The Latest on Myelofibrosis Treatment

Dr. Ruben Mesa

March 2022

What advances are being made in myelofibrosis treatment options?

I would break down the advances in a couple of ways because there’s truly probably over 20 drugs that were presented at ASH, which just the number itself should really give people a sense of, wow,  that’s really exciting.

These are 20 drugs specifically being developed for myelofibrosis. And they’re looking at it in different ways, and it’s a dramatic change from before.

What patients should know is that they’re all being tested in parallel so that if Drug 7 really is enormously beneficial, its path might become much quicker and people’s ability to get at it becomes much faster.

People sometimes say, should I take them all? Clearly, we were testing these in parallel. And each one might be better for one person versus the other.

But even if you’re not on one of those trials, you may still well benefit from what we learned from that trial.

Whether it’s beneficial or sometimes if a trial is not beneficial, we still learn:

• Why did it not work?
• Maybe it was the right idea, but the wrong drug?
• Maybe it was the right drug, but it was the wrong dose. So we learned from each of these.

The role of the 4 JAK inhibitors for myelofibrosis

But the key takeaways are, one, that there are four JAK inhibitors, and I suspect in the end, they will all be approved.

Ruxolitinib & fedratinib

There’s two that are approved: ruxolitinib and fedratinib. Reduce spleen, improve symptoms may help to improve survival.

Pacritinib

There is pacritinib, which is the most likely to become approved soon and particularly helpful for people who have a very low platelet count, but also those possibly with anemia.

Momelotinib

And then there is momelotinib, which particularly seems to also help anemia. All of them help spleen and symptoms.

I envision that if all four drugs are approved, let’s say by 2021, we’ll have more factors in terms of which drug we use, in which patient at which time. There will be, again, much discussion as to how one optimizes that.

But the patients will likely be on a JAK inhibitor:

• Which one?
• What dose do they switch from one or the other?
• All active questions.

Drugs in combination with a JAK inhibitor

In parallel, there are conservatively 10 to 15 drugs that are looking to improve myelofibrosis in different ways that may be used along with a JAK inhibitor from the very beginning. Or you start with a JAK inhibitor. