & Gaps in Transplants & GVHD
Stephanie: Dr. Holtan, you did mention that only a fraction of potential transplant candidates even get referred. What is contributing to this under-utilization? How can we address those barriers?
Dr. Holtan: We have an educational gap. The transplant field is vastly different in 2024 than it was even in 2021 and certainly way different than it was in the ‘80s or ‘90s, so we have to do a better job of communicating. What have been the advancements in care? How have we improved on the availability of donors? We no longer need a perfect match. How have we reduced graft-versus-host disease and improved other toxicities so that more patients are able to be reached?
There’s a lack of referral and also fear from the patient’s side as well. We have a lot of education to do to share that it is different today, much safer, and hopefully we can be able to take care of a lot more patients in the future.
Dr. Kosuri: Many of the old thoughts that we have about transplant are that you have to be a certain age or how scary it is and things of that nature. It’s on us to educate both referring providers as well as patients to understand that things have improved over time both from an access standpoint as well as supportive care standpoint.
The supportive care has changed over the last decade significantly and that’s why we’re able to take patients who previously the field would not consider, even if they were in good shape.
There can be a patient who is 50-some-odd years old but has been beaten up because of the disease or the treatment, so transplant would be very difficult for them, whereas we can have a 70-year-old who is running a half marathon. It’s not just numerical age; it’s the physiology of what the patient’s body is at the time that we’re considering transplant.
I totally echo what Dr. Holtan’s saying. It’s about education and casting our net very wide with regard to patients and patient advocacy groups as well as physicians or the referring providers.
We’re seeing so much change because of our understanding of the biology of the diseases that we’re dealing with coming into transplant, the technical aspects of the transplant, and GVHD prevention.
Dr. Satyajit Kosuri
GVHD Treatments Final Takeaways
Ashley: There are resources and support available. It’s never too early or too late to explore clinical trials when you’re talking about GVHD and clinical trial options during the transplant process.
Dr. Kosuri: Over the last decade, I have had more hope as a clinician in the field of transplant. Even though it’s trying to move, the field has been set in its ways for a very long period of time. But within the last 5 to 7 years, we’re seeing so much change because of our understanding of the biology of the diseases that we’re dealing with coming into transplant, the technical aspects of the transplant, and GVHD prevention, like the 1703 study.
There are many trials looking at the initial treatment of graft-versus-host disease and how to get patients off of steroids quicker. With chronic graft-versus-host disease that is far off, more severe, and more fibrotic, there are ways to manage that.
I want to emphasize Dr. Holton’s work regarding biomarkers. For a long period of time, our approach when it comes to GVHD was if we try something and it fails, we try another agent and provide more immune suppression. We’re hoping to minimize that approach where you throw something at a wall and see what sticks. It may be different for each patient. Do we need GVHD treatment in patients who have certain symptoms? If it is graft-versus-host disease, how do we know when to come off therapy or how to add therapy? That’s where the biomarker becomes very, very important.
I can’t emphasize enough how nutrition, exercise, and sleep are key to help recovery and resilience. I want people to know that they have more control than they think.
Dr. Shernan Holtan
Dr. Holtan: I want patients and their families to know that they have a lot of control in these processes. I believe very much in the principle of self-efficacy. Yes, this is a medical treatment that we are delivering, but there’s a lot a person can do for themselves and that their family can do together to help make the process easier.
I can’t emphasize enough how nutrition, exercise, and sleep are key to help recovery and resilience. I want people to know that they have more control than they think and look for ways that they can help build up their strength and resilience, lean on their network, and use these tools and resources to help build up the spirit and body to be able to withstand the trials and tribulations that certainly lie ahead. The medical advancements are real, but people also have a lot of control and they should know that.
Meredith: Hope is incredibly important. Recognition that you do have control is imperative. Be selfish and put yourself first. Don’t try to take care of all the people around you to the detriment of yourself. If you don’t want to do something or can’t meet with somebody, don’t do it.
Continue to find meaningful and fulfilling activities so that the illness doesn’t become your identity. You have an illness, but you’re not defined by that illness.
The LLS, being a partner of ours on this program, is such a great resource. The CTSC provides amazing one-on-one support in terms of understanding clinical trials, finding, enrolling, and even staying on them.
We hope that this program was empowering and that you’re able to take away not just from this program but from the many stories that we have.
Gwendolyn Jackson initially experienced heavy menstrual cycles, back pain, and bloating, which her doctor suspected to be fibroids. Despite regular tests, including an HPV test and ultrasound, her symptoms persisted. Later, clear fluid leakage led to an ER visit where an MRI and biopsy confirmed cervical cancer.
She underwent a hysterectomy, followed by chemotherapy and radiation, but further tests revealed the cancer had spread, drastically changing her prognosis. Severe side effects from treatment, including weakness, nausea, multiple strokes, and heart attacks due to dehydration, required intensive therapy. Despite initial hesitation, she joined a clinical trial at MD Anderson, which has helped manage her condition more effectively than traditional chemotherapy.
Throughout her journey, Gwendolyn faced misconceptions about clinical trials and the stigma of cervical cancer within the African-American community. Financial challenges resulted in losing her job, insurance, and assets. She found crucial support through Cervivor, an online community for women with cervical cancer.
Gwendolyn’s experience highlights the importance of self-advocacy in healthcare, the life-saving potential of clinical trials, and the need for greater awareness and support for cancer patients.
Name: Gwendolyn J.
Diagnosis:
Cervical Cancer
Staging:
Stage 4
Initial Symptoms:
Heavy menstrual cycles
Severe back pain
Stomach bloating
Treatments:
Chemotherapy
Radiation
Tisotumab vedotin (innovaTV 301 clinical trial)
This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
I started having heavy cycles, severe back pain, and bloating in the stomach.
I went to the doctor regularly. When I went for my well-woman exam, I told my doctor. He said, “I think you have fibroids. It’s very common in the African-American community.” That’s what it sounded like to me. “We’ll run some more tests.”
My symptoms persisted, so I went to my mother because I’m that girl who thinks mom can fix everything. I told her, “I’m having very heavy cycles. I don’t know what’s going on. The doctor said he was going to run some tests. They haven’t called me back yet.” She said, “You’re going through pre-menopause. I went through the same thing at the same age. It’s just pre-menopause.”
My cycle wasn’t getting any better. I finally went back to my doctor and he ran some tests. He did the HPV test and it came back negative. I was still having symptoms, so he said, “I’m going to do an ultrasound.” He did and said, “I see fibroids, so we might have to do a hysterectomy.”
In October 2020, while I was at work, I started leaking clear fluid from my vagina. I knew I wasn’t pregnant, but it felt like my water bag had burst. I said, “Okay, this is not good.”
When I saw cervical cancer written on that paper, I lost it. He wrote it down before they even found out I had it.
Going to the ER
I wish I could remember the name of the doctor who saved my life. I don’t know what would’ve happened if it wasn’t for him and that MRI.
When I went to the emergency room, a younger doctor who looked like he had just become a doctor said, “I want to run some more tests on you. I don’t feel comfortable with everything you told me. What can we lose? Let’s do an MRI.”
After the MRI, he came back and said, “I see fibroids, but I see something under the fibroid, so I’m going to send you to a gynecologist specialist, so they can run more tests because I’m not sure,” but he put “cervical cancer” on my paperwork.
I went home and did the worst thing I could do. I went online and searched “cervical cancer.” My father passed away from cancer, so when I saw cervical cancer written on that paper, I lost it. He wrote it down before they even found out I had it.
Diagnosis
Seeing a Specialist
I went to the specialist who said, “We have to run a biopsy. Calm down. Don’t worry. You’re pretty healthy. I see all the tests they’ve done. I don’t think you have cervical cancer. It might just be fibroids.”
Getting the Official Diagnosis
I was diagnosed during the COVID pandemic, so I had to go by myself. On the way, I talked to my mother and my sisters. Everybody said it was just fibroids. My sister said, “We have fibroids. We had to have a hysterectomy too.” They were reassuring me, so that’s what I thought.
I went in thinking I had fibroids and left finding out I had cancer. You will never forget the day. I was diagnosed on November 17, 2020.
I started treatment right after I recovered from the hysterectomy. I thought it was just a preventative measure to make sure I was okay.
Reaction to the Diagnosis
When you first hear, “You have cancer,” it doesn’t register. For some reason, I thought I was exempt because I was helping people with cancer. I started my nonprofit in memory of my father who died from lung cancer. I thought, I eat right. I run five miles every morning. I don’t smoke. I don’t drink. What did I miss?
Cervical cancer has this stigma that people who get it are either prostitutes, have a high sexual drive, or don’t go for their well-woman exam. That’s not me. On the way home, I thought it was something I did wrong.
I wanted to find out for sure first. The doctor put it on the chart and then gave me paperwork for the referral. I was left alone not knowing if this really was true. That two-week wait was difficult mentally.
Treatment
Hysterectomy
They said, “We’re going to go in and remove the whole tumor. After, you’ll do radiation and that’s it. Your life will be back to the way it was,” so that’s what I thought.
I had a full hysterectomy on December 17, 2020. The tumor was 9 centimeters. Before I went in, they were telling me, “You’ll be fine. After we remove the tumor, radiation will take care of everything else.”
After 6 to 8 weeks, I went for radiation. My doctor did some blood work and he was concerned with the results. He said, “The blood work didn’t change. Something isn’t right. I’m going to do an MRI and a PET scan. We have to see what’s going on.”
After I had the hysterectomy, they said, “We’re going to do radiation and you’ll take a chemo pill. That’s just protocol.” I started treatment right after I recovered from the hysterectomy. I thought it was just a preventative measure to make sure I was okay. They were thinking they got everything not knowing that it was spreading.
The chemo was so hard on me. Some days, you can’t get out of bed. Some days, you don’t have an appetite.
Cancer Spread
They found out that my cancer had spread to my hip bone, my legs, and my spine. Imagine going from everything is going to be okay to find out you have 16 months to live.
I said, “God, I don’t want to die. I just had grandchildren. I just turned 49. I haven’t hit 50 yet. I’ve been waiting to be 50 all my life. Please give me more time.”
When they realized it spread, my team had to come back together and treat me differently. They were going to try a bone marrow transplant, but they couldn’t do it because of how mine spread. My insurance would no longer approve it.
Knowing that was all they could do, I got scared. I have anxiety and depression, and I take medication for them now. I’ve never had depression before, but because of all of this, I take medication for it.
Chemotherapy & Radiation
I didn’t want a port. I asked, “Can we figure out something? Is there a way that I can take pills?” I took chemo pills and did radiation.
Side Effects of Chemotherapy & Radiation
The chemo was so hard on me. Some days, you can’t get out of bed. Some days, you don’t have an appetite. You don’t want to eat. You look at food and get nauseous. People don’t understand that. It’s not that we don’t want to. I’m trying. I’m showing up every day and doing the best I can. I used to tell my dad, “Come on, you can eat. Come on, you can get out of bed.” Now, I understand.
The radiation that targeted my cervical cancer was terrible. It burned the lining of my stomach and I kept getting infections.
I used to help my dad button and zip his clothes. I have the same issues now. I can’t button or zip. These are everyday things that we take for granted. I also felt numbness in my fingers and my feet.
I couldn’t keep anything in my stomach. I was vomiting and had diarrhea. They were giving me medication for everything, but nothing was working.
I feel so weak and cold all the time. I always have a heater with me, but I was so, so weak that I didn’t think I was going to make it. My daughter and the guy I was dating at the time were very helpful. They would bathe me and help me get up.
Because I lost so much weight and wasn’t strong, even my doctor was saying, “You’re getting weaker and weaker.” He kept prescribing me medication for nausea. They finally found a prescription that worked for me and that I love.
Radiation burned my face. It was burning and itching at the same time. My face swelled up and blistered. My doctor told me about a cream I could use, which cleared up my face.
The radiation that targeted my cervical cancer was terrible. It burned the lining of my stomach and I kept getting infections. I never want to do that again ever.
Strokes & Heart Attacks
When I went to the hospital, the ER doctor said, “She has high blood pressure.” I said, “No, I don’t have high blood pressure.” When he checked, my blood pressure was very low. When they ran tests, he said, “You’re having a stroke and a heart attack, and it’s because you are severely dehydrated. You need fluids in the body to make all the organs work.” I didn’t even know you could have a stroke or a heart attack from being severely dehydrated.
I had to stop treatment temporarily because I was in inpatient therapy for 14 days.
Recovering from the Strokes & Heart Attacks
I couldn’t walk, so I was in a wheelchair. I had to stop treatment temporarily because I was in inpatient therapy for 14 days and then I went to the Centre for Neuro Skills in Webster, Texas. I always speak so highly of them because they gave me my life back.
When I came in, I felt so helpless. I wouldn’t use the restroom, even though I was there from 9 to 2 o’clock. I didn’t want anyone to take me. I ended up getting a UTI and people there had to tell me, “We’re here to help. We want to make you better. You have to allow us to help you. You’re still the same person.”
I had three mild strokes. They didn’t understand the last one I had. They said, “Usually when you have a transient ischemic attack, you bounce right back.” I didn’t, so he said the last one wasn’t a TIA. It was a regular stroke because I had all the symptoms. I had to go from a wheelchair to a walker to a cane.
Because of the strokes, I can’t remember exactly what chemo I was on.
Joining a Clinical Trial
I met a doctor at one of Cervivor’s retreats. She was different if that makes sense. I knew that she cared about people. She said, “When you get back to Houston, let’s stay in touch,” because she worked at MD Anderson. I said, “My treatments are not at MD Anderson.” She said, “Let’s just stay in touch.”
My doctor never brought up clinical trials. I was doing some research. I kept hearing other patients talk about clinical trials when I went to the doctor. I decided I was going to ask my doctor, but I want to have information before I go in. I wanted to educate myself.
My doctor said, ‘This is great, but these clinical trials are at MD Anderson. If you can get in, go there. I’ll send your medical records over.’
I reached out to the doctor at MD Anderson and asked about clinical trials. She gave me all the information, told me which ones she recommended, and sent an email right away. It was after hours and she was volunteering her hours to help me. She’s still a big supporter of mine. She still checks on me and asks how I’m doing.
I took the information to my doctor and my doctor said, “This is great, but these clinical trials are at MD Anderson. If you can get in, go there. I’ll send your medical records over.”
My dad enrolled in clinical trials at the end and I said, “Y’all not helping him. This is not helping him.” My dad was such a great guy. He said, “This is how they’ll find out if it works for someone else. If it doesn’t work for me, they know it doesn’t work. If I can help someone, that’s what I want to do. I want to help someone.”
I didn’t understand at that time because I wasn’t a patient. But when you become a patient, you feel that way. If it doesn’t work for me, we know we have to try something else. If it works for me, that means this could be it. If I have to go through all of this to make sure it can save me and someone else, it’s so worth it.
When I went to MD Anderson, they had to do all the scans themselves. Their team comes in and speaks with you, and they have a team for everything. Even though I had cervical cancer, they also had a bone cancer specialist.
They redid all the tests I already had to make sure what they had in the file matched. Once they did everything over and made sure I was good to go, they started talking about treatment.
The clinical trial I’m on is called innovaTV 301. It’s a phase 3 study of tisotumab vedotin.
I like tisotumab vedotin better than traditional chemotherapy. It’s not so hard on my body.
Side Effects of Tisotumab Vedotin
They gave me medication for nausea and vitamin B12. So far, so good. The steroids are putting weight on me. I was a little nauseous at first, but the pill helped with that.
I lost my hair. I went bald when I first started and then it started growing back.
With bone cancer, being cold is a no-no for me. It’s very painful, so I wear a lot of warm-ups or layers to try and stay warm. Even in the summer, when I feel cold, I’ll be in warm-ups. I tell people all the time to be nice to people in warm-ups because you never know why they’re wearing them even when it’s warm out.
I noticed my appetite was not the same. I’ll crave something because of the steroids, but when I get it in front of me, I might take one or two bites and then I don’t want it anymore.
I like tisotumab vedotin better than traditional chemotherapy. It’s not so hard on my body. Do we know if it’s working? I don’t know if they think it’ll work. They’re buying me more time, so if that’s what it can do, I’m okay with that.
In the African-American community, clinical trials are frowned upon…In our mind, we still think we are being experimented on.
Misconceptions
In the African-American community, clinical trials are frowned upon. I think it goes back to when they were using African Americans for experiments and being the guinea pigs. In our mind, we still think we are being experimented on. If you tell anybody you’re doing clinical trials, they think you’re being a guinea pig.
I didn’t have the support. Everybody supports you when you’re going through chemo, but when it comes to clinical trials, they think you’re letting them experiment on you. They don’t care. I have to keep it to myself. I’ll tell people who are battling cancer that I’m in clinical trials, but other people, I don’t.
When it comes to the medical team, sometimes we feel like we’re not being heard. At first, I felt like my doctor wasn’t hearing me when I said it wasn’t fibroids and that something was going on, but they kept brushing me off.
I thought it was just Black women who go through that. Being in the teal and white community and the Cervivor community, I found out that it’s women as a whole. They are not listening to us.
Insurance Coverage
People think that if you want to be a patient at MD Anderson, you can just show up. It doesn’t work like that. When I first found out I had cancer, I wanted to go to MD Anderson because they’re number one. My insurance wasn’t in their network so they couldn’t take me.
While I was going through all of this, I still had insurance because I was still employed. They took excellent care of me during that time, but they could only take me so far. I was getting temporary disability, but my doctor put “permanently disabled” on my paperwork, so I had to resign from my job. They knew I wasn’t coming back, so they said, “You’re going to have to figure out your insurance yourself.”
Even with insurance, I was paying $2,000 to $3,000 for treatment. I lost everything. I lost my cars and my townhouse. The clinical trial was free for me, so that was good. They just had to make sure everything lined up.
I needed people who understood what I was going through, the stigma that comes with it, and that we have a voice. We didn’t do anything wrong.
Finding Support Online
I felt like nobody understood what I was feeling or going through. My mother kept saying, “It’s going to be okay,” but I told her, “What if it’s not? What if I die? What if this is my story?” But, of course, she didn’t want to hear that. “No, you’re going to be okay.”
My sisters were supportive, but nobody knew what I was going through. The only person that I felt I could talk to was deceased. My father would be the only one that would know what I was going through.
I went online and found Cervivor. I needed them more than they probably knew. I needed people who understood what I was going through, the stigma that comes with it, and that we have a voice. We didn’t do anything wrong.
I went to a retreat because I needed to be around these women. I needed them to love on me and I needed to love on them. They gave me hope. They said, “You can do this. You can fight this. Don’t give up. We support you.” They have a group chat where they talk about whatever they’re going through. If somebody doesn’t respond, they all get nervous.
Words of Advice
Cancer taught me to slow down because I was always on the go. I never slowed down to notice anything. Now I would stop and notice things. “Did you know mom has roses in front of her house?” And then I would stop and smell them.
Everything matters to me now because I don’t know how long I have. When I had my stroke, I couldn’t walk and we take that for granted. Even going to the restroom, I needed someone to help me and I appreciate that so much now.
Clinical trials can save us. I’m doing pretty well. It’s working for me. I’m still alive because of the clinical trial. My brother, who has cancer, is on a clinical trial and doing well too.
A doctor told me, “When you go into the doctor’s office, they are working for you. You are not working for them.” When you have that in mind as you’re going in, it’s different.
If you feel like something is not right, speak up. If there’s a treatment that you don’t want to do, say it. We get so nervous when we go in that we freeze up. Use your voice.
Cancer taught me to slow down because I was always on the go… Everything matters to me now.
In addition to Gwendolyn’s narrative, The Patient Story offers a diverse collection of cervical cancer stories. These empowering stories provide real-life experiences, valuable insights, and perspectives on symptoms, diagnosis, and treatment options for cancer.
Symptoms: Intermittent spotting during or after sex, unpredictable menstrual cycle, abdominal pain particularly under the rib cage Treatments: Chemotherapy (cisplatin & paclitaxel), immunotherapy (Keytruda), surgery (total abdominal hysterectomy with bilateral salpingo-oophorectomy & omentectomy)
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Shyreece’s story began with an unexpected onset of symptoms. After experiencing sudden shortness of breath, she was soon diagnosed with advanced-stage cancer following a series of hospital visits and tests. Visit her first in-depth patient story here.
She underwent various treatments, including chemotherapy and clinical trials, experiencing both successes and setbacks. While some treatments provided relief, others led to significant side effects and the progression of her cancer.
Her cancer journey is marked not only by the challenges of the disease and its treatments but also by her resilience and determination. She stresses the importance of self-advocacy, informed decision-making, and community support. She also became an advocate for understanding biomarker testing and exploring every possible avenue for treatment, including participation in clinical trials for new therapies.
Despite the challenges, Shyreece remained steadfast in her faith and determination to live fully. She shares her story through writing and mentoring, offering hope and encouragement. As she continues her fight, she approaches each day with unwavering resolve and a commitment to living without fear.
In addition to Shyreece’s narrative, The Patient Story offers a diverse collection of non-small cell lung cancer stories. These empowering stories provide real-life experiences, valuable insights, and perspectives on symptoms, diagnosis, and treatment options for cancer.
Thank you to Pfizer for its support of our patient education program! The Patient Story retains full editorial control over all content.
This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
Such heaviness and shortness of breath came over me out of nowhere. I thought, What is this? From that moment, I knew something was wrong
Introduction
It’s been 10 years for me. Before the cancer diagnosis, my answer was, “I’m Shyreece. I’m a teacher and I love kids. I’m so glad to have overcome so many obstacles to teach and do wonderful things.”
When cancer hit me, I thought, Who am I? Where do I go from here? What do I take from this battle that I’m in and can’t seem to get out of? On any given day, I could be floored on my back and the next moment, I’ll be coaxing myself to get up and go to the bathroom.
Pre-diagnosis
Initial Symptoms
My students and I were getting prepared for spring assessments. After they came in from lunch, I said, “Let’s get ourselves ready and do a little brain break dance,” and then everything got heavy. The kids were moving, wiggling their arms, having a good time, and, for whatever reason, I couldn’t do it with them anymore.
I said, “Kids, you guys are going to have to sit down.” I had to hurry and sit down. Such heaviness and shortness of breath came over me out of nowhere. I thought, What is this? From that moment, I knew something was wrong, but I kept pushing past it. That’s what superheroes do, that’s what super teachers do. We push through it. We keep going.
That weekend, my boss came in and said, “We’re moving you to a more administrative role.” I said, “This is great. Now I’m excited again.” But when Monday came, I couldn’t carry my book bags into the office. It was such a short distance from the parking lot to the front door of the school, but I couldn’t do it. When I finally got in and started trying to catch my breath, somebody heard me wheezing and said, “Shyreece, you need to go to the ER.”
I didn’t know what was going on, but that started a two-week journey to being diagnosed.
Going to the ER
My husband picked me up from work at about 7:00 pm and took me to the ER. The doctor said, “You’re not going anywhere. You’re in such a state that we don’t even trust your husband to take you to the hospital. We’re going to take you by ambulance.”
I didn’t know what was going on, but that started a two-week journey to being diagnosed with stage 4 ALK-positive lung cancer. We didn’t even know what ALK meant. I learned that along the 10-year journey.
Diagnosis
Five doctors were standing in my room and they were as confused as I was. The hospitalist said, “We don’t know what’s going on on the surface, but I’m going to send this to the University of Michigan.”
He waited for the results to come back and when he got them, he said, “Oh my goodness.” He came in, held my hand, and told me, “You have cancer,” and then called the local cancer clinic.
Something in my gut said to go to the University of Michigan. When I got there, they said, ‘We have an inhibitor we want you to try. It’s promising.’
Treatments
Carbo-Pem-Bev
They had no idea what to do next, but she said, “Shyreece, I’m going to go ahead and load you up with the best chemotherapy mix that we can possibly give you right now.” I said, “Okay, let’s do it,” so I started with carbo-pem-bev (carboplatin-pemetrexed-bevacizumab) at the local clinic.
I didn’t know what I was asking for. We had to do it overnight. It was a long night, but I took it like a champ. I had the most angelic nurse that night. She was amazing. It was her first time treating me and it was my first time going through such an ordeal.
Crizotinib
Something in my gut said to go to the University of Michigan. When I got there, they said, “We have an inhibitor we want you to try. It’s promising and we want you to start that in April.” That’s when I started crizotinib.
AT13387 Clinical Trial
I joined a clinical trial of AT13387 (HSP90 inhibitor) times two cycles with concurrent crizotinib. I didn’t feel right with that one. I did everything that I was asked to do during the trial, but I withdrew due to significant diarrhea.
In the middle of the night, I would have to drink oral electrolytes quickly enough to stop the spasms. They were out of control. It was a couple of days or so after the cycle. I lived through that and didn’t like it at all. It didn’t give me a good quality of life. After I came off of it, I felt a little bit better, so I was able to enjoy my anniversary around that time.
After withdrawing and feeling a little bit better from the nausea and cramping, according to some scans around the time, there were improvements in some areas. For example, I used to have to do an abdominal CT scan, but I didn’t have to do that anymore, so something got better there, but I didn’t know what. I didn’t have to focus on getting some of the areas scanned.
After the trial, there was some metastasis. The University of Michigan said, “You can’t use crizotinib anymore, so you can stop taking it.”
Alectinib
I waited and had to fight for alectinib. I had to get it approved by insurance so that I could start taking it. The doctor said he was fighting behind the scenes with me to get the insurance to approve it so that I could start taking it. Even though I started panicking, he said, “Shyreece, it’ll be worth the wait.”
Everybody needs to understand what biomarker testing is and how to read certain test results when they come back.
Treatment Decision-Making
When I hear clinical trials, I hear another opportunity to step out in faith. At first, I didn’t want another clinical trial. I would have to be on my deathbed and have 24 hours to live before I do another clinical trial, but that’s not where I’m at right now. I’ve changed. I’m thankful I’ve had 10 years and kept up with enough.
Whatever decision I make, I’m not going to waver on it. I’m solid in my faithfulness. I’m going to make it knowing that this is what I’m choosing today. I hope that this encourages somebody else to live their best life with no fear. I’m not going into any trials with fear. It’s another opportunity to live my life with faith.
Somebody can benefit from me. I need them as much as they need me. I give love to people who need it and the relationship that they have with me, so I’m going to be present and I’m going to live.
Let the medicine do what it’s going to do, but know that it’s not everything. Whatever regimen I’m doing at the moment is what works best. That’s what I keep telling myself.
Biomarker Testing
Something told me that I did not have regular lung cancer. Nothing made sense to me and yet I was this close to dying. Everybody needs to understand what biomarker testing is and how to read certain test results when they come back. When I looked into it, I learned that there were different types of lung cancer. It opened up a whole new window of options.
In my situation, it seemed like biomarker testing was already done but the results weren’t disclosed to me. The test that the hospitalist sent out had some information in there. Stanford didn’t do a repeat biopsy. They trusted all the records from the University of Michigan. When they looked at them, they highlighted: stage 4 ALK, rearranged bronchogenic. That’s when I first heard those terms.
Six years went by before I found out what biomarker testing was. I learned that through LUNGevity, who heard about me through an ALK-positive online cancer group. The doctor at Stanford said, “Shyreece, have you heard of the ALK Positive group? Look them up. I heard that they just had their first summit.”
I started digging. Then-president Gina Hollenbeck and I started conversing. Sad to say, she’s no longer here. She lived eight years with the same cancer that I have. I have a lot of stories about the loss of friends with the same biomarker. That’s how I started talking about biomarker testing and doing a lot of the advocacy work that I’m doing now.
We have to be empowered. For patients who are getting these diagnoses, self-advocacy is a must.
Message to Other Patients & Care Partners
We have to be careful with the words we use regarding remission. The CT scan showed no evidence of disease. Friends and family even thought I was healed because I looked good and didn’t look like I had cancer. I’m so sick of hearing that. I don’t even have the energy for it anymore.
We have to be empowered. For patients who are getting these diagnoses, self-advocacy is a must. If you’ve been shy all your life, then you better grow out of it. I had to grow out of it and quickly.
I moved around all these clinics and doctors, and all of them didn’t want to have a meeting to see what was going on and what was best. I had to piece everything together. Advocate for yourself. You become a self-advocate when the flame of other voices lights you. What are you advocating? Who are you advocating for? What gives you strength and power? Nine times out of ten, it will come from something else that motivates you.
This is the time to just really lock in and go all in. This is war.
Advocating for Yourself
I always say when you’re advocating, get yourself locked arms. I love watching some war movies, like the movie called, “300.” I love it when they get ready to go to battle. Come on, they lock…formation, and then you can see them taking their shields. It’s in front of them. They locked in and they’re ready to go.
When you get ready to advocate, who are you locked in with? Find a group of folks who you can lock in with. This is not for the faint of heart. This is the time to just really lock in and go all in. This is war.
I have made it no secret in my faith. Now, there were some people in the beginning. They knew me as Sister Pompey, Sunday School teacher, and all this. But when I got a diagnosis, they were like,”Where is your faith now?”
I did take a tumble. I did take a hit, but I’m gonna tell you right now, I wouldn’t take [anything else] for my journey now. Look, if I die, I am the Lord’s and if I live, I am the Lord’s, so whether I live or die, I am the Lord’s. I’m going from life to life. I’m going to live my life.
I know this is not Scripture, but Gandhi said learn as if you’ll live forever, so maybe that’s why I keep reading all these reports and stuff. I’m going to learn as if I’ll live forever, but I’m going to live as if I’ll die tomorrow.
I’m living it all. I’m leaving it all out on the field today. Everything that was ever given to me, I’m giving it all, give it all, give it all. I’m not holding nothing. When I go to bed tonight and I’m [worn] out and I’m tired, I don’t have time for depression. I’m too tired.
You’ve got to connect to something bigger than yourself. That’s all I’m saying.Let the medicine do what it’s going to do, but you just know it’s not everything.
I do want to say for you or anybody else who’s watching, please, one of the things that I look for, I love giving back and I love sharing my story and my journey. [Here’s] a link to my book. It’s on Amazon — Fruititude: Growing Spiritual Virtues Through Adversity. I’m always giving back to children and families, so any way that you can support, that would be great and I would really appreciate it.
Thank you to Genmab, AbbVie, and Incyte for their support of our patient education program! The Patient Story retains full editorial control over all content.
This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
Stephanie Chuang: My name is Stephanie Chuang. I’m the founder of The Patient Story. The genesis of The Patient Story was my non-Hodgkin lymphoma diagnosis at 31 years old. I remember how overwhelmed I felt and didn’t even know what questions to ask my doctor. What do I do? Where do I go? But it was more like what do we do? Where do we go? Because as we all know, a cancer diagnosis impacts so much more than the patient.
We know there are so many things to consider, but I believe the core of what can make a difference is empowering ourselves to be more active in our care. I’m so thankful for advocates in every form, including other patients, care partners, and healthcare providers who invest so much time and energy in ensuring that we get the best care and know what clinical trials may be an option for us and not as a last resort.
This program is produced by The Patient Story in collaboration with The Leukemia & Lymphoma Society, an incredible advocacy organization that has free resources for patients and care partners in blood cancers, and an organization that has supported more than 85% of blood cancer treatments approved by the FDA to date.
We want to thank Genmab, AbbVie, and Incyte for their support of our educational program. Their support allows us to ensure we can continue to publish stories and programs that are free for patients and care partners. As with all our programs, The Patient Story retains full editorial control over the content.
While we hope you learn a lot, it is important to note that these discussions are not a substitute for seeking medical advice, so please speak with your own medical team about what’s most appropriate for you.
Our patient moderator is Dr. Robyn Stacy-Humphries. Not only is she a long-time respected physician in the Charlotte area, but she is a three-time DLBCL patient and survivor, and someone I’m lucky to consider a friend. I admire her so much for the advocacy work that she does as a physician and now as a patient advocate. Robyn, thank you so much for joining us and leading our discussion.
Robyn Stacy-Humphries, 3x DLBCL Survivor
Dr. Robyn Stacy-Humphries: I’m Robyn Stacy-Humphries, a three-time diffuse large B-cell lymphoma survivor. I’m one of the first patients in the United States who received CAR T-cell therapy in 2016.
Nilanjan Ghosh, MD, PhD
Dr. Nilanjan Ghosh: I’m Nilanjan Ghosh, the head of hematology at Levine Cancer Institute at Atrium Health. I also lead the lymphoma division. It’s a real pleasure to be here to discuss DLBCL as well as follicular lymphoma with my colleagues.
Kulsum Bano, MD
Dr. Kulsum Bano: I’m Kulsum Bano, a community oncologist who works at Levine Cancer Institute. It’s a privilege to take care of patients with lymphoma and an honor to be here to talk to everyone. Thank you.
Justin Favaro, MD, PhD
Dr. Justin Favaro: I’m Justin Favaro, a physician, medical oncologist, and hematologist in Charlotte, North Carolina. I’ve been in private practice for 18 years. I see a wide spectrum of different types of cancer, with a special interest in malignant hematology, lymphoma, and leukemia. I love the science of this disease and the technology, and I love to learn more from you all as we try to tell you what we know about this disease. It’s a pleasure to be here.
Diffuse Large B-cell Lymphoma (DLBCL)
Robyn: Diffuse large B-cell lymphoma is the most common of the non-Hodgkin lymphoma types. It is very aggressive and, without treatment, most people’s survival rate is only one year.
We are also going to talk about follicular lymphoma. There is some overlap, but follicular is an indolent lymphoma. People may present or be asymptomatic. It can progress rapidly or it can last for years. DLBCL and follicular lymphoma are managed differently.
First, we’re going to talk about diffuse large B-cell lymphoma. Dr. Favaro, what are the current treatment options for diffuse large B-cell lymphoma when a patient is first diagnosed? What you do with your patients?
Current Treatment Options for DLBCL
Dr. Favaro: Before I talk about this disease, try to imagine a cancer cell as a ball. It’s a little simplistic, but if you think about a ball, in the middle of the ball is where all the DNA is. The DNA is the recipe for what makes a cancer cell what it is. There are 30,000 genes. This DNA in the middle of that cell is making all these proteins that make that cancer cell grow and make it do what it does in your body.
On the inside part of that ball are all these proteins. We’re going to talk about some of these proteins. These proteins circulate around the inside of that cell and make the cancer cell grow.
On the outside of that ball are spikes. There are different types of spikes on the outside of the cell. They’re called receptors. We can use those spikes and target cancer cells with our treatments.
CHOP
Dr. Favaro: The initial treatment for lymphoma goes back to 1976 when a combination of different chemotherapy drugs was first approved. CHOP is a combination of three different chemotherapy drugs (cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate) along with prednisone. Back in the 1970s, we were giving chemotherapy that attacked and killed all these fast-growing cells. It wasn’t targeted to spikes or proteins.
R-CHOP
Dr. Favaro: About 20 years ago, we discovered rituximab, which is a targeted therapy. It’s an antibody, a Y-shaped molecule that targets CD20, which is one of the spikes on the outside of the cell. We found that this is a great advance in cancer treatment.
If we added rituximab to all that chemotherapy, patients did better. They lived longer and had a much better chance of going into remission. R-CHOP has been the standard first-line treatment for diffuse large B-cell lymphoma for over the last 20 years.
pola-R-CHP
Dr. Favaro: Finally now, we have a new drug called polatuzumab vedotin, another targeted treatment and Y-shaped molecule. This time, it binds to CD79.
Polatuzumab vedotin added to rituximab, which hits CD20, and two different chemotherapy drugs plus prednisone (pola-R-CHP) is the new standard of care for the treatment of diffuse large B-cell lymphoma. Studies have shown that the response rate and survival is about the same versus the old regimen, but it looks like at two years, the remission rate is better if you take the new regimen of pola-R-CHP. This is the newest treatment for this disease.
Treatment Options for Relapsed Patients
Robyn: Unfortunately, even with these advances and the durable remission rate of 80% or so with the current therapy, there’s 20% where it doesn’t work. Patients will relapse very quickly. Dr. Ghosh, what happens in these patients whose initial therapy fails? What do we have to offer them now?
Autologous Stem Cell Transplant
Dr. Ghosh: In the past, the standard for patients who are eligible for an autologous transplant would be to get salvage chemotherapy, like RICE (rituximab, ifosfamide, carboplatin, and etoposide), R-DHAP (rituximab, cisplatin, cytarabine or cytosine arabinoside, and dexamethasone), or R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin).
If they are chemosensitive, meaning the tumor shrunk with chemotherapy, then they would go for an autologous stem cell transplant, which is high-dose chemotherapy followed by giving them their own stem cells back.
CAR T-cell Therapy
Dr. Ghosh: As immunotherapy advanced and as we learned more about ways to harness the immune system to fight against cancers, this was applied to diffuse large B-cell lymphoma and a novel treatment came about: CAR T-cell therapy.
Initially, it was approved after two prior lines of therapy. Patients would have had to gone through a transplant and if the transplant failed, they would get CAR T-cell therapy, or if they got chemo and then got CAR T-cell therapy as the third-line treatment. But then knowing that it was very powerful even in the third-line setting, there were some randomized clinical trials directly comparing it with transplant.
In the second-line setting, we are thinking a lot in terms of CAR T-cell therapy, reserving transplant for patients who relapsed late but are transplant candidates.
Dr. Nilanjan Ghosh
There were three large, randomized phase 3 studies that compared efficacy and toxicity of CAR T-cell therapy with that of autologous transplant. Two of those trials were positive in terms of ensuring that the primary endpoint, which was free of disease, progression-free, or event-free survival, was better compared to transplant. One of those studies actually showed overall survival was also better compared to transplant.
The current standard of care if somebody was refractory to front-line chemotherapies, like R-CHOP, pola-R-CHP, or R-EPOCH, or if they have relapsed within one year, the second-line therapy would be CAR T-cell therapy.
One of the CAR T-cell therapies called liso-cel was also used for patients who were not eligible for transplant, like older patients. Patients could get liso-cel as a second-line therapy if they had late relapse but were not considered to be transplant candidates, like if they had some organ dysfunction which would preclude them from getting a transplant.
In the second-line setting, we are thinking a lot in terms of CAR T-cell therapy, reserving transplant for patients who relapsed late but are transplant candidates. They could get salvage chemotherapy. If chemosensitive, go for transplant; if not, then still go for CAR T-cell therapy.
Follicular Lymphoma
Current Treatment Options for Follicular Lymphoma
Robyn: Follicular lymphoma is actually very common. It’s managed in the outpatient setting and Dr. Bano has seen quite a few of these cases. How do you manage these patients in your clinic?
Dr. Bano: I agree, it’s very common to see follicular lymphoma. It’s a different kind of disease process compared to DLBCL in the ways that patients present. It’s not the typical storm of symptoms that you expect with DLBCL. Follicular lymphoma tends to be slower-growing and presents in a way where most patients are even asymptomatic on initial presentation. They’ll have scans for something else, we’ll find enlarged lymph nodes, they’ll have biopsies, and that’s how we find it a lot of the time.
The way to approach treatment is a little bit different when you compare it to a more aggressive lymphoma like DLBCL. Sometimes, we’re thinking about stages like we generally do with lymphoma. The treatment differs based on what stage you are.
If you have a localized group of lymph nodes that are involved, a lot of times, if patients are asymptomatic, we watch and wait. Sometimes, if they have symptoms from a bulky lymph node enlargement, they can get radiation. A lot of times, we’ll combine that with CD20 monoclonal antibodies, as Dr. Favaro very nicely explained, that target these lymphoma cells directly. That is usually the option in limited stages of disease, like stage 1 and stage 2.
As we approach further spread out disease like stage 3 or stage 4, a lot of folks are asymptomatic and have a low burden of disease. We tend to watch and wait. That’s still an option.
Because of the indolent nature of follicular lymphoma, there’s a chance that it may come back, but we try to treat it and keep it in under control for as long as possible with milder therapies.
Dr. Kulsum Bano
Broadly, follicular lymphoma also is divided based on its grade. Not all follicular lymphoma comes equally. Some of the cases are lower grade, meaning the cells that are involved are not as actively dividing and do not appear as aggressive. For those patients, we tend to steer more toward the watch and wait and low tempo of therapy.
The more aggressive varieties, like the grade 3s, which is divided into 3A and 3B, we look more toward the DLBCL kind of treatment because these tend to act like a more aggressive lymphoma. In that scenario, we look more at chemotherapy plus immunotherapy, like R-CHOP. That usually tends to be the front line of therapy for follicular lymphoma.
It’s very varied. It’s a broad spectrum depending on stage as well as grade, but it tends to be a slow-growing disease in general. For those who get front-line treatment, some get even rituximab with bendamustine. Not everyone needs multi-agent chemotherapy.
A lot of times, we do a finite amount of chemo and follow it up with rituximab maintenance for up to two years. Every eight weeks, they get a rituximab infusion and that keeps patients in remission for a long, long time.
But as we talk about the difference in the nature of the two diseases, follicular versus DLBCL, there is also a difference in the treatment goals for these diseases. DLBCL is more aggressive and, as we were discussing earlier, we talk about a curative approach. Because of the indolent nature of follicular lymphoma, there’s a chance that it may come back, but we try to treat it and keep it in under control for as long as possible with milder therapies.
Treatment Options for Transformed Follicular Lymphoma (tFL)
Robyn: As a radiologist, there are a lot of CT scans and PET/CT involved where you monitor the lymph nodes. Unfortunately, even when someone’s in remission for two years, even after 10 years, it can come back aggressively. Dr. Ghosh, what do you do with a follicular lymphoma that is aggressive, has failed all treatments, and has transformed into diffuse large B-cell?
Dr. Ghosh: The first thing to think about when follicular lymphoma comes back is when it comes back. If it comes back within two years of front-line chemo-immunotherapy, then it’s considered to be progression of disease in 24 (POD24). Even if it has come back as follicular lymphoma, it’s a more aggressive variant. In long-term studies, the survival for that type has not been good. Many research studies have focused on this POD24 group to see what treatments would be effective.
The second thing to think about is: what does it come back as? As we discussed, follicular lymphoma can come back as low-grade follicular lymphoma, so grade 1, grade 2, or grade 3A.
Robyn: That’s based on pathology or the way it looks under a microscope.
If it’s aggressive B-cell lymphoma, then the treatment would be more like DLBCL. If it’s low-grade follicular lymphoma, you would treat more like the low grades.
Dr. Nilanjan Ghosh
Dr. Ghosh: When it comes back, it’s important to get a PET/CT scan and try to biopsy the most aggressive lymph node. A person might have multiple lymph nodes and if you only biopsy one, it could be low-grade follicular lymphoma. You don’t want to miss another lymph node with a high grade because the treatment would differ.
Convenience is important and sometimes a very bright lymph node may be in an inaccessible site, which makes it challenging. Try to biopsy the most active lymph node. If it’s aggressive B-cell lymphoma, then the treatment would be more like DLBCL. If it’s low-grade follicular lymphoma, you would treat more like the low grades.
PET scans are good, but the biopsy is where the money is, so put it under the microscope. Let the pathologist tell us what it looks like and then we can decide what to do.
In general, if it is follicular lymphoma, there are many treatment options in the second-line setting. Our commonly used one, if rituximab plus chemotherapy has been used before, is a lenalidomide-based treatment in combination with a monoclonal antibody like rituximab or obinutuzumab.
Subsequently, CAR T-cell therapy has been very effective in follicular lymphoma. Bispecific antibodies are also approved and very effective in follicular lymphoma.
In follicular lymphoma, the disease can relapse 10 or 12 years later… CAR T-cell therapy has not been around for that long.
Dr. Nilanjan Ghosh
CAR T-cell Therapy for Follicular Lymphoma
Robyn: Follicular lymphoma traditionally has been viewed as incurable. But with CAR T-cell therapy, there is now possibility of a cure. Is that correct?
Dr. Ghosh: Yes, there is a possibility. The only long-term follow ups we have with follicular lymphoma being curative is allogeneic transplant, which have been around for decades. Follicular lymphoma can come back. DLBCL typically doesn’t have late relapses. There can be some, but usually relapses occur early. In follicular lymphoma, the disease can relapse 10 or 12 years later. What that implies is that you would have to follow people for more than a decade or perhaps even two decades to be sure that the disease doesn’t come back.
CAR T-cell therapy has not been around for that long, so we don’t know for sure, but there are hints though. We now have data that patients who were POD24 (patients who had front-line chemotherapy and their disease came back within 24 months) got CAR T-cell therapy and their disease hasn’t come back even beyond two years, which means the second-line treatment was more effective than the front-line treatment. This typically doesn’t happen in cancer. If that is there, then you’re overcoming the bad disease biology.
If it doesn’t come back after 5 years, after 10 years, and after 15 years, with follicular lymphoma, that’s when we’ll know. With DLBCL, you can have quicker readouts because if it doesn’t come back in two, three, or five years, then you’re likely cured.
Robyn: We have a CAR T-cell therapy online support group and we have several patients who had follicular lymphoma and who are 4-5 five years out from CAR T-cell therapy and in remission, so it’s very encouraging.
Bispecific Antibodies
Robyn: Moving on to exciting new treatments, Dr. Favaro, would you talk about bispecifics? What’s been approved and how do they work?
Dr. Favaro: Bispecifics are a fascinating field of medicine. The first bispecific that was approved was blinatumomab, which was approved for acute lymphocytic leukemia (ALL).
It’s a very small, V-shaped molecule. One part of the V would attach to your T cell, the other part of the V would attach to your cancer cell, and it will bring them together so the T cell can kill the cancer cell. If you flood your body with these, you can bring all the cancer cells next to your T cells and get a lot of death of the cancer cells.
We still use it for acute lymphoblastic leukemia. The problem with that molecule is that it has a very short half-life. It’s a small molecule and it would be degraded quickly, so you have to use continuous infusion and treatments in the hospital.
Over the last few years, they’ve developed better molecules that are more stable. Instead of a V shape, it’s actually a Y shape. The long part of the Y stabilizes that protein so it doesn’t degrade so quickly. These Y-shaped proteins still do the same thing, bringing the cancer cell next to the T cells, and they are now available for patients with lymphoma.
Epcoritamab
Dr. Favaro: There are two that are approved for diffuse large B-cell lymphoma patients who have had at least two prior treatments. One is called epcoritamab (EPKINLY). It’s a subcutaneously administered drug that attaches to the T cell and the cancer cell, bringing them together.
They’re seeing very high response rates in the 60% range and almost 80% in some cases, where for 80% of the patients that take this drug, their lymphoma shrinks down and up to 60% will have a complete response where their lymphoma completely goes away.
It’s a great new treatment. However, when you do this, you get a lot of release of cytokines and proteins in the body and they can cause side effects, almost like you have the flu or a fever, and can even get worse. Sometimes, you can have low blood pressure. We have to be very careful about how we dose these treatments.
We start with a low dose once a week and gradually bring the dose up. The side effects usually happen in the first month or so. Once you get to the higher dose level, then you’re basically taking an injection once a month.
Glofitamab
Dr. Favaro: There’s another drug called glofitamab. It’s a very similar molecule that does the very same thing, except it’s given intravenously. We step up the dose of the treatment over a period of a month and then the patient gets IV therapy every three weeks. It’s a limited duration of treatment. For that particular drug, it’s about 12 cycles or eight months of therapy.
The results we’re seeing with these two drugs are that most patients will have a complete response and you can see that being a long, durable, complete response.
Mosunetuzumab
Dr. Favaro: There’s also a BiTE (bispecific T-cell engager) therapy that’s approved for follicular lymphoma as well. This is a drug called mosunetuzumab and is given intravenously in a similar step-up dosage. This is given for a total of either eight cycles if you go into complete response or 17 cycles if you have partial response. We’re seeing great results with that as well in patients who have had at least two prior treatments for either diffuse large B-cell lymphoma or follicular lymphoma.
Robyn: Is this performed as an outpatient?
Dr. Favaro: It’s outpatient. There’s a risk of a severe reaction. In the early onset of the trials, most patients had to be admitted in the hospital after their second treatment or so because when you step the dose up, that’s when these side effects can happen.
The other two drugs can be given completely in the outpatient setting. We have a protocol set up for epcoritamab. You take the injection once a week for the step-up dose of that first month. As the dose is increased, you get steroids before getting the treatment and for three days afterwards. That seems to really reduce the side effects.
There’s a whole lot of education and prevention that goes into preventing and treating side effects immediately.
Dr. Justin Favaro
Side Effects of Bispecific Antibodies
Dr. Favaro: You have to understand these side effects and how to manage them, so we do a lot of education for our patients. Again, most of these side effects happen within the first month.
CRS (Cytokine Release Syndrome)
Dr. Favaro: There are three major side effects of those treatments. One is called CRS (cytokine release syndrome) and that’s where a lot of cytokines are released as the dose is increased. There are certain stages. CRS can manifest as a fever or if it gets worse, you can get low blood pressure and sometimes have to be admitted to the hospital.
We give steroids and, when needed, a drug called tocilizumab. Almost always, we’re able to reverse those side effects, but it’s something we do educate patients about and keep a close eye on.
Dr. Favaro: The second side effect, which is much less common, is called ICANS (immune effector cell-associated neurotoxicity syndrome). You can have neurologic changes, difficulty with thinking or decreased mentation, and some weakness of the muscles. Again, this is very rare, but it’s all about education, watching for that, and treating appropriately.
Infection
Dr. Favaro: The third big one is infection. We do treat with prophylactic antibiotics to prevent infection and sometimes we give IVIG to boost the patient’s immune system if needed.
There’s a whole lot of education and prevention that goes into preventing and treating side effects immediately. It’s amazing to have these drugs as options now for our patients.
With glofitamab and epcoritamab, as more time goes, we are starting to see a flattening of the curve for some patients… we’ll know over time how that looks, but it’s remarkable progress.
Dr. Nilanjan Ghosh
Success Rate of Bispecific Antibodies
Robyn: Dr. Ghosh, what bispecifics are you using and what kind of success have you seen?
Dr. Ghosh: We have all the bispecifics that are approved as well as those in clinical trials. We’ve been using mosunetuzumab for follicular lymphoma and glofitamab and epcoritamab for DLBCL.
For DLBCL, we usually do CAR T-cell therapy as second line. Studies have shown that even if CAR T-cell therapy has failed, patients have a very good response with both epcoritamab and glofitamab. These were phase 2 studies and remarkably had the same complete response rate. Epcoritamab showed about a 40% complete response rate and glofitamab also had a similar complete response rate.
Epcoritamab is subcutaneous, glofitamab is IV. Epcoritamab is given indefinitely until progression or if someone has bad side effects so they stop. Glofitamab, as Dr. Favaro mentioned, is given for 12 cycles.
I wouldn’t say choosing between the two can be tricky. Both have very similar efficacy, but you have to decide which one is going to work for somebody who lives far away and who wants limited-duration therapy.
Rather than focusing on the differences, the 40% complete response rate is the most important thing to take home. CAR T-cell therapy failed many of these patients. We don’t have very long-term data for the high-risk population in these studies who were refractory to previous treatments and yet did well.
With glofitamab and epcoritamab, as more time goes, we are starting to see a flattening of the curve for some patients. There are patients who got complete remission. They may still relapse, but there are some patients who will get into longer remission. We don’t have five-year data from either of the two, so we’ll know over time how that looks, but it’s remarkable progress.
In general, mosunetuzumab has lesser CRS compared to glofitamab and epcoritamab, but is also used more commonly in follicular lymphoma. Again, all these are done in the outpatient setting.
We have been involved in clinical trials combining mosunetuzumab and polatuzumab. A very effective strategy and though not yet approved, many other studies are ongoing.
The other thing we’ve done is combined bispecific antibodies with front-line treatment. We did a clinical trial of taking glofitamab and R-CHOP in the front line and we’ve seen remarkable remission rates.
Robyn: 80%?
Dr. Ghosh: Higher. When you combine glofitamab with R-CHOP in the front-line setting, the complete response rates are in the 80%. In DLBCL, we focus more on complete responses. Partial responses are okay to mention, but they are very temporary, so we want to focus on complete responses. Sometimes a partial response may turn into a complete response.
Clinical Trials of Bispecific Antibodies
Robyn: There are so many new exciting therapies and our panel has submitted some trials for bispecifics that they’re particularly excited about. What are some of these new trials that are revolutionizing treatment for lymphoma?
EPCORE DLBCL-3
Dr. Ghosh: The EPCORE DLBCL-3 clinical trial is looking at patients who are in the front-line setting and are not eligible for anthracycline-based treatments. They would get either epcoritamab or epcoritamab plus lenalidomide. If somebody has congestive heart failure or some cardiac problems that will preclude them from getting anthracycline-based chemotherapy, then instead of doing R-mini-CHOP or R-CHOP, they could get onto this study.
If bispecifics are moved up from more advanced relapsed/refractory treatments to earlier, can we get chemo-free front-line treatments? That is an effort with the EPCORE DLBCL-3 study.
EPCORE NHL-5
Dr. Ghosh: The EPCORE NHL-5 clinical trial is looking at epcoritamab plus lenalidomide in relapsed/refractory DLBCL. It has shown remarkable activity. It has not been directly compared with epcoritamab alone in the same study, but we have results from epcoritamab alone and that is a complete response rate of 40%. With epcoritamab plus lenalidomide, I believe the complete response rate goes up to the 50s and close to 60%.
Lenalidomide is an immunomodulatory drug. Combining an immunomodulatory drug with an antibody, which is also a kind of immunotherapy, we’re trying to focus on harnessing the immune system to fight against the lymphoma.
Glofitamab + Pola-R-CHP
Dr. Ghosh: Another powerful combination is glofitamab plus polatuzumab-R-CHP. As Dr. Favaro mentioned, pola-R-CHP showed improvement over R-CHOP. That has become a new standard. It showed improvement in progression-free survival compared to R-CHOP. If that is the backbone, can we further improve on that? That’s how we have made improvements over time.
CHOP came in the 70s. R-CHOP was approved in 2006 and showed improvement over CHOP. Pola-R-CHP showed improvement over R-CHOP. If we add a bispecific antibody to pola-R-CHP, can it show improvement over pola-R-CHP?
Glofitamab and pola-R-CHP is a study which we have done at the Levine Cancer Institute as well and it’s been done worldwide and has shown amazing effects. I saw one of my patients very recently who was in this study. He had an extremely explosive DLBCL about two years ago and he’s still in remission.
There are a lot of trials for diffuse large B-cell lymphoma that are moving a little bit more away from chemo and going toward these targeted therapies.
Dr. Justin Favaro
Glofitamab + Polatuzumab
Dr. Ghosh: Glofitamab and polatuzumab is another ongoing study. Taking polatuzumab, a CD79b antibody drug conjugate, and combining it with glofitamab showed high complete response rates. Similar studies have been done for mosunetuzumab plus polatuzumab as well.
A lot of these combinations are being done with the common theme being chemo-free. Some have chemo. CHP is chemo and antibody-drug conjugates are also chemo, but antibody-drug conjugates are very targeted chemo. It targets only the cells where the antibody binds to those spikes, so there is much less collateral damage.
The focus is trying to do less in terms of lowering the side effects, improving the efficacy, and improving quality of life and quantity of life. When you put that all together, the field is moving very well toward immunotherapies. I think these are all really good clinical trials.
Robyn: It’s very exciting. For the audience, the most common used anthracycline is doxorubicin, which is also known as the Red Devil. It can cause cardiotoxicity even in young people, who can end up with congestive heart failure at a young age. Other medications used, like cyclophosphamide, can cause neuropathy, which in some cases is irreversible. To move away from these medications and have the same results or better is great for quality of life and very, very encouraging.
Dr. Favaro: These are all great trials. There are a lot of trials for diffuse large B-cell lymphoma that are moving a little bit more away from chemo and going toward these targeted therapies.
Dr. Favaro: There’s another interesting trial combining four different drugs and none of them are really chemotherapy. There’s an oral drug that’s a BTK inhibitor called zanubrutinib, another monoclonal antibody called tafasitamab (MONJUVI), plus lenalidomide and rituximab. Of the four different drugs, two of them are targeting the spikes, one of them is targeting a protein inside the cell, and the lenalidomide is there to stimulate the immune system, the T cells, to grow and attack the cancer.
A newly diagnosed patient with no prior chemotherapy is seeing a very nice response rate. In this particular trial, they started with this and if they went into a complete response, then they got two cycles of chemotherapy and went back on the targeted therapy.
I like the idea of targeting some of these molecules on the outside or the inside, combining it with something that turns the immune system on as a way to eliminate some of those long-term potential side effects from chemotherapy. I think that’s the theme that we’re seeing here.
CAR T-cell Therapy
Robyn: I’m one of the first patients to get CAR T-cell therapy. I’m going to have the experts explain it, but as a patient, I compare it to Pac-Man. You put the T cells in and the little Pac-Man goes over and eats the cancer cells.
CAR T-cell therapy is new. I received tisagenlecleucel in 2016 as a phase 2 trial. It’s been very successful for me and I’m very, very grateful. I was able to go back to work as a physician. I have a great quality of life. Most of my side effects are from the chemotherapy, which did save my life but I wish I hadn’t had those.
This is a great therapy and now, not only is CAR T-cell therapy used for blood cancers, but it’s also being used in trials for solid tumors and autoimmune diseases, such as lupus, scleroderma, and glioblastoma.
Dr. Favaro, can you explain CAR T-cell therapy?
Dr. Favaro: T cells are part of your white blood cells that circulate around your body. They’re constantly looking to treat infection or try to treat cancer and that’s part of their job. Why can’t they kill cancer cells on their own? Because cancer cells learn how to hide. There are certain proteins they can take away from their surface, so your normal T cells can’t find the cancer cells sometimes and that’s part of the reason why cancer cells can grow in your body.
How do we stimulate those T cells and make them angrier and more attracted to kill and attack those cancer cells? In my mind, that’s what CAR T-cell therapy is.
The whole process starts by taking out your T cells. We do that as a part of an apheresis process that happens in the clinic or in the hospital. Those T cells are sent off to a company that will take those T cells and reengineer them in the lab to become CAR T cells. Those T cells that are now transformed will attach to a CD19 spike on a lymphoma cell.
The whole process takes about two weeks. The CAR T cells are infused back into the body. They have this new protein on the outside of their cell called chimeric antigen receptors (CARs). They go into the body and attack the lymphoma cells. It’s pretty amazing technology.
The data shown with diffuse large B-cell is that you can get a 40% long-term remission rate in patients who have had prior treatment but now the lymphoma has come back. Those are amazing results and Robyn is a testimony to that.
The downside is it takes a long time. This is a process and you have to wait. There’s also the issue of insurance authorization. Medicare pays for these treatments, but insurance companies take a long time. You have lymphoma that’s growing in your body and we have to wait to get this whole process done.
It requires you to take other treatments, like lymphodepleting chemotherapy, to control the lymphoma before we can get the CAR T-cell process done. Once you collect the cells, it takes about two weeks to get them back. It could take up to six weeks from the time you meet until infusion day.
There’s a lot of thought about how we can make this process better. The companies that make these products are telling us that 8 out of 10 patients who are eligible aren’t getting CAR T-cell therapy. Maybe they don’t live close to a big academic hospital center or it takes too long and their cancer is growing too quickly.
A lot of the research is focused on making the process faster. Can we create CAR T cells in the lab so we don’t have to go through this whole process? That’s what we’re looking to talk about down the road.
The goal has also been to see if we can lower the intensity and the incidence of CRS and neurologic toxicities.
Dr. Nilanjan Ghosh
Side Effects of CAR T-cell Therapy
Robyn: Dr. Ghosh, you have spearheaded CAR T-cell therapy in Charlotte, did the first cases, and have a lot of experience. I would love to have you talk about the side effects of CAR T-cell therapy.
Patients are terrified of the CRS and ICANS. Meanwhile, they’re not as terrified of a stem cell transplant, which has more side effects. How you do you manage the side effects? What kind of results have you seen with CAR T-cell therapy?
Dr. Ghosh: We have had significant experience with CAR T-cell therapy at our center because we participated in some of the clinical trials, which led to the approval of CAR T-cell therapy. It’s certainly a learning curve on how to manage CRS and ICANS.
When we think about CRS, these are serious side effects, but what’s important is these are reversible for the most part. Some clinical trials report very high rates of CRS and some even with ICANS. Most of these happen early on and within a few days of receiving CAR T-cell therapy.
They are managed with a team of physicians, nurse practitioners, nurses, and pharmacists who are very, very in tune with how to manage these side effects. We also have help from ICU doctors, neurologists, and infectious disease specialists, so it’s a team approach.
Each grade of CRS and ICANS has its own treatment. As the grade goes higher, treatments can intensify. The mortality from CRS and ICANS is extremely low. The reversibility is extremely high.
CAR T-cell therapy is underutilized because of the fear of side effects, but the potency which it has far outweighs the risks associated with it
Dr. Nilanjan Ghosh
CAR T-cell therapy has a 40% long-term remission rate and, more importantly, it’s a one-time treatment. You come in, get three days of lymphodepleting chemotherapy followed by a couple of days rest, get the CAR T cells, and then a week of monitoring for CRS or neurologic side effects. If nothing happens, then you remain outpatient. If they happen, then we treat them and reverse them, then monitor for infection risk after.
The treatments can include acetaminophen, fluids, oxygen, steroids, and other drugs, like tocilizumab and anakinra. What we have seen is by doing these measures and being aggressive in terms of treatment, these side effects are reversible.
The goal has also been to see if we can lower the intensity and the incidence of CRS and neurologic toxicities. There are drugs which can be used. For example, prophylactic steroids can sometimes lower the intensity of CRS and that has already been approved. There are multiple ways, but if you have a team who has been doing it for a while and can react immediately, the side effects can be managed.
Another side effect, which is not very common but very important to address, is macrophage activation syndrome or HLH (hemophagocytic lymphohistiocytosis). Again, that is also managed with medications. We are able to recognize it early by monitoring things like ferritin and other markers as well.
I feel that CAR T-cell therapy is underutilized because of the fear of side effects, but the potency which it has far outweighs the risks associated with it, especially now that it’s been so long and we’ve been able to manage the risks in a relatively protocolized manner.
Be aware of side effects, but don’t be freaked out by them.
Dr. Nilanjan Ghosh
Robyn: My therapy was pretty much outpatient. I think that some of the treatments are drifting toward outpatient until you actually need to be inpatient, which decreases your risk of infection and increases your quality of life. My understanding is that a lot of hospitals are trying to move toward that, but it depends on the type of CAR T and also the patient.
Dr. Ghosh: The patient and caregiver. Another very important thing for CAR T-cell therapy is you need to have a caregiver. If someone is having confusion, you need a caregiver if you’re outpatient to be able to call and say that there’s something wrong.
Even in an outpatient setting, for the initial part, there are very frequent follow-ups, almost daily, so distance from the center can be an issue. If someone lives close by, you can do it outpatient. If someone lives far, it may be hard to go back and forth. We are working very hard to try to overcome barriers to CAR T-cell therapy.
Be aware of side effects, but don’t be freaked out by them. If CAR T-cell therapy is right for you, go for CAR T-cell therapy at a place where they know how to manage these side effects and get the benefits.
The first person to ask about trials would be your physician, but no matter how good the physician, they won’t know about all the trials in the United States and the world. Another resource is ClinicalTrials.gov, which is what my husband and I utilized when we were looking for a trial though it’s a little bit harder to navigate. Trials are accessible, but you have to be your own advocate to some degree.
Dr. Ghosh: For anyone who has barriers to clinical trials, remember that we would not be here today if not for clinical trials. Even CHOP came through a clinical trial, which was started in the early 70s. Everything came through clinical trials.
Robyn: Again, I’m an example. I was one of the first who got CAR T-cell therapy through a clinical trial. I’ve told other patients that sometimes, the best treatment you can receive is through a clinical trial.
Dr. Ghosh: Cancer clinical trials don’t compare a cancer drug and a placebo. They have a well-established cancer regimen and may add one drug to it, but those who are not getting the study drug get the best established cancer regimen. Unlike other diseases where you can get a placebo versus the study drug, this is a serious, life-threatening disease so you’re either getting the standard of care or the new promising drug. If it’s a phase 1 or phase 2 study, everybody gets the same treatment.
Robyn: Ina lot of trials, patients have been through all these standard treatments. They may have had CAR T-cell therapy or BiTE therapy then the lymphoma comes back. What do you do? That’s where these companies are on the cutting edge of developing newer treatments.
Cancer clinical trials don’t compare a cancer drug and a placebo. They have a well-established cancer regimen and may add one drug to it, but those who are not getting the study drug get the best established cancer regimen.
Dr. Nilanjan Ghosh
TRANSCEND FL
Robyn: I know some people who are in the TRANSCEND trial for follicular lymphoma. There’s a lot of people enrolled in that. From what I’ve seen from the data from ASCO, it looks like it’s very successful.
Dr. Ghosh: TRANSCEND FL took patients with relapsed/refractory follicular lymphoma and treated them with liso-cel. It’s been reported and has fantastic efficacy with very high complete response rates in the 90s.
The follow-up is not very long, so that’s one downside, but the FDA is doing a priority review to see if this is good enough that it should get approval in follicular lymphoma. It also has been done as second-line treatment and that has very, very good activity in the second-line setting.
SWOG S2114
Dr. Ghosh: Remember we said that 40% patients with large B-cell lymphoma will get long-term remission after CAR T-cell therapy. What about the other 60%? We always have to think about the people who didn’t benefit. We have a great example of benefit right here, Robyn, but there are others who didn’t.
Complete remission is the most important thing for diffuse large B-cell lymphoma. What about people who get partial remission or stable disease and it didn’t grow? That’s not good enough because within a few months, many of those patients will progress. What if you can intervene before that with bispecific antibodies and polatuzumab?
This S2114 study is a trial which is trying to improve the outcome of patients who are in partial remission or have stable disease by adding drugs post CAR T-cell therapy and trying to see if they would benefit and convert them into complete remission. This is a national trial and we have it open at our site as well.
ELARA
Dr. Ghosh: The ELARA study is looking at tisagenlecleucel for relapsed/refractory follicular lymphoma. This is showing high response rates, low CRS, low neurotoxicity, and durable remissions. Now with three-year follow-up and showing that nearly close to 60% of patients are in remission.
This is a one-time treatment given three years ago and patients are still in remission. Many of those patients are in that POD24 group, where they had progressed within 24 months, so their first remission was two years and now the second remission has been lasting for three years. I hope the remission will last for 5, 7, 10, 15 years, but only time will tell. That’s where whether it’s curable or not will come in for follicular lymphoma.
A lot of companies are developing CAR T cells in the lab that are engineered so they can go in and attack the lymphoma cells, but the body’s immune system won’t attack them and kill them.
Dr. Justin Favaro
Other Clinical Trials
Dr. Favaro: It’s exciting to see CAR T-cell therapy patients in follicular lymphoma and seeing long-term responses. That’s a disease that tends to relapse over and over.
Robyn: People can go on with their life.
Dr. Favaro: The other trials I do like are looking at CAR T-cell therapy patients who don’t have a complete response. Let’s bring in BiTE therapy for those patients as well to try to get them into complete response.
We’re part of a national network of cancer clinics called OneOncology and some of our clinic sites are looking at doing outpatient CAR T-cell therapy. There are different products that are now approved. Liso-cel is one that has the least side effects and is the most predictable.
In outpatient clinics in the OneOncology network, we’re doing CAR T-cell therapies and watching them as an outpatient. They can be watched for four days. It’s pretty predictable that at day four is when a lot of the side effects happen for that particular product.
That’s one example of how we’re moving things more toward the outpatient by monitoring patients while they’re at home. If it’s day four and the patient is starting to have side effects, we bring them in, keep an eye on them for a few days, take care of the side effects, and send them home.
There are a lot of companies developing new CAR T-cell therapies. Why do we need to take the T cells from the patient, reengineer them, and put them back? What about taking regular cells? You can take a culture of human cells and, believe it or not, take stem cells and turn them into T cells in the lab.
A lot of companies are developing CAR T cells in the lab that are engineered so they can go in and attack the lymphoma cells, but the body’s immune system won’t attack them and kill them because these are foreign cells to the body.
One of the other trials happening in the OneOncology network is using allogeneic CAR T cells, meaning they come from a different person. They’re engineered in a way to help your body accept them and see if you can get a response.
Multiple companies are doing this and, in some cases, these are patients who have been through everything. We get a response and a reduction in their lymphoma by using these foreign cells created in a lab. To me, that’s where the future is: looking at this in the outpatient setting and having it ready for the person when they need it.
Robyn: It’s also less costly because it’s technically off the shelf, which should be excellent.
Treatment Sequencing
Robyn: At some of the meetings, people still talk about bispecifics versus CAR T-cell therapy and in which order. We talked about bispecifics after CAR T-cell therapy. Some people are saying bispecifics should be done before CAR T-cell therapy.
Dr. Ghosh: CAR T-cell therapy came first. Outside of blinatumomab, which was for ALL, most of our DLBCL and follicular bispecifics came later. Naturally, by the time bispecifics were available in trials, CAR T-cell therapy had already been around. We know that after CAR T-cell therapy, bispecifics are very active, but what we didn’t know was the reverse.
Recently, a European study was presented and showed that if you use bispecifics before CAR T-cell therapy, you can still get really good activity from CAR Ts. On that study, bispecifics failed a lot of patients so they went on to get CAR T-cell therapy, which was then effective.
In the United States, bispecifics are not approved in the second-line setting, while CAR T-cell therapy is, so undergoing CAR T-cell therapy before bispecifics makes a lot of sense. We don’t have long-term data for bispecifics in the second line but we do have data saying that if it didn’t work, at least CAR T-cell therapy may be able to rescue those patients.
That was a very good study. Overall, we do great in oncology in terms of getting new drugs approved, but we don’t do a great job in sequencing them. That’s left a lot to the physician in discussion with the patient because not everything from the menu is going to be available or accessible right away.
With disease, you may have to do something right away because you can’t wait for six weeks or so to get CAR T-cell therapy. If CAR T-cell therapy is available, then you may want to wait and do the bispecifics later.
In DLBCL right now, I would do front-line treatment of CAR T-cell therapy and bispecific antibodies. In follicular lymphoma, you could do the reverse. It’s a more indolent disease. We don’t know about curability as much. We know that mosunetuzumab works well in relapsed/refractory follicular lymphoma. You have long-term remissions and you could save exa-cel or tisa-cel and, if liso-cel does get approved, then liso-cel for later.
As we are seeing longer data, you have to think: do you want to be on a treatment where you are coming in frequently versus getting a one-time treatment? The treatment where you’re coming in frequently has lesser side effects than the one-time treatment, so it’s a discussion.
Will clinical trials ever be done to answer the sequencing question? I don’t know. I think we’ll learn over time. What will matter is the side effects and the durability of the response. Any response which is durable will be higher in the flowchart compared to the ones where relapse will happen sooner.
Folks who’ve gotten chemotherapy upfront are often left with life-limiting or daily activity-limiting side effects, like neuropathy, so it’s extremely exciting to have this option of chemo-free treatment without long-lasting side effects.
Dr. Kulsum Bano
Possibility of Chemo-Free Cancer Treatment
Robyn: I’ve been in medicine for a long time. When I trained in medicine, oncology was still relatively barbaric, I would say. Chemotherapy and cancer treatments involved cutting, burning, and poisoning. Way back in the 80s, they didn’t even have antiemetics or ports, so giving people doxorubicin was difficult to say the least.
We’ve progressed dramatically. Oncologists have found ways to decrease nausea and take care of neuropathy, but the side effects are still there. Do you see chemo-free treatment of cancer in the future? Perhaps in the next 10 to 15 years?
Dr. Bano: I think that’s the direction we’re slowly heading in. A lot of these trials are slowly moving treatments that were thought to be more exciting and more novel approaches from the fourth to the third, to the second, and then slowly into the front-line setting. That happens over time because the more we learn, the more experience we have with all of these wonderful patients who’ve been on trials and given us this knowledge.
As a community oncologist, that’s extremely exciting because I hope to see patients for years to come who are going to be disease-free and who’ll just be monitored. Folks who’ve gotten chemotherapy upfront are often left with life-limiting or daily activity-limiting side effects, like neuropathy, so it’s extremely exciting to have this option of chemo-free treatment without long-lasting side effects. People are going to live longer with these disease-free intervals. It’s very exciting and hopefully that’s where we’re headed.
Dr. Favaro: I think it’s a combination of things. If you look at chemotherapy, these are chemicals that kill fast-growing cells and that’s pretty good against lymphoma. These often are fast growing, especially diffuse large B-cell lymphoma, so it’s been very active treatments that have put people into long-term remission. But the downside of chemotherapy is the potential long-term side effects plus it’s harder to go through, so what can we do?
Cancer cells are complicated. We’ve got the DNA inside the cell, which has 30,000 genes and over 100 probable mutations in those genes. You’ve got all these crazy proteins in the cell. A lot of them are active and helping the cell grow. Then there are the different spikes outside of the cell.
You have to think about how you attack not just one protein or one spike but multiple targets. A trial I mentioned took a BTK inhibitor and attacked the protein inside and had a couple of drugs attacking the spikes on the outside. That’s probably where we’re going to head to avoid treatments that are so toxic.
Multiple targeted agents is the way to go. For example, with BiTE therapy, we know what happens with those patients. It’s very effective pretty early, but what’s going to happen down the road? Will there be a potential risk of the cancer coming back?
You’re taking the T cell, bringing it to the cancer cell, turning that T cell on, and killing the cancer cell. But over time, those T cells get tired, which is something called T-cell exhaustion, and don’t want to work as well. Sometimes it’s as simple as giving people a break from treatment to let their T cells recover.
But the other thing I think that we’re going to head toward down the road is limited duration therapy but baking something in. You give BiTE therapy, but because we know the T cells can get exhausted, we need to add in another targeted therapy to kill some of those proteins and give 2 or 3 of those for a limited duration. I hope that’s where we end up to finally wipe out the disease for good.
Improving Access to Cancer Care
Robyn: One of the things that all of us as doctors are focused on is access to care. In my case, there was no CAR T-cell therapy offered nearby. My oncologist here had to coordinate with an oncologist who was in a trial in Ohio and my team in Charlotte did a fantastic job. Dr. Ghosh, what do you do in the academic center to reach out to community doctors? How do we improve access to care?
Dr. Ghosh: Late 2017 is when we moved forward with signing up for the TRANSCEND study, which eventually led to approval. Once we signed up for the study, we were the only center in all of North and South Carolina to offer CD19 CAR T-cell therapy before any other center. We got patients from everywhere in that study.
Access is certainly a very, very big issue for CAR T-cell therapy. It becomes even bigger because you need a caregiver. How do we overcome some of the socioeconomic barriers? The caregiver would have to take some time off. Typically, we need patients to be within a one-hour radius, so they would need local housing.
The first part of access is providing education and understanding the benefits of CAR T-cell therapy and referring the patients in a timely manner. It could take up to 6 to 8 weeks to get CAR T-cell therapy, so if you wait for the referral, then it may not be doable because the disease will take off. Early referral is extremely essential for CAR T-cell therapy.
There’s a lot of fine-tuning involved, so the team together with the patient decide what’s best. We try to do this in a really timely manner.
Dr. Nilanjan Ghosh
Patient navigation can be very helpful to help find resources, whether it’s local housing or any type of support. I think that’s essential.
Insurance can be a barrier, especially in terms of single-case agreements, but we are trying very hard. We have a study in which we are looking at the effect of these insurance problems on patient outcomes, so that is a barrier we’d like to overcome. Some barriers are within our control, some are not.
There are ways to control the disease. Giving the right treatment is very important. For example, we have learned that if you give bendamustine, then that can mess up your CAR T-cell therapy. Bendamustine kills T cells, so if you kill T cells before you collect them, then those T cells aren’t going to work. Either you won’t have much or if you have enough, they may not be as functional and not be able to do the job.
What is the right treatment to use if you’re planning to do CAR T-cell therapy? There are so many available. Do you want to modify your regimen somewhere so that you can control the disease but perhaps not kill all your T cells before you collect them? Do you want to wait? But if you wait, then the disease may take off and that may not work.
There’s a lot of fine-tuning involved, so the team together with the patient decide what’s best. We try to do this in a really timely manner. We coordinate very well with all our regional sites within the Levin Cancer Institute as well as beyond.
The bigger challenge is those who live far away. Do they want to come to Charlotte to get CAR T-cell therapy or would they rather not do it because it’s not feasible to come? That’s where eventually having outpatient CAR T-cell therapy done locally comes in and having the expertise to manage the side effects if they happen.
We have more CAR T-cell therapy centers today than two years ago. I hope it keeps getting better and better so that more patients all over get access to this treatment.
We also don’t want to have the treatments in an environment where there isn’t the expertise to manage the side effects because then it becomes very hard. Somebody who came in for a potential curative disorder and perhaps were going to be cured succumbed to the side effect because the team was not able to manage them. That wouldn’t be right either.
The other part of it is coming up with protocols to lower the incidence of side effects without compromising efficacy. This is where the clinical trials of some of the products that have less CRS and less ICANS come in. Not zero, unfortunately. I don’t think we’re going to get there.
Infections can be there, but we know how to manage them. Please communicate quickly so that they can be managed appropriately.
Dr. Nilanjan Ghosh
Robyn: Zero is impossible. What if there are trials at Memorial Sloan Kettering in New York or MD Anderson in Texas? The idea is that people can follow up with their local oncologists.
Dr. Ghosh: After the CAR T-cell therapy. It’s a one-time treatment.
Robyn: That’s what happened in my case. Sometimes you have to go somewhere else for treatment or to join a trial and then do follow-up blood work and scans locally to make it more convenient for the patient.
Dr. Ghosh: The most important thing for CAR T-cell therapy is that there are two side effects that can persist after being discharged.
One thing to watch out for is low blood counts, which is an important one and can persist for a little bit of time. For the most part, that’s because of the lymphodepleting chemotherapy given prior. But sometimes, if patients have had many prior treatments, low blood counts can also be because now they’ve developed MDS (myelodysplastic syndrome) or a pre-leukemia situation.
It’s important to pay attention to the low blood counts to see if it’s getting better or persisting for a very long time, then looking at the bone marrow to see if they have developed something else because there are other reasons for low blood counts other than CAR T-cell therapy.
Second is infection risk. CAR T-cell therapy takes out the B cells because normal B cells also express CD19. You can check immunoglobulin levels and give IVIG. Vaccine responses also go down, so if someone had a vaccine for flu or COVID, they may not be able to respond well, so people become prone to infections.
Patient education is very important as well as letting your doctors know. I always advise patients that if they have a cold or something, reach out to their doctors first. Many times, we would react to it faster. We won’t give a Z pack for a cold. We’ll get them in, get a swab, check what virus is there, and check the immunoglobulin level.
Give them antivirals, if antivirals are available. Give them IVIG, if the IgG is low to help them overcome that infection. Get some imaging needed to see if there’s pneumonia. When the immune system is low and you get a virus and sit on it for some time taking an antibacterial, which is not going to work because it’s not a bacterial infection, it can get worse.
We educate our patients that infections can be there, but we know how to manage them. Please communicate quickly so that they can be managed appropriately compared to some other person who is not as immunocompromised.
Final Takeaways
Robyn: This has been a great discussion. If there’s something you would like to tell the people about diffuse large B-cell lymphoma and follicular lymphoma, treatments, and the future, what final statements would you like to give?
Dr. Favaro: There is so much to learn for patients and doctors. These new treatments come out and it’s our job to learn about them. CHOP came out in 1976. It was our job to learn how to give it and also how to manage any side effects that come up. That’s the same with CAR T-cell therapy.
Quite frankly, 4,000 papers come out every day in health care. There’s a ton of information coming out. We are constantly learning and educating patients about these new treatments.
The cooperation that we have as a community practice with academic centers is very important. When we see patients who need CAR T-cell therapy, we refer them and take them back to help manage potential side effects. The technology that’s advancing to make these treatments less toxic is key. We used to have to admit patients overnight for epcoritamab, for BiTE therapy; now we can do it all as an outpatient. That’s the type of thing that’s happening on a daily basis.
Physicians will never go away. We are here because we know you. We take care of you as a person, but we are going to see more and more about artificial intelligence coming into health care. It’s happening. We do need to look at that and embrace that.
Somebody comes in with lymphoma. What should their treatment be? There are so many different factors: age, personal health, disease, potential treatments, and side effects. It takes a good physician to understand the data. But over time, there probably will be the development of assistance to doctors with artificial intelligence and neural networks that I think will help. There are journals about AI in oncology and I think this is going to be the future for health care as well.
Dr. Bano: None of us in medicine work in a vacuum. It’s a concerted effort getting these patients to the most advanced treatments out there. In the community, our responsibility is to know that these even exist and to maintain that chain of communication with the academic centers to get our patients the care that they need, but we always serve as home base. We give patients the feeling that, yes, we’re sending you away, but you’re always going to come back and we are here to take care of you for years to come.
It’s always been a great collaboration between community and academics, getting that relationship established, and always having that chain of communication to ask questions and get opinions. It doesn’t always have to be advanced therapy. Sometimes you get a challenging case that you want to discuss with someone who has seen something like this before.
It’s very exciting to see what’s on the horizon. It’s exciting to see what we can do for our patients. It’s a learning process. Every day, we learn something new.
In the community, our responsibility is to know that these even exist and to maintain that chain of communication with the academic centers to get our patients the care that they need, but we always serve as home base.
Dr. Kulsum Bano
Dr. Ghosh: I cherish the community-academic partnership. I’ve cherished that over the years. That helps patients to get their treatment locally but also get access to a specialist who treats that disease. When I started, lymphoma treatments were not as effective but were simple. You get the first line, another option for the second line, then after that, there were 1 or 2 options and that’s it.
Now, there are a lot of options. When you have so many options, each with their unique side effects and sequencing is not worked out, how do you know which is best for you? There are so many intricacies. If you use this, then the next treatment could be a problem.
Trying to find the right option, keeping abreast of what comes out, and keeping pace with how this is moving along can be challenging. That’s where the academic-community collaboration can be very good. Patients can always go back to the community to get their treatments, have access to a new clinical trial or the latest treatment, and have really good care.
I encourage participation in clinical trials, knowing that these are ethical and vetted by institutional review boards. That is how we have come to where we are and I hope that we get into more chemo-free treatment options.
Some chemo is still very effective. I would not say anthracyclines have saved many lives. They have been around for 50 years, but if we can achieve our goal with less toxicity and by harnessing the immune system, that would be fantastic.
Robyn: I’m honored to be here. Shout out to The Patient Story and the unique ability of patients to get their voice out and for people to do their research online. As a physician and a former patient, it’s very important to be your own advocate, to research, to ask questions, and to keep your mind open. Sometimes clinical trials are the best treatment, so do consider them.
Consult with your doctor. It’s okay to get a second opinion at some points. Medicine has come a long way. When I first started, there was not much available. The survival rate for non-Hodgkin’s was about 30-40%.
I hope that everyone gets treatment and gets in remission like myself. At that point, you need to live your life. Enjoy your family, travel, work, stay healthy, and exercise. Don’t let cancer define you. It’s part of you, but there’s much more to you, so enjoy life.
You need to be your own advocate. If you feel like something that’s been recommended is not working for you, you have all the right to get a second opinion.
Dr. Kulsum Bano
Q&A
Getting a Second Opinion
Robyn: Joan asks, “What is the polite way to get a second opinion without being rude?”
Dr. Bano: Very rarely are there egos in medicine. As a physician, you try to make the best decision for your patient knowing that there may be something out there that is newer or better. Everyone is entitled to a second opinion and that’s how we learn more.
If somebody comes back to me with a different treatment approach and says somebody else recommended this, that’s something I would definitely encourage. You need to be your own advocate. If you feel like something that’s been recommended is not working for you, you have all the right to get a second opinion. You’re not being rude at all. You’re entitled to that and it’s actually encouraged if that’s what you feel is right for you.
Robyn: I agree. Even in radiology, we get asked for second opinions all the time. Doctors are human. We are not perfect. We can look at the same case and have different opinions. We’re not insulted. We’ve all been trained to work together and I would say that happens 99% of the time. There are always exceptions.
If you look at the commonly used CAR T-cell therapy, the complete response rate is much higher than the complete response rate for epcoritamab.
Dr. Nilanjan Ghosh
Epcoritamab vs. CAR T-cell Therapy
Robyn: Don asks, “I’m on epcoritamab. We considered CAR T-cell therapy, but wouldn’t be able to provide the 24/7 care required. So far, it’s working very well. How does it stack up compared to CAR T-cell therapy?”
Dr. Ghosh: They have never been compared head to head, so there is currently no clinical trial which takes half the patients and gives them epcoritamab and half the patients get CAR T-cell therapy. The best way to compare two groups of patients is if they were randomized on a clinical trial, had similar characteristics, and then followed over time to find out the effectiveness of one versus the other.
If not, you’re comparing across trials and when you do, it’s flawed because the patients who went for epcoritamab may have very different characteristics than the patients who went for CAR T-cell therapy. In fact, many patients who went for epcoritamab on a clinical trial already had CAR T-cell therapy, so how could you compare the effect of CAR T-cell therapy with a drug used for post-CAR T-cell therapy failures?
Having said that, we are left with no choice but to compare across trials. I will say that if you look at the commonly used CAR T-cell therapy, the complete response rate is much higher than the complete response rate for epcoritamab. Epcoritamab is around 40%. CAR T-cell therapy complete response rates are usually in the 50s to 60s.
That being said, it comes down to the 40% number because even if CAR T-cell therapy gets a higher complete response, some people will start relapsing despite getting a complete response. We know that with CAR T-cell therapy, about 35 to 40% people will have long-term remission.
We don’t have long-term data yet with epcoritamab. The complete response rate is 40%, but some of those will progress over time. We don’t know whether it will go down to 30% or 25% as we go up to five years, but we will find out over time.
At this point in time for DLBCL, we feel that CAR T-cell therapy is better, but if it’s not feasible, bispecific antibodies would be the next best option. The important thing is: are you getting complete remission or not? If it’s complete remission, we see long-term sustainability. If it’s not complete remission, then we start seeing early progression.
Epcoritamab is targeting CD20 and CAR T-cell therapy is targeting CD19 — two very different ways of attacking the lymphoma. CAR T-cell therapy is still a great option for those who choose epcoritamab for whatever reason.
Dr. Justin Favaro
Dr. Favaro: Another point is that a lot of patients on the epcoritamab trial had CAR T-cell therapy before. If you have somebody who’s never had CAR T-cell therapy and you had the option of CAR T-cell therapy or BiTE therapy, which one do you choose if you’re eligible for both?
It comes down to logistics and what’s going to be a good fit for you. Keep in mind that if you would need CAR T-cell therapy later, you can still get it because a study at ASH 2023 showed that if even if you had BiTE therapy before, you’re still eligible to get CAR T-cell therapy later.
Epcoritamab is targeting CD20 and CAR T-cell therapy is targeting CD19 — two very different ways of attacking the lymphoma. CAR T-cell therapy is still a great option for those who choose epcoritamab for whatever reason. You can still have a great outcome. It doesn’t necessarily matter how you sequence it.
The hope is that whatever treatment you’re getting works for you and you won’t need anything else. But if you do, there are options available and there will be even better treatments in a few years.
Dr. Nilanjan Ghosh
Robyn: If for some reason this doesn’t work and you decide to get CAR T-cell therapy, a lot of the hospitals have come a long way with helping people get 24/7 care. There are options. Hopefully you won’t need them since epcoritamab is working well, but know that there are things that the hospitals are now aware of and they’re trying to assist patients with those.
Dr. Ghosh: There are many devices coming out for 24/7 monitoring, especially in the outpatient setting. Companies are coming up with devices to monitor your oxygen level, heart rate, and temperature then feed them back to the electronic medical record and create alerts. At least from the standpoint of vital sign monitoring, people are trying to overcome this barrier.
Understand that 24/7 support, even if it is for a short time, is a lot for a caregiver, especially if the caregiver has to work. You can rotate caregivers. You don’t need to have just one. Most places will allow multiple caregivers.
Epcoritamab is a good option if you’re not able to do CAR T-cell therapy. You can still have very long remission and perhaps not need further treatment ever again. The hope is that whatever treatment you’re getting works for you and you won’t need anything else. But if you do, there are options available and there will be even better treatments in a few years. Maybe allogeneic CAR Ts will hit a big wave. We don’t know yet, but we’ll find out.
Dr. Favaro: That’s the advantage of getting BiTE therapy upfront. If you need something later, it may be a lot easier with a lot fewer side effects and it can be done as an outpatient. With epcoritamab, you can get steroids and don’t need to be in the hospital. As we make more progress with CAR T-cell therapy, maybe we can do that as an outpatient to reduce severe side effects. Sometimes there’s an advantage to waiting as the technology advances.
Dr. Ghosh: If it’s accessible, knowing the track record of CAR T-cell therapy and that now we have five-year data, we still like to sequence CAR T-cell therapy before bispecific antibodies. Over time, we’ll find out if things change and do it in reverse.
Remission After Bendamustine & Rituximab (BR)
Robyn: Diana asks, “What is the median length of remission after the first B&R treatment”
Dr. Ghosh: For which disease?
Robyn: I would assume it’s follicular lymphoma, but we don’t know what stage. Let’s assume it’s stage 2.
Dr. Bano: If it’s stage 2 follicular lymphoma, generally you have a sustained response after B&R treatment. We’re looking at about five years or so. We need more information to answer that question appropriately.
Dr. Ghosh: It may also depend on whether rituximab maintenance was used. It could be a little bit different with maintenance versus without. I’ve even seen patients who are 10 years out after bendamustine and have not relapsed. Some people will relapse, so it’s a whole spectrum.
There are treatments now that will attack both follicular lymphoma and the transformed lymphoma, so sometimes you want to harness that.
Dr. Nilanjan Ghosh
Possibility of a Repeat Transformed Follicular Lymphoma (tFL)
Robyn: “If you have follicular lymphoma that transformed into diffuse large B-cell, went into remission after treatment, but a few years later, the follicular lymphoma came back, what is the probability that this will transform again?”
Dr. Ghosh: With indolent follicular lymphoma, there’s a small percentage of transforming every year. As more years go by, that risk accumulates. If it’s already happened, will a second transformation happen? It’s possible, but the likelihood goes down because it’s a random event.
Is it a relapse of the previously transformed follicular lymphoma? That’s hard to sort out, but usually what happens with the transformed disease, if the transformed disease has been in remission for a long time, that’s an aggressive lymphoma and usually, aggressive transformers respond well to whatever the treatments were given to them, especially since long-term remission was achieved.
The likelihood of what comes back is often the indolent lymphoma and we see this sometimes with transplant. I had a patient who had follicular lymphoma, had treatment, had a relapse of the follicular lymphoma, had another treatment, then her lymphoma transformed, and we gave her transplant for that. Years later, the aggressive transformed lymphoma went away and she had a relapse again, but this time, it was back to follicular. The aggressive lymphoma never came back. What we did at the time was CAR T-cell therapy for the follicular lymphoma.
There are treatments now that will attack both follicular lymphoma and the transformed lymphoma, so sometimes you want to harness that. For example, axi-cel is approved for follicular lymphoma and for DLBCL. When you use a treatment like CAR T-cell therapy, you are basically killing both. Ultimately, it’s all coming from one B cell. It may be transformed, but if you attack that B cell clone, then both the low-grade and the high-grade can go away. Similar with bispecific antibodies. They attack both. Many of the treatments we use now, especially some of the more modern treatments, have activity against both follicular lymphoma as well as the transformed component.
The fortunate part about lymphoma is that you can target lymphoma cells. You will deplete your own B cells, but we can mitigate that.
Dr. Justin Favaro
B-cell-based Immunotherapy
Robyn: “CAR T-cell therapy is a great new treatment, but as I understand, it targets all B cells and not just the cancerous ones, leading to a depleted immune system that can last a long time. Is there any current research on a similar immunotherapy treatment than can identify and attack the cancer cells and not the normal B cells?”
Dr. Ghosh: That would be something we would love to have. We are fortunate that we have been able to identify antigens. Dr. Favaro mentioned those spikes. Imagine if those spikes were not only in B cells but in liver cells, heart cells, and kidney cells, then CAR T-cell therapy would go and kill all of those.
Fortunately, this is what we can get away with as CD19 is expressed only in B cells but not in other normal tissues — not even on T cells or other parts of the immune system. Many other diseases don’t have that. We are starting to work with some solid tumors which have these, but it’s been difficult. Even in diseases like acute myeloid leukemia, you don’t have things that are specific to that cell.
With B cells, you’re more prone to infections, but you can still get IVIG, which is a immunoglobulin supplementation to help reduce your risk for infections. We currently don’t have spikes on the surface of just cancerous B cells but are absent on normal B cells, but that would be something which I hope the future researchers can identify.
Robyn: I believe there are studies that show B cell recovery over time. A lot of people will gradually recover and it doesn’t affect their remission rate. Everyone is unique. Some people with low IgG can get infections, some people do fine. There are patients who haven’t had CAR T-cell therapy who have primary B-cell aplasia and do fine and a lot of them don’t need IVIG. It’s a case-by-case situation. Most people have had some infection, but most people have been fine and living a normal life even without IVIG.
Dr. Favaro: The challenge with the solid tumor CAR Ts that they’re trying to make right now is finding the antigen on the lung cancer, for example, that won’t damage or destroy the lung. The fortunate part about lymphoma is that you can target lymphoma cells. You will deplete your own B cells, but we can mitigate that with prophylactic antibiotics, IVIG if needed, and taking precautions so you can still live your life.
Masking, especially if you’re in a crowded area, and frequent hand washing would be advisable. As more time passes, those restrictions start coming down a lot.
Dr. Nilanjan Ghosh
Post-CAR T-cell Therapy
Robyn: Michael asks, “What are the overall risks as far as activities, food, etc., for post-CAR T-cell therapy patients?”
I have not been avoiding anything for many years, but I’m eight years out at this point. There are initial precautions because a lot of people have low ANC (absolute neutrophil count) and some other depletion.
Dr. Ghosh: Right after CAR T-cell therapy, blood counts are low. Sometimes we even need to give growth factors to improve blood counts. The risk is going to be higher in terms of infections initially than a few months out. If the blood counts recover, especially neutrophil counts, then certain infection risks go down.
B cells always take time to recover. As the lymphocyte count recovery takes longer, your immune system is compromised and that’s where the possibility of viral infections happen. Masking, especially if you’re in a crowded area, and frequent hand washing would be advisable. As more time passes, those restrictions start coming down a lot.
Ultimately, you have to live your life, but still be cautious. If you do get an infection, then alert your providers so they can do some tests to find out if it’s a mild infection or something that needs to be worked up or treated.
In terms of food, you have to take certain precautions in terms of raw food while your neutrophil count is low, but that typically happens in the immediate post-CAR T-cell therapy phase. As more time goes, those usually are not an issue.
Robyn: You need to have a team take care of you. Your oncologist will move out of your realm because they have people who are very sick to take care of. I do encourage everyone to get an internist or an immunologist who can take care of the day-to-day.
Second CAR T-cell Therapy
Robyn: “Does CAR T-cell therapy work a second time if it didn’t keep the complete response the first time?” Can you have a second CAR T?
Dr. Ghosh: Not commercially. CAR Ts are approved once in the commercial setting, but we have clinical trials which will allow a second CAR T. For example, there’s a clinical trial using natural killer cells that are modified to become CARs or chimeric antigen receptor expressing cells. In that clinical trial, we allow patients who have had a commercial CAR T but it failed. Some of the allogeneic CAR T-cell therapy trials will allow patients who have had a previous CAR T-cell therapy.
There are other CAR Ts coming out. For example, we have a CD19/CD20 bispecific CAR T trial, which we are about to open. In that clinical trial, if someone had commercial CAR T, that is probably not allowed because the CD19 CAR T had already failed. But let’s say you have another clinical trial targeting CD22 and people have had the traditional CAR T, now you are using CAR T again but it’s different spikes. If you’re going against a different spike with a clinical trial, that would be doable. But if it’s the same one, then likely not.
The second time will be in a trial unless a CAR T-cell therapy gets approved that allows previous CAR T treatments.
Newer Monoclonal Antibodies
Robyn: Mike asks, “I’m still unsure about some of the things I’ve heard more recently because I don’t know if I have access to them. What about newer monoclonal antibodies? Do they still play a role?”
Dr. Favaro: There are definitely other options out there. Monjuvi is a monoclonal antibody against CD19 that has been looked at in relapsed lymphoma in combination with lenalidomide. Loncastuximab, which is one of these antibody-drug conjugates, is an anti-CD19 with a chemotherapy payload. It’s going to attach to your CD19 spike and internalize the chemotherapy right into that cell. It’s given via IV every three weeks.
These are two really good options for patients who, for whatever reason, CAR T-cell therapy or BiTE are not working or not available. These easily given off-the-shelf and approved by insurance.
When your blood counts are low and you’ve gone through therapy, there’s a risk of fungal infection as well.
Dr. Kulsum Bano
Cannabis & Non-Hodgkin’s Lymphoma
Robyn: “Cannabis and non-Hodgkin’s lymphoma. Are there any benefits?”
Dr. Bano: It’s a question that comes up pretty frequently. There may be some misinformation out there and some misconceptions of prevention of cancer with cannabis, and I don’t think there’s any founded data.
Certainly, people think about it in terms of symptom control. We do have medications that use the cannabinoid derivatives in a medical form, such as dronabinol, that we use for nausea and appetite stimulation for patients who have gone through chemotherapy.
Generally, we discourage smoking of cannabis only because there are a lot of additives that could be associated with it. When your blood counts are low and you’ve gone through therapy, there’s a risk of fungal infection as well.
There’s a lot of unregulated things that we don’t know what we’re dealing with. I don’t think there are any recommendations that can be definitely given. I don’t know that there are benefits per se, but it’s a discussion to have with your physician about what works for you and what doesn’t.
You need a small amount of protein, usually seafood, mostly vegetables on your plate, and some whole grains for carbohydrates. All these things are important.
Dr. Justin Favaro
Keto Diet
Robyn: “Can you speak about the keto diet? Is it effective against cancer? Is it helpful in any way?”
Dr. Favaro: It’s probably the most common question we get as oncologists every day. What can I eat? What should I eat?
My general recommendation is the Mediterranean diet. If you talk to nutritionists and look at the studies, you need several components to your diet. You need a small amount of protein, usually seafood, mostly vegetables on your plate, and some whole grains for carbohydrates. All these things are important.
I believe the keto diet takes out all carbohydrates, so you’re dealing with a lot of protein and a lot of fat. There are downsides of that for the rest of your body. Your cholesterol could go up and that could be damaging to your heart. Your body needs sugar and glucose.
For example, let’s look at a PET scan. What’s lighting up on the PET scan? Besides the lymphoma, it’s your heart and your brain. They need sugar to work. You don’t need sweets all the time, but you need complex carbohydrates. Maybe switch to whole grains and whole wheat pasta instead of white pasta. That’s only a portion of your diet, about 25%. The majority is vegetables and lean protein.
If you look at some of the recent studies that have come out that have looked at who lives the longest with cancer and what diet they follow, the winner seems to be the vegan diet in terms of cancer survival and decreasing risk of recurrence. This is cancer broadly and not lymphoma. But sometimes that’s a hard diet to follow, so a Mediterranean diet is a reasonable diet for most people to follow.
Robyn: Everybody wants control. You want control of your disease.
I have to add: Exercise helps. Studies in breast cancer and prostate cancer — because they’re so much more common and easy to study — showed that even for people who have never exercised before, if they walked 30 minutes a day, they had a longer remission rate and cure rate.
I encourage everyone to exercise. That doesn’t mean you have to do CrossFit because that may lead to shoulder injuries; we see that in radiology. You can do any type of walking or cycling. If you look at other studies, it’s not only the diet. People are active. Get yourself moving.
There have been studies done, not particularly in cancer, that show that insulin resistance is improved with intermittent fasting.
Dr. Kulsum Bano
Intermittent Fasting
Robyn: “Does intermittent fasting help patients with follicular lymphoma or any cancer? Does sugar play any part?”
Dr. Bano: There have been studies done, not particularly in cancer, that show that insulin resistance is improved with intermittent fasting. At any point, when you have dysregulation in your blood sugar control, that tends to lead to other medical complications. There is some role to play in improvement in outcomes. I don’t know that it’s been studied particularly.
Robyn: There are studies with BMI. People who are obese have a higher incidence of all sorts of cancers and have poorer outcomes. There are a lot of reasons for that. It’s multifactorial, but eating healthy and exercise make sense.
R-EPOCH vs. R-CHOP for Triple-Hit DLBCL
Robyn: “Is there any strong evidence that R-EPOCH is better than R-CHOP for triple-hit diffuse large B-cell?”
Dr. Ghosh: This type of aggressive lymphoma is one of the most aggressive variants. R-EPOCH is still considered as the standard of care for this disease based on a lot of retrospective data. There is no clinical trial taking patients with double-hit or triple-hit lymphomas and giving half of them R-CHOP and half of them R-EPOCH.
However, there was a large clinical trial which took all patients with diffuse large B-cell lymphoma and gave half of them R-CHOP and half of them R-EPOCH, and R-EPOCH was not shown to have a better efficacy. They were similar, but it was not really better.
That study was inconclusive in terms of the improvement for double-hit patients. If you ask most doctors, double-hit patients will still be getting R-EPOCH because there’s a lot of good retrospective data showing better long-term responses with R-EPOCH compared to R-CHOP.
We have an ongoing study where we are monitoring different types of cells post-CAR T-cell therapy.
Dr. Nilanjan Ghosh
Patient Group That Benefits More from CAR T-cell Therapy
Robyn: John asks, “We’ve talked about complete response rates and durable remission rates following CAR T-cell therapy. With the much larger patient population, have you seen any trends emerge as to which patients tend to do better in terms of a better response rate, a better complete response rate, as well as a more durable remission with CAR T-cell therapy?”
Dr. Ghosh: People have tried to figure it out. Before you start any treatment, you want to know if this treatment is going to give long-term remission for this person versus someone else. We are not there yet, but we have some ideas. It’s not perfect.
With CAR T-cell therapy, we know that if someone has very bulky disease and fast-growing bulky disease, CAR T-cell therapy will not give great outcomes. Unfortunately, nothing else does so people still go for it, but sometimes you want to debulk while waiting because CAR T-cell therapy is a weeks-long process.
For example, if there’s one site of bulk, we often can do radiation. There are new radiation techniques. One is called “boom boom” where short, very effective radiation is done to shrink the tumors, perhaps even express all these antigens, and have a better kill.
Bulky tumors can often cause T-cell exhaustion quickly so if they get overwhelmed with the tumor, then those T cells can get immune tolerance. There is also a subpopulation of these T cells that can cause immune suppression.
We have an ongoing study where we are monitoring different types of cells post-CAR T-cell therapy and checking them multiple times to see if we can identify patients who might have relapsed and had one type of immune repertoire versus those who had long-term remission and have a different type of immune repertoire.
We presented the initial data at ASH 2023, but hopefully, we’ll do a little bit more analysis on that and try to understand it better. We have samples taken pre-CAR T-cell therapy to see what may be the characteristics of a person that could predict long-term response.
We also have a study with BiTE. We are doing it for patients who are getting mosunetuzumab. We are collecting samples before and after treatment, and trying to identify which type of T cells may be associated with a better response versus a not-so-durable response.
CLL vs. Follicular Lymphoma
Robyn: Tim asks, “Can you define CLL and how it complements follicular lymphoma?”
Dr. Ghosh: CLL is chronic lymphocytic leukemia, which is under non-Hodgkin lymphoma. CLL is circulating disease in the blood. There is a lymphoma component to it called SLL, small lymphocytic lymphoma. It’s essentially the same disease. SLL is in the lymph nodes, CLL is in the blood. If there are more than 5,000 circulating lymphocytes, then it is a definition for CLL. If it’s below that, it’s called MBL, monoclonal B-cell lymphocytosis.
CLL is an indolent form of lymphoma circulating in the blood but could also be in the lymph nodes, spleen, and bone marrow. Like follicular lymphoma, it belongs to the same indolent non-Hodgkin lymphoma group considered as less aggressive.
CLL has tremendous progress where we have given up chemotherapy, so that’s where it’s a little bit different. You heard about R-bendamustine. We used to use that in CLL. In the past, we used to think we could use the same treatment for all indolent lymphoma.
We have relied on targeted treatment, like BTK inhibitors — ibrutinib was the first generation, then acalabrutinib and zanubrutinib, now pirtobrutinib — and then BCL2 inhibitors like venetoclax (VENCLEXTA). These have all come either in sequence or in combination.
Liso-cel got approved very recently for CLL, so now you have CAR T-cell therapy available as well. Chemotherapy was FCR and BR. We don’t really use those anymore. They’ve been shown to be inferior compared to these newer drugs that we have.
Special thanks again to Genmab, AbbVie, and Incyte for their support of our independent patient education content. The Patient Story retains full editorial control.
Daniella recounts her journey through a stage 2 PMBCL diagnosis. She underwent chemotherapy and CAR T-cell therapy, and ultimately achieved remission. Initially attributing her symptoms to allergies, she experienced a persistent cough that worsened over time, accompanied by night sweats and low-grade fevers. Concerned by her symptoms, she sought medical attention and underwent various tests, leading to a diagnosis of primary mediastinal B-cell lymphoma (PMBCL).
Facing the shock of her diagnosis as a 28-year-old with no prior health issues, Daniella embarked on a treatment journey that included chemotherapy, fertility preservation, CAR T-cell therapy, and radiation. Throughout her treatment, she experienced side effects such as hair loss, fatigue, nausea, and fever, but she found strength in focusing on the present moment and relying on her support system, including family, friends, and medical professionals.
Despite setbacks and challenges, including a bout of COVID-19 and the discovery of residual disease after chemotherapy, Daniella remained resilient. She underwent CAR T-cell therapy, navigating delays and side effects, and ultimately achieved remission.
She acknowledges the ongoing emotional and psychological impact of her cancer journey, emphasizing the importance of taking things day by day, seeking support, and connecting with others facing similar experiences. As she continues to navigate survivorship, she encourages others facing cancer to lean on their support networks, seek professional assistance when needed, and remain resilient in the face of adversity.
In addition to Daniella’s narrative, The Patient Story offers a diverse collection of primary mediastinal B-cell lymphoma (PMBCL) stories. These empowering stories provide real-life experiences, valuable insights, and perspectives on symptoms, diagnosis, and treatment options for cancer.
Name: Daniella S.
Diagnosis:
Primary Mediastinal B-Cell Lymphoma (PMBCL)
Staging:
2
Initial Symptoms:
Prolonged cough
Low-grade fever
Night sweats
Treatment:
Chemotherapy (R-EPOCH)
Radiation
CAR T-cell therapy
This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.
I grew up in the Tri-State area. I work for a large communications firm in New York City and live in Jersey City with my fiancé and dog.
Pre-diagnosis
Initial Symptoms
The journey started in the summer of 2022. It began with a tickle in my throat, which was very vague, and I attributed it to either allergies or the dry air in my apartment.
After a while, that tickle turned into a cough, which didn’t go away. After a few weeks of having that cough, I decided to go to urgent care. They thought I had bronchitis, which I thought was likely. I figured whatever I had probably turned into bronchitis. I was working a very high-paced job, was very career-oriented, and dismissed a lot of my initial symptoms.
The doctor said it was the night sweats that concerned him the most. I don’t think that he thought of a potential cancer diagnosis because I was otherwise healthy.
Symptoms Worsening
My symptoms got worse. When I went to urgent care, I was diagnosed with bronchitis and they treated me with steroids. My cough improved, which was great, but when I went off the steroids, my cough came back immediately. I went back to urgent care and they thought I had pneumonia.
The cough lasted four weeks before I thought it seemed like a long time to be going through it. I also started to develop a low-grade fever in the evenings. Even further along, I started to have night sweats, which I later learned was one of the symptoms of lymphoma.
The night sweats became apparent to me because they came with low-grade fevers. That’s when I thought I needed to see a doctor urgently because I knew that I was sick.
The doctor said it was the night sweats that concerned him the most. I don’t think that he thought of a potential cancer diagnosis because I was otherwise healthy. He was ticking off other things that it could be, but he called out the night sweats as concerning.
The night sweats got progressively uncomfortable to the point where I was waking up in the middle of the night to change my clothes. But I attributed that to some infection that had gone on for too long and now becoming severe. I didn’t even consider cancer.
My mom pushed me to ask for a chest X-ray from the urgent care doctor. The radiologist thought it was pneumonia, but the doctor scared me when I was told that it could be tuberculosis. I decided to get a second opinion.
Getting a Second Opinion
I sent the X-ray to my cousin, who’s a radiologist. She said the X-ray would be a lot worse if I had pneumonia. She pushed me to get a CT scan. I went to my primary care doctor and got a CT scan, which immediately revealed a large mass in the center of my chest.
My cousin prepared us for the different possibilities, but it was still very much a shock.
Diagnosis
This was something that we were anticipating at this point. My cousin prepared us for the different possibilities, but it was still very much a shock. I was an otherwise healthy 28-year-old with no prior history of anything and no history of lymphoma.
My primary care doctor asked me, “Do you work around any chemicals?” I said, “Unless you’re talking about the chemicals from the New York City subway, I don’t. I work in an office. I work on the computer.”
It was a huge shock when I was initially diagnosed. Upon receiving the results of the CT, we immediately went to the ER. From there, the process started in terms of finalizing my diagnosis.
Reaction to the Diagnosis
It was a crazy out-of-body experience for me. I would say I was somewhat primed for it. I was with my fiancé at the time, but I don’t know how primed he was for it. I remember seeing his face and the color draining from it. I immediately had an out-of-body experience and emotionally shut down in a way.
I knew that I needed to go to the ER so I didn’t have time to process what it all meant. The moment I received the news, I was shaking.
From that point on until the day I heard I was in remission, every moment of my life was lived minute by minute. I remember thinking to myself, I’m going to the ER. I’m going to the front desk. I’m telling them what’s going on. I’m sitting in my chair, waiting. They’re going to take me back to the ER.
I was living moment to moment, doing my best to not anticipate what was next. My life went from everything being planned to getting through by the minute, by the hour, or by the day. It was a big mindset shift for me.
In the initial moments of my diagnosis, I distinctly remember thinking that this couldn’t be happening to me. This is too insane. I was supposed to get married in seven months.
I thought that I couldn’t do this. I have an extreme fear of needles. How am I going to make it through knowing that they’re going to need blood work? I actively avoided needles for a long time and any blood work that wasn’t necessary. That’s how bad my phobia was so that was one of the main things that I discussed with everybody because that was tough for me.
The interventional radiology team that did the biopsy was wonderful in keeping me calm throughout the process. They were so confident in what they were doing that it made me feel more relaxed and very well taken care of.
Doing the Biopsy
I was admitted upon going to the ER. They had my CT results. From there, there were various consultations with doctors and potential surgeons to understand what we should be doing about the mass, considering that it was pushing on my chest and my heart, causing me to cough and some fluid to build up in my lungs. There was a lot of discussion on what we should be doing at this point.
They ultimately decided that they didn’t need to do anything urgently, but they scheduled a biopsy for me. They went back and forth to decide what type of biopsy to do. Ultimately, they went with a needle biopsy to get pieces of the tumor in my chest to be able to do the diagnosis and staging.
They wanted to do the biopsy before the weekend. I wanted to be knocked out during the whole process, but unfortunately, I had breakfast that morning before I knew that they were going to do the biopsy. To do the biopsy under anesthesia, I wasn’t supposed to eat, so they had to do the biopsy while I was awake. Luckily, they gave me lorazepam (Ativan) via IV so I was able to calm down before the biopsy.
Honestly, that experience went well and opened my eyes to a lot in terms of how this medical process works. The interventional radiology team that did the biopsy was wonderful in keeping me calm throughout the process. They were so confident in what they were doing that it made me feel more relaxed and very well taken care of. It was the first procedure that happened to me in my journey that made me feel like I could do it. That was the first moment of encouragement for me, knowing I could get through this.
Additional Testing
Following the biopsy, I had to have additional CT scans of my head, neck, and stomach. I also had to have a bone marrow biopsy to confirm the staging to see if the lymphoma was anywhere else.
The bone marrow biopsy was done under anesthesia. I was a little sore afterward and a little nauseous from the anesthesia, but otherwise, it was fine.
Getting the Official Diagnosis
After all of that testing, I got my final diagnosis a few days later. It was confirmed that I had stage 2 PMBCL or primary mediastinal B-cell lymphoma.
I started the fertility preservation process while I was still in the hospital.
Fertility Preservation
I was lucky to be able to do fertility preservation before starting chemotherapy, which I realized after my treatment was very rare. There were a lot of things that lined up that allowed me to do fertility preservation.
The fertility clinic is inside the hospital. When I was diagnosed, they kept me in the hospital for 10 days while they were doing all the procedures and monitoring. During that time, my doctor consulted with the fertility doctor at the clinic and she was able to come down to see me and talk to me about my options.
I started the fertility preservation process while I was still in the hospital. Had the clinic not been in the hospital building itself, they probably wouldn’t let me be discharged to undergo fertility preservation. When I decided to move forward, I was able to go to the clinic and do the tests that they needed. Otherwise, I don’t know if they would have let me so I was very fortunate in that sense.
Honestly, it took me a while to figure out that this was even going to be a part of the journey, but upon hearing what my options were, I was firm in my decision. That being said, I was also very scared because I knew it involved a lot more needles. Of course, that wasn’t fun, but I was no longer operating in what I wanted, but more so what I needed to do.
I went to the fertility clinic every day for blood work. They would monitor me and how my eggs were growing because they gave me hormones to stimulate my eggs so they could retrieve them.
I was doing hormone shots in the evening and going to the clinic so they could check on how my eggs were growing. After the clinic visit, I would go down to the cancer clinic where the doctor would check me. They were afraid that my cancer would grow since it’s a very aggressive lymphoma, that my symptoms would get bad again, and that I would need to start chemotherapy immediately.
I would go to the fertility clinic and then the cancer clinic every morning to see my doctor and get checked out. Then I would get myself an emotional support bagel and lay around all day and think about what was going on.
The fertility preservation process was not that bad. Besides some minor discomfort and minor bloating, it was very manageable.
They were able to retrieve seven eggs. My fiancé and I decided to fertilize all seven eggs in the hope of creating healthy embryos.
Egg Retrieval
Upon my egg retrieval, my doctor warned me that my body was fighting something so there was a chance that they might not be able to get any eggs. I went in understanding that it might not turn out how we wanted, but they were able to retrieve seven eggs. The procedure was done under anesthesia, which was something I was very familiar with at the time. The egg retrieval process itself was fine.
I had the egg retrieval done in the morning. I was out of there probably by noon or 1 o’clock. After they did the retrieval, they brought me to the recovery area. When I woke up from anesthesia, they wanted me to walk around a little bit before sending me home. That evening, I was admitted to the hospital for my first round of chemotherapy.
Embryo Freezing
They were able to retrieve seven eggs. My fiancé and I decided to fertilize all seven eggs in the hope of creating healthy embryos because that’s what my doctor recommended. If I were to freeze seven unfertilized eggs, they might not survive the thawing process. Embryos are a little more robust. They’re a little tougher so my doctor recommended trying to fertilize all seven eggs.
We had to wait a few days to find out how many of those eggs were fertilized and how many of those fertilized eggs turned into big enough embryos for us to freeze. We ended up being able to freeze five embryos, which is pretty good when you consider that we fertilized only seven eggs to get five good-quality embryos. That was a success.
Truthfully, I was so happy with how the experience went. Knowing that I had five embryos in storage was a big motivator for me and gave me a lot of hope that even beyond surviving cancer, I would still be able to have a family. I was thankful to be able to have that possibility.
If your fertility doctor can talk to your oncologist and make a plan, there can be workarounds that would allow you to do it.
Everybody’s scenario is different, but if it’s important to you, definitely explore every resource and avenue that you can to do it. It’s not easy, but it’s not too difficult if you want it and if it’s really important to you.
I’m a huge proponent of doing everything you can, advocating for yourself, and asking how you can get fertility preservation done. If your fertility doctor can talk to your oncologist and make a plan, there can be workarounds that would allow you to do it.
I had to be on blood thinners during the whole process. I gave myself blood thinner shots every morning while going through fertility preservation. My doctor was afraid that I would develop blood clots, especially considering the hormones. There were risks, but there are also ways to mitigate those risks and work around them. Advocate for fertility preservation, if it’s important to you.
Treatment
Discussing the Treatment Plan
Everything was moving pretty fast. I celebrated my birthday in the hospital. I was diagnosed on September 29th and turned 29 on October 1st, which was a very surreal experience to celebrate my birthday in the hospital during this time.
My doctor was very communicative about my treatment options, even though we were still confirming what type of lymphoma I had and what the staging was. He went through the options of either doing R-EPOCH chemotherapy or R-CHOP chemotherapy, both of which are similar to each other.
R-EPOCH is what he was leaning towards. He explained that R-EPOCH was going to be done inpatient at the hospital for five days. I would get chemo for five days, wait for three weeks, go back for the next round, and do that cycle for six rounds. R-CHOP would be outpatient.
After receiving my diagnosis, he said that I was going to do six rounds of R-EPOCH chemotherapy, which equated to about six months of treatment. I would be in the hospital receiving chemotherapy, come in to see him a few days later, and then two weeks after that, be back in the hospital for my next round of chemo.
The anticipation of side effects was worse than any side effects that I felt. I had a lot of anxiety about what I would feel and what I would be going through.
Side Effects of Chemotherapy
My oncologist explained what I could expect from the chemo, the first one being hair loss. He noted that I would be fatigued and that I could be nauseous. He was very good. He wrote down everything for me. He also drew pictures of where the lymphoma was. It was very helpful in those moments for him to write everything down for me.
He explained to me that I should expect to feel pretty crappy the week after chemotherapy and have a good week during that second-week break before I would be in for my next round.
The anticipation of side effects was worse than any side effects that I felt. I had a lot of anxiety about what I would feel and what I would be going through, but none of my worst nightmares came true except one.
The side effects were quite manageable. The hair loss was something I knew was a given upon diagnosis, so I tried my best to not focus on it. I didn’t want to give the thought of losing my hair power. What I was most concerned about was losing my eyebrows, which was tough.
After the first round of chemotherapy, I started to lose my hair, which was traumatic — I don’t think there’s any way that it can’t be. I cut my hair short before starting chemotherapy with the hope that it wouldn’t be as apparent when it did fall out, but it fell out in clumps in the shower. It was constant. I woke up with hair on my pillow. It was very hard to go through that process.
Once I was able to shave my head, it felt so much better because then I wasn’t constantly dealing with hair falling out in clumps. I bought a lot of head wraps and wore a lot of beanies. I was going through treatment during the winter time mainly, so I was able to do that. I tried to not give it so much power and kept telling myself that it would come back.
The side effects compounded as I got more and more chemo. As I went through the rounds, the side effects got a little tougher.
I struggled with fatigue and some nausea. The nausea wasn’t overwhelming and I was able to take ondansetron (Zofran) to handle it, but it was mainly overwhelming fatigue and an overall feeling of malaise. I would explain to my friends that it was like a bad hangover, a feeling of not having any energy and can’t get out of bed.
I stayed with my parents because they lived close to the hospital. There were days when I only stayed on one floor because I was afraid that if I went down the stairs, I wouldn’t have the strength to come back up or I would lose my balance.
There was always a general feeling of unwellness between cycles. My body would rebound in the last week and I would start to feel a little bit better and have a little bit more energy.
The side effects compounded as I got more and more chemo. As I went through the rounds, the side effects got a little tougher. Overall, I considered myself pretty lucky in the way that my body was able to handle all of the chemotherapy.
I had to deal with one bout of COVID during my second cycle of chemo, which was awful. My symptoms weren’t awful, but getting COVID set off a bunch of logistical headaches with my chemotherapy that were tough to deal with and manage. I had to advocate hard for myself. That was a tough roadblock, but we got through it.
Post-Treatment Scans
I finished treatment in February 2023. We were feeling very confident about how things were and how the treatment went. I had a good midway scan. They saw that the mass in my chest was shrinking a lot. Everything was moving back into place, as my doctor said. Things were clearing up so it was a good sign that the chemotherapy was working, which was great.
When I received the news that there was still residual disease, that was truly crushing not only for me but for my family and my fiancé who were on their own journeys considering my cancer diagnosis.
I had to wait a month after I finished my last day of chemotherapy to have my last PET scan where two spots lit up. That was tough because we weren’t expecting it. There’s a 50% chance there could be inflammation and a 50% chance that it could be residual disease.
We had to do another biopsy, which was a little bit more invasive. They put me under for that one because they needed to get samples to see if it was residual disease, which it was.
Truthfully, those weeks were the toughest. After my diagnosis, I was able to tell myself that it was just six months of my life. I was going to be able to get through this and then everything’s going to go back to normal. I was going to get my life back. That’s what got me through the six rounds of intense chemotherapy, saying that it was only six months and that I could do this.
Since I had residual disease, I was going to be on this ride for a lot longer and I didn’t know what to expect. My doctors were very encouraging. Considering that I was so young, didn’t have a prior history, could handle the chemotherapy, and that it would probably work, I had a good chance of being cured.
We were holding on to that hope, but when I received the news that there was still residual disease, that was truly crushing not only for me but for my family and my fiancé who were on their own journeys considering my cancer diagnosis. It was heartbreaking news for all of us. There were definitely a lot of tears.
My team very quickly referred me to a larger cancer hospital and connected me with the CAR T team there. They had already gotten the ball rolling for me to do CAR T-cell therapy.
There were a lot of questions about whether or not I needed CAR T-cell therapy or additional radiation to clear up the small spots that were left over. There was a lot of back and forth.
CAR T-cell Therapy
I knew about CAR T-cell therapy because I read stories on The Patient Story about other patients who had lymphoma and have gone through CAR T-cell therapy. I understood the basics and what patients can expect to go through. My family had a lot of learning to do. But again, I was still living moment to moment, day by day. What were the next steps? Who do I need to talk to about CAR T-cell therapy?
While I knew about it, it was still very scary to me. Mentally, I was at a point where I didn’t want more treatment, but, at the same time, I knew that I had to steel myself for additional treatment.
Once I met with my CAR T-cell therapy team, I felt like I was in very good hands. There were a lot of questions about whether or not I needed CAR T-cell therapy or additional radiation to clear up the small spots that were left over. There was a lot of back and forth.
My case was presented to a lymphoma tumor board where multiple doctors weighed in. I also got second and third opinions on CAR T-cell therapy from other oncologists. After speaking to the other doctors, I felt very confident in moving forward with CAR T-cell therapy because there was a consensus that it was the next step for me, with some radiation in between.
Once I knew that CAR T-cell therapy was the best next step, I mentally was ready for it. You don’t have a choice, so you have to be ready. I felt very confident going into it.
All’s well that ends well. I was focused on the mission and the mission was to get my T cells and send them out.
Process of CAR T-cell Therapy
My team went over in detail what the process entailed, so that made me feel a lot better because I was prepared for what to expect. They gave me resources and booklets. They connected me with a resource that will help sponsor hotel stays close to the hospital because you have to stay close to the hospital when you receive CAR T-cell therapy.
There was a little bit of a wait of a few weeks to a month between the first meeting with my team and cell collection day.
The first step is collecting the T cells. They do that by putting your blood through a machine that separates your T cells, which are then sent to the manufacturer of the CAR T that you’re going to be receiving. I received liso-cel (Breyanzi).
If you have good veins, they can do it through the peripheral veins in your arms. I have small veins that are very hard to access, which is why I have needle phobia. They had to put a catheter in my neck. It’s not comfortable. However, I was given lorazepam and I told myself that I could get through this. They put the catheter in my neck specifically for T-cell collection and then immediately after, they would take it out.
We hit our first stumbling block. My neck catheter wasn’t working so they had to stick my veins. Luckily, I had a good team of people who were able to find a vein and complete the T-cell collection.
The T-cell collection day is pretty long. You’re sitting in a chair and can’t move because you’re connected to the machine. My advice is to bring snacks, your tablet or laptop, and be prepared to watch a lot of Netflix. I was living day to day, so I knew I could get through it.
I didn’t experience any side effects after the T-cell collection other than being a little bit tired. During the collection, you might feel that your body or lips are tingling, which has something to do with the calcium level in your body, so they will give you some calcium to help supplement but it’s not uncomfortable or painful. It’s just a weird feeling.
It was a little bit crazy for me but, again, through the journey and the experience, I told myself I could get through this. All’s well that ends well. I was focused on the mission and the mission was to get my T cells and send them out.
[I had] to get special permission from the drug manufacturer to use my T cells, which put my CAR T-cell therapy in jeopardy of being pushed back.
CAR T-cell Infusion
CAR T-cell infusion day came. Unfortunately, there were some delays in the schedule, which was very stressful. The drug manufacturer has to test your T cells. My T cells were considered too robust or too healthy and were labeled as out of range so that required me to get special permission from the drug manufacturer to use my T cells, which put my CAR T-cell infusion in jeopardy of being pushed back.
They were able to have a meeting and they approved for me to use my T cells. But then they were mislabeled so during the shipping process, they had to be sent back and then re-shipped, which was very stressful because my CAR T-cell infusion date was pushed back. I was very worried because this was happening in May. I wanted to at least have a summer and go to the beach so I wanted my CAR T-cell treatment over and done with as soon as possible.
Mentally, I was prepared for the process, but I didn’t prepare myself for the potential setbacks. While that was very stressful at the moment and I advocated a lot for myself to make sure that everything was going to turn out okay, I eventually ended up getting my CAR T-cell infusion done at the beginning of June.
You first receive three days of lymphodepleting chemotherapy, which is a low-dose chemotherapy done in the hospital as an outpatient. I was able to go back to the hotel that I was staying at nearby.
After three days of chemo, they gave me two days to rest before the infusion. I felt crappy after. It made me much more nauseous. I did not feel good. At points, I thought I could faint or lose consciousness. I felt pretty crappy during those two days that I wasn’t receiving anything. They do their best to give you what you need, such as anti-nausea drugs.
When they were pushing the CAR T cells in, I felt a garlicky or cream corn taste in my mouth, which is something that happens.
By the time infusion day came around, I was feeling much better. I went to the infusion center and the CAR T cells were brought in a little cooler. It wasn’t an infusion bag that they held. It was a syringe.
I had a PICC line where they would give me chemo through so they pushed the CAR T cells through my PICC line for about five minutes. They monitor you very closely in terms of your vitals. Beforehand, they pre-medicate you with diphenhydramine (Benadryl) to prevent any allergic reaction.
When they were pushing the CAR T cells in, I felt a garlicky or cream corn taste in my mouth, which is something that happens. It was fine though. I didn’t mind or anything.
Overall, the CAR T-cell infusion was not a big deal. They monitor you for the rest of the day. The infusion itself took less than 30 minutes. They monitored me for a few hours and upon discharge, I went back to the nearby hotel that I was staying at.
You have to come back to the hospital every day for regular blood work. They’ll ask you a bunch of questions because CAR T-cell therapy has two main side effects: cytokine release syndrome (CRS) and neurotoxicity.
CRS is noted by high fevers and other symptoms. Neurotoxicity is when your handwriting gets messed up, you’re not able to answer questions, your speech is jumbled, etc., so they were testing me for those things.
While it certainly wasn’t easy, I wouldn’t say that anything that happened was unexpected. They prepared us for the side effects that I could experience.
Side Effects of CAR T-cell Therapy
When I went into the hospital on day one, I was fine. They did blood work. I looked okay, so I went back to the hotel. I couldn’t be out in public, but we were able to take a walk outside and get fresh air.
That evening, I started to develop a fever, which they expected. I went to the ER and they put me in a room where I spent about five days dealing with high fevers and a general feeling of unwellness. I was weak and tired
My main side effect from the CAR T-cell therapy was on-and-off fever. I received a few doses of tocilizumab, which is what they give to control CRS, and one dose of steroid. The steroid knocked me out. I took the best nap of my life. For four hours, I was finally able to sleep. I was struggling with the fevers so with the help of the medications, I was able to recover.
After five days in the hospital, they were able to discharge me. I went back to the hotel because I still had to be monitored closely before I could be sent home.
While it certainly wasn’t easy, I wouldn’t say that anything that happened was unexpected. They prepared us for the side effects that I could experience. The most anxiety-inducing was waiting, being in the hospital, and not knowing how bad it was going to get.
I remember focusing hard on the tests that they would give me in terms of assessing my mental status because I was really scared that, at any minute, I could be losing it. But they assured me that I would be okay and, luckily, everything was so.
The first thing my fiancé and I did coming from the doctor’s office was go to the beach. It was a wonderful moment and a real first moment of victory where we were able to breathe for the first time in a little bit.
Radiation
After the T-cell collection, I immediately went to radiation, which is a whole other process. They had to do a CT scan of my chest to understand where they had to radiate. They gave me tiny little tattoos that nobody else would notice except me to mark the areas.
During radiation, I was doing breath holds to lift the area that they had to radiate. I needed to lift it away from my lungs and my heart as much as I could so that there was no scatter to my other organs, which is something that they tried to avoid. They want to do their best to radiate just the area that they have to.
The breath holds were tougher than I thought because you have to hold your breath exactly right for them to radiate the exact spots. It felt like a hard yoga class where you have to breathe a certain way and hold your breath. It was tougher than I initially imagined.
I did ten rounds of radiation and ten rounds of radiation with those breath holds made me very tired. Honestly, I wasn’t expecting to be so tired from radiation. Luckily, I didn’t have any other side effects.
Follow-up Protocol
After my CAR T-cell therapy, which was a month total from the time I got my infusion to when I was allowed to go home and started seeing the doctor on a less frequent basis, they determined that I was safe to go home. I took it easy and took things day by day.
I had a PET scan scheduled at the 60-day mark. The results showed that I was 100% in remission. There was no evidence of disease.
The first thing my fiancé and I did coming from the doctor’s office was go to the beach. It was a wonderful moment and a real first moment of victory where we were able to breathe for the first time in a little bit. We were sitting by the ocean, having lunch, and then we saw dolphins jumping. You don’t see that often in New Jersey, so we took it as a good omen for things to come.
It was a turning point and the biggest moment for my mom, honestly, who was my main caregiver during the entire time. She said the last time she was this happy was the day that she gave birth to me, so it was an emotional moment.
I didn’t know who I was anymore. I was still me in many ways, but in other ways, I wasn’t.
Cancer Survivorship
Survivorship is honestly very difficult. In a way, it’s more difficult than going through cancer. Once you’re able to pick your head up, everything else starts to come into focus again. That’s tough sometimes because you finally start to take stock and understand what was lost in a way. For me, a big part of it was my identity.
I didn’t know who I was anymore. I was still me in many ways, but in other ways, I wasn’t. Honestly, I don’t know if I’ve found myself again even at this point, but it’s a continuing journey and I’m still on the ride.
Words of Advice
Honestly, what helped me was taking things day by day, moment by moment, whatever time increment to get through difficult moments. I would tell myself, “I just need to get through these 10 minutes. If I can get through 10 minutes, I can get through 20 minutes. If I can get through 20 minutes, I can get through the next hour.” During those tough times, when I was in pain and wasn’t feeling well, and when I was struggling, that’s what helped me get through.
It’s important to have a good support system. I had a lot of cheerleaders in my corner, mainly my family, my fiancé, and my fiancé’s family. They were there for every step of the way. Being able to lean on those who are there to support you is huge.
If you don’t have people close to you to support you, definitely lean into the resources that are provided to you. There are a lot of cancer centers that provide free social workers for cancer patients. I saw a social worker and she was very helpful. She had a lot of experience and, based on her experience with cancer patients, understood what I was going through. She helped me through some of the tougher moments as well.
Connect with others who are going through the same experience as you. It doesn’t have to happen all at once. It’s certainly a journey. Upon diagnosis, I wasn’t ready to talk to anyone, do anything, or reach out to anyone. But as I went through the process, I became more and more comfortable about reaching out and it was a huge help to me. Don’t be afraid to reach out and ask for help where you need it.
Being able to lean on those who are there to support you is huge. If you don’t have people close to you to support you, definitely lean into the resources that are provided to you.
Role: Hematologist-Oncologist Focus: chronic lymphocytic leukemia (CLL) & leukemia and lymphoma | CAR T, targeted therapy Provider: Medical College of Wisconsin
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Ruth Fein Revell: Hi and welcome to our program, Clinical Trials Update: What to Know in Myelofibrosis Care. My name is Ruth Fein Revell and I’ve lived with a myeloproliferative neoplasm (MPN) for nearly 30 years.
I was diagnosed with essential thrombocythemia in 1995, polycythemia vera about 20 years later, and myelofibrosis in 2018. I’ve also lived with a number of complications from dangerous blood clots and hemorrhages that put me in the ICU to debilitating headaches, bone pain, and extreme fatigue.
I’m a health and science writer and very fortunate to be in a clinical trial for the last four years with amazing results, eliminating my symptoms, and significantly reducing my bone marrow.
I’d like to give special thanks to GSK for supporting this educational program. We want to note that The Patient Story retains full editorial control of this entire program. This is not meant to be a substitute for medical advice.
Joining us is Dr. Naveen Pemmaraju, a top expert in MPNs and myelofibrosis from MD Anderson. Dr. Pemmaraju, it’s so nice to see you. Thanks for joining us and for being a part of this program. Can you tell us more about yourself and what drew you to MPNs?
Naveen Pemmaraju, MD
Dr. Naveen Pemmaraju: Thanks for having me. I’m a professor of leukemia at MD Anderson in Houston, Texas. I serve as the executive director for cancer medicine and as the director for our rare disease program, including blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Ruth: It’s always great to see you and to speak to you. You offer so much to the MPN community and we really thank you.
JAK inhibitors are not JAK2 mutant-specific inhibitors, so that’s why they work in patients whether they’re JAK, MPL, CALR, triple-negative, or have no mutations.
Dr. Naveen Pemmaraju
Standard of Care: JAK Inhibitors
Ruth: We now have four JAK inhibitors and one one of them was just approved. Walk us through this. First of all, how does a JAK inhibitor work?
Dr. Pemmaraju: The basic premise is that MPN cells signal through a specific pathway called the JAK/STAT pathway.
A regular cell uses the JAK/STAT pathway for normal blood cell growth, differentiation, and lifespan. Now take an MPN cell and that pathway is hijacked and used in a malignant way, so those cells keep growing and dividing. It’s like a light switch that’s turned on that doesn’t go off.
Interestingly, the JAK inhibitors are not JAK2 mutant-specific inhibitors, so that’s why they work in patients whether they’re JAK, MPL, CALR, triple-negative, or have no mutations.
JAK inhibitors are based on the principle that the JAK/STAT pathway and the cells are overactive and not working properly. JAK inhibitors aim to block that malignant activity and restore normal growth.
Ruxolitinib was the first-ever approved JAK inhibitor. Since 2011, three JAK inhibitors have been US FDA-approved: fedratinib in 2019, pacritinib in 2022, and momelotinib in 2023. The four currently approved JAK inhibitors have some interesting similarities and differences.
[Ruxolitinib] works very quickly in relieving the symptom burden for our patients with MPNs.
Dr. Naveen Pemmaraju
Ruxolitinib
Dr. Pemmaraju: Ruxolitinib, the first and longest in class, is a JAK1/JAK2 inhibitor. This drug was simply amazing in the original clinical trials, which were COMFORT-I and COMFORT-II, led by Serge Verstovsek and Professor Claire Harrison.
In those studies, we learned a few things about ruxolitinib. One is that it works very quickly in relieving the symptom burden for our patients with MPNs. It can shrink the spleen rather quickly as well, so quickly that the hallmark ended up being at week 24 by six months.
Some side effects to look out for over time in this otherwise well-tolerated drug have been the development in some patients of opportunistic infections, such as herpes zoster or shingles, weight gain, and non-melanoma skin cancers.
Basal cell and squamous cell cancers of the skin are already common in our patient population, so a lot of our patients end up seeing a dermatologist. Most of our patients don’t necessarily discontinue for those side effects, but we need to watch out for them.
All patients who are going to get treated with fedratinib should have their thiamine level checked.
Dr. Naveen Pemmaraju
Fedratinib
Dr. Pemmaraju: Fedratinib improves symptoms and decreases spleen size, but it has a very notable toxicity or side effect, which garnered an FDA black box warning. It’s a very serious potential side effect called encephalopathy. Some have seen it to be Wernicke’s encephalopathy, but on later analysis, not exactly.
Wernicke’s encephalopathy is a name for a syndrome that can cause problems with thinking and even balance and can result from severe nutritional deficiencies. For fedratinib, it appears that it displaces vitamin B1 (thiamine) so what we see is the linking of those. All patients who are going to get treated with fedratinib should have their thiamine level checked because the encephalopathy can be related to that.
Patients can have GI side effects with fedratinib, like nausea, vomiting, and diarrhea, so we have to watch out for that, particularly in our older and more frail patients.
The unique thing with pacritinib is for several years, it was being watched for the development of cardiac and/or bleeding signals.
Dr. Naveen Pemmaraju
Pacritinib
Dr. Pemmaraju: Pacritinib is an interesting agent. Again, all these are trying to hit the JAK/STAT pathway, but this hits other pathways outside of that and that may be part of its benefits and toxicities.
It helps to shrink down the spleen and improve the symptom burden of patients, but the unique thing with pacritinib is for several years, it was being watched for the development of cardiac and/or bleeding signals.
I and others have done a lot of evaluation and analysis, including post-approval. We’re not seeing a high signal for that, but that’s something you have to be aware of if the patient is on a blood thinner, having chest pain, or having heart surgery.
Not only did [momelotinib] show improvement in the spleen size and symptoms, but what’s interesting — and pacritinib is showing this as well — is having an improvement in anemia.
Dr. Naveen Pemmaraju
Momelotinib
Dr. Pemmaraju: Momelotinib is the most recently approved JAK inhibitor. Again, not only did it show improvement in the spleen size and symptoms, but what’s interesting — and pacritinib is showing this as well — is having an improvement in anemia. Now that’s important.
Ruxolitinib and fedratinib don’t necessarily do that and, in some cases, it can make it transiently worse. Momelotinib has ACVR1 inhibition. Pacritinib also showing that as well unleashes a new era for our patients of JAK inhibitors having beneficial side effects, such as improvement of anemia and potentially, thrombocytopenia.
You have to watch out for GI side effects with fedratinib, pacritinib, and even momelotinib. In the earlier studies of momelotinib, there was a signal for peripheral neuropathy. I want to put those forward as an overview. There are some subtleties and differences, if one reads further.
Ruth: Thanks for that explanation. I’ve heard a lot of people say that they have a different mutation, so a JAK inhibitor isn’t going to help them, but we know that that’s not the case, so thanks for your explanation of how they work.
There isn’t a single molecular test. The decision is based on clinical factors and the art of medical decision-making.
Dr. Naveen Pemmaraju
Switching JAK Inhibitors
Ruth: How do you know which JAK inhibitor might or might not work and which one to try first? How is that decision made?
Dr. Pemmaraju: The decision to switch JAK inhibitors is not scientific. We’re not there yet. At some point, I envision that we’ll have a decision tree, like our colleagues in CML. But right now, there’s no molecular test, so it is the art of medicine. It is clinical decision-making.
There are some factors, if one looks up in the NCCN and other guidelines. One is platelet count. Ruxolitinib and fedratinib should be given to patients who have a certain amount of platelets and that’s where pacritinib was able to get its approval.
Pacritinib is specifically approved in the front-line setting for patients whose platelet count is less than 50, for example. The NCCN guidelines and other groups say that once you use pacritinib in later lines, maybe you don’t have to pay attention to the platelet as much, but that’s obviously for debate.
Another factor is the GI signal. If you have someone who has a known encephalopathy syndrome or thiamine deficiency, then fedratinib is not going to be one that you would choose.
Finally, you have to look at some of these subtle side effects that we mentioned earlier, such as GI and neuropathy, to help you choose.
The bottom line is there isn’t a single molecular test. The decision is based on clinical factors and the art of medical decision-making.
Switching can have financial cost repercussions, new toxicities when a patient was otherwise doing ‘okay,’ problems with access to the drug, and could uncover idiosyncratic side effects that may be specific to that patient and weren’t seen in the studies.
Dr. Naveen Pemmaraju
Ruth: So it’s possible that somebody could start on one JAK inhibitor and at some point switch to another. Is that an issue if you change?
Dr. Pemmaraju: This is a great important point about switching JAK inhibitors and what are the indications. There are several buckets here.
First is clear disease progression in terms of the spleen. If you have a patient who’s been on a certain JAK inhibitor for a sufficient amount of time and you have a spleen that previously shrunk but now starting to rise again, that could be considered disease progression and an indication to switch.
Second is worsening MPN symptom burden to the point where the patient’s quality of life is affected.
Third is blast count, peripheral blasts or bone marrow blasts, going up.
Fourth is the progression of the disease to an outright higher level of disease, what we call an accelerated blast phase.
The development of these clinical factors, such as the platelet count, may matter if you have a patient who’s on ruxolitinib, for example, and you consistently have platelets below 50, then that’s an indication to switch, for example, to pacritinib. If you have a patient who has anemia, you may think about momelotinib.
These are some of the reasons to think about switching. But again, there isn’t a molecular test or a definitive moment to switch. Switching can have financial cost repercussions, new toxicities when a patient was otherwise doing “okay,” problems with access to the drug, and could uncover idiosyncratic side effects that may be specific to that patient and weren’t seen in the studies.
Finally, you have a question about withdrawal and overlap, so these are things I think we’ll all work out together over the coming years as we have these JAK inhibitors in the clinic.
The story of JAK inhibitors is an evolving story and it’s evolving at three levels.
First is the science of it alone. In 2005, I was at Johns Hopkins with Alison Moliterno and Jerry Spivak, and I remember the day that the JAK2 mutation V617F was elucidated. From that time to now, we have JAK inhibitors that are amazing, so science is still evolving.
Second is the clinical part, as we’ve discussed. When to switch, how to switch, what are the factors, etc.
Third is the future. How do we combine these drugs with a second agent and potentially a third agent? What are those cross-reactivities? How does that benefit the patient to start those upfront rather than later on? You have this evolving area that’s quite exciting but also quite daunting not only for the patients and the clinic but for researchers.
This is preliminary data, but it was so encouraging that they are now moving on to a phase 3 randomized global study.
Dr. Naveen Pemmaraju
Clinical Trials: Combination Therapy
Selinexor & Ruxolitinib
Ruth: We’re seeing some really exciting updates as far as combination therapy. Let’s talk about clinical trials, starting with selinexor plus a JAK inhibitor and then move on to other combinations.
Dr. Pemmaraju: At ASH 2023, Dr. Sri Tantravahi from Utah presented the first public data of front-line combination, updated I should say, of selinexor with ruxolitinib. This is untreated patients with myelofibrosis, intermediate to high risk, who were given the combination rather than ruxolitinib, which would be considered the standard or JAK inhibitor.
Although it was early on and only a few patients, very surprisingly and amazingly, the group showed that there’s a high rate of activity in spleens being reduced as well as symptom burden being increased.
Now, this is preliminary data, but it was so encouraging that they are now moving on to a phase 3 randomized global study. The combination selinexor-ruxolitinib, so the XPO1 inhibitor plus JAK inhibitor, versus JAK inhibitor alone. Those data will be eagerly awaited.
This is also, if I may say, a fascinating study.
Dr. Naveen Pemmaraju
Navitoclax & Ruxolitinib
Ruth: What about the BCL inhibitor navitoclax?
Dr. Pemmaraju: A second combination is that of the BCL-XL inhibitor navitoclax with ruxolitinib, which I presented as an oral presentation at ASH on behalf of my colleagues. This is also, if I may say, a fascinating study.
We globally enrolled 252 patients into a randomized, double-blind, placebo-controlled study of ruxolitinib plus navitoclax, which is not yet approved for any indication, versus ruxolitinib alone. Again, we had intermediate to high-risk patients, around 80-plus percent of intermediate-2 patients.
What we found is a very outstanding rate of 60-plus percent of patients in the combination arm having an SVR35 at week 24, so spleen volume reduction of 35% or more, versus only 30-plus percent in the control arm, which was ruxolitinib alone. The waterfall plot showed that almost all patients benefited from the combination.
In terms of statistical analysis, the primary endpoint of spleen reduction was met with a high statistical significance, but the symptom burden difference was not yet found to be statistically significant. Both groups had reductions, so there was a numerical reduction of the symptoms in both the combination and the ruxolitinib alone, but there was no statistical difference.
The study is ongoing for collecting for maturity and overall survival duration, so this was a preliminary presentation at 15 months follow-up. We’ll stay tuned to see how it gets updated over the next congresses.
Great safety, but you have to watch out for thrombocytopenia, which is low platelets, and watch for that signal very closely.
Luspatercept & Ruxolitinib
Ruth: Another combination being investigated is the use of a shot called luspatercept to boost hemoglobin or fight anemia, and that also is being used with ruxolitinib. Can you tell us more about that one?
Dr. Pemmaraju: Luspatercept is a fascinating molecule. It’s already FDA-approved in the myelodysplastic syndrome setting. In the MPN setting, we think it has a similar activity to improve hemoglobin and anemia, which is an urgent, unmet medical need.
The initial studies have shown positive data, which is either luspatercept by itself, usually given every three weeks, or in combination with the JAK inhibitor ruxolitinib. Those studies are ongoing and we eagerly await those results in the coming year or two.
When the group looked back at certain subsets, including the intermediate-1 patients and others, it appeared that there was a benefit in both spleen size and symptoms.
Dr. Naveen Pemmaraju
Pelabresib & Ruxolitinib
Ruth: We’ve also had the MANIFEST trial, which is the trial that I happen to have been on for the last four years, and that’s a different drug, s pelabresib. Could you talk about that combination and what you think the potential is?
Dr. Pemmaraju: Another exciting combination presented at ASH 2023 was that of the MANIFEST-2, which is ruxolitinib plus a new agent pelabresib, a bromodomain or BET inhibitor, which is not yet FDA-approved for any indication.
This encouraging data set was presented by Dr. Raajit Rampal from Memorial Sloan Kettering. It’s the second-largest study ever conducted in the myelofibrosis front-line space, which included 430 patients. They also randomized ruxolitinib-pelabresib versus ruxolitinib alone in the control, mostly intermediate-1 to intermediate-2 patients, so a slightly different population.
They showed a very similar profile. A highly statistically significant primary endpoint was met, which is SVR35 at week 24. The symptoms in all comers, although showing a numerical decrease in both groups, did not quite meet statistical significance.
When the group looked back at certain subsets, including the intermediate-1 patients and others, it appeared that there was a benefit in both spleen size and symptoms.
The supposition is the same as navitoclax. These two are the first ever in our field, resulting in phase 3 global, double-blind, placebo-controlled, front-line, untreated myelofibrosis patients with a novel combination of pelabresib and navitoclax, neither of which are FDA-approved for any indication.
I would say my editorial comment is super exciting for the field that we even did it. Both were international studies largely conducted during the pandemic and involved lots of patients and investigators.
The primary endpoint was met for both of them. The symptoms were not quite met in either study in terms of statistical significance so the question asked is three-fold.
What is the utility of following the symptom burden scale in combination studies, something that was designed 15 years ago for a single-agent JAK inhibitor?
Do we expect a combination to improve symptoms over ruxolitinib alone, or because you’re introducing a second drug, you’re going to introduce new toxicity?
On behalf of my colleagues, maybe it’s time to reevaluate: what are the endpoints for our patients with myelofibrosis? Perhaps in addition to reducing spleen size and improving symptoms, we should be factoring in overall survival, progression-free survival, and bridging to stem cell transplant. This is the time to talk about it because these combination studies are difficult, if not impossible, to judge based on the COMFORT-I and COMFORT-II studies.
Imetelstat is in an ongoing phase 3 trial, which is in the second-line setting and beyond, against the best available therapy (BAT).
Dr. Naveen Pemmaraju
Telomerase Inhibitors
Ruth: Let’s go beyond JAK inhibitors. There are other drugs being studied. Can you help us understand other approaches?
Dr. Pemmaraju: There’s an exciting alphabet soup of clinical trials and drug molecules out there. It’s exciting for our patients to know that there are people around the world who care about MPNs, so it’s good to know that despite COVID, we have a lot of innovation.
We’re adding a new trial once a week, so it’s almost impossible to keep up, but I do want to give some sampling of what’s going on.
Imetelstat is very important for everyone to know. It’s a first-in-class telomerase inhibitor. Some people have heard of telomeres. They are the little ends on the ends of chromosomes that help to determine aging and possibly even cancer biology.
Imetelstat is in an ongoing phase 3 trial, which is in the second-line setting and beyond, against the best available therapy (BAT). I praised this trial because it’s the first and, to my knowledge, only phase 3 trial that has overall survival as its primary endpoint. Hopefully, it will give us a readout in the next year or two.
MDM2 Inhibitors
Dr. Pemmaraju: MDM2 inhibitors have gotten a lot of press in all MPNs. This is a key pathway that has to do with guarding the cell TP53. It’s an oral drug that has been studied before. As a class of drugs, there may be some GI side effects to watch out for, but in the later trials we’ve seen, the groups have figured out a way to address that by either adjusting the dosing schedule or dosing frequency.
I’m excited to see where that area goes. Right now, the lead trials are MDM2 inhibitors with ruxolitinib as an add-on approach or a suboptimal approach. You’re already on a JAK inhibitor. You have an okay response, not a great one, but not quite ready to come off of it, and then you add the MDM2 inhibitor. Those studies are actively ongoing and I think we’ll be excited to see those results.
The good thing about myelofibrosis is whether you’re JAK, CALR, MPL, or triple negative, you respond to JAK inhibitors and novel agents alike.
Dr. Naveen Pemmaraju
Genetic Mutations in Myelofibrosis
Ruth: What if someone’s myelofibrosis isn’t driven by a JAK mutation but a different mutation, is there a different approach? We’ve also been hearing about a cancer vaccine related to CALR, so could you walk us through both?
Dr. Pemmaraju: There’s a two-part answer to the question of molecular mutation targeting in MPNs. Historically and in the clinic right now, there is no difference at the moment.
The good thing about myelofibrosis is whether you’re JAK, CALR, MPL, or triple negative, you respond to JAK inhibitors and novel agents alike. That’s an interesting thing that suggests that there’s a common pathway.
But for the future, yes. Already in the clinic in 2024, we expect a new era to begin, which is, for the first time, to have mutant-specific approaches for both JAK2 and CALR. I expect that we’ll see multiple different drugs targeting mutant JAK2 specifically. The hypothesis is: could that be better and more specific than targeting the whole pathway? Let’s see. You’ll see phase 1 trials there.
CALR turns out to be a really good target, especially for immune therapy targeting. That’s only new science in the last five years. There are vaccine approaches either by themselves or with other immune drugs, such as ipilimumab. There’s an exciting bispecific molecule, which is a mutant CALR x CD3 bispecific antibody that I and others will be working on.
There are also going to be other ways to target CALR. You have multiple different ways of targeting mutant-specific approaches, but let me highlight these are phase 1 clinical trials. They’re backed by animal preclinical data. Now we need to see how they do in the initial trials.
For the first time, I’m seeing sustained improvement in the anemia of MPN, specifically myelofibrosis. We have three different categories trying to address this for our patients.
Dr. Naveen Pemmaraju
Anemia in Myelofibrosis
Ruth: Dr. Pemmaraju, you mentioned that many people suffer from anemia when hemoglobin is low. We know they can feel extremely fatigued so much that it interferes with their quality of life, which I know from personal experience, unfortunately. With what you’ve described, do you feel like we’re getting better tools to fight anemia and hopefully avoid people needing more frequent transfusions?
Dr. Pemmaraju: Yes. For the first time, I’m seeing sustained improvement in the anemia of MPN, specifically myelofibrosis. We have three different categories trying to address this for our patients and it’s simply exciting.
First is the JAK inhibitors themselves. As we mentioned earlier, the first initial ones did not improve and may have worsened the anemia transiently in some patients. Now these second- and third-generation JAK inhibitors are improving the anemia and possibly through the inhibition of ACVRL1, so that’s exciting.
Second is the additional agents, such as luspatercept. You can add on an agent that works outside of the JAK inhibitor that aims to stimulate the hemoglobin and improve the anemia.
Third is these novel agents. When you look closely at the navitoclax and pelabresib data sets, in those two particular instances, you have some people who get anemia as toxicity, but you also have patients who have anemia improvement with the combination, maybe better than with ruxolitinib alone. These three approaches, we’re already seeing in the clinic in phase 1, 2, and 3 clinical trials.
Out of all of these theoretical things, a lot of times what our patients are suffering from is anemia. When the hemoglobin gets below 7, 6, 5, or 4, it’s not even compatible with life, much less quality of life. Anything we can do to reduce the burden of getting transfusions, missing appointments, and missing life events is going to be a big breakthrough, and I’m starting to see that.
If a transplant is available and indicated, it is the only curative approach for myelofibrosis.
Dr. Naveen Pemmaraju
Role of Stem Cell Transplant in the Treatment of Myelofibrosis
Ruth: Typically, a doctor will tell a patient that the only cure for myelofibrosis is having a stem cell transplant. With these new medical therapies, my question is always the same: do you see a changing role for transplants?
Dr. Pemmaraju: The role of stem cell transplant in myelofibrosis is one of great importance still. While I’m personally excited about all of these drugs in development, two things are important.
First, none of these have been shown to create a long-term cure in and of themselves for myelofibrosis. Second, if a transplant is available and indicated, it is the only curative approach for myelofibrosis.
Having said that, the realistic problem with allogeneic transplants is that it’s not available for everyone because of their comorbidities, how frail versus how fit they are, matching, the infection rate, and the mortality rate. As patients get older, it may be tougher at some centers and for some folks to do it. There are some real limitations.
The other problem is that out of all of our patients, the vast majority are not going to transplant. Improvements are being made with transplants every day. Haploidentical transplant, which is a half match, is becoming more of a standard, so that gives the donor pool exponentially more options.
Trying to reduce graft versus host disease, which are complications after the transplant, with medicines are revolutionizing the field.
As I’ve traveled all over the world, people can do stem cell transplants in economically diverse situations. The transplant procedure itself can be highly expensive. Interestingly, even though cost-effectiveness is an issue, in some locales, if you can do a transplant and potentially cure the disease, it can lead to an improvement in socioeconomic status overall.
There are some cool, important things happening. But it’s an important point that even with all the excitement of these medicines and medicine combos, we’re still not at the point where we’re talking about a cure, so if you have the availability and indication for transplant, you have to pursue that consideration.
We have brand new approaches that we didn’t have a few years ago. There is a lot of data and science, so there’s hope.
Dr. Naveen Pemmaraju
Final Takeaways
Ruth: Let’s put all of this together. For those of us living with myelofibrosis or others who are concerned about progressing to myelofibrosis, what do you want to leave them with? When you total up everything we’ve talked about, how do you want to leave the conversation?
Dr. Pemmaraju: This discussion was very exciting because it left me with even more hope than when I started the day. I would leave our patients, caregivers, family members, advocates, and stakeholders with a message of hope and positivity. It’s not blind hope and positivity. It’s not based on hunches or ideas. It’s based on data.
The last three years in particular, I would call it — and I do not use this phrase lightly — a golden era for research for the MPN, specifically including myelofibrosis.
There are four areas to highlight and to be very excited about for our patients and families. First is the development of new JAK inhibitors. We mentioned the four that are already approved in the US, so let’s get them available all over the world. There are several more in clinical development.
Second is the JAK inhibitor combinations. Very exciting data from ASH. Let’s see the new combinations. Maturing data for navitoclax, pelabresib, and selinexor.
A third area of excitement and hope is that of anemia-improving agents.
Finally, the delineation, description, and demonstration of brand-new molecular pathways inside the cells that were never known before. New insights and ways of approaching. We mentioned potential immune therapy approaches, like the CALR mutation. It’s exciting that we have brand new approaches that we didn’t have a few years ago. There is a lot of data and science, so there’s hope.
Ruth: Dr. Pemmaraju, thanks so much for being with us today. You’re always a pleasure to talk to and so informative to our guests. We really appreciate your time.
Dr. Pemmaraju: Thank you so much for having me. This was a very thought-provoking and stimulating discussion.
Special thanks again to GSK and AbbVie for their support of our independent patient education content. The Patient Story retains full editorial control.
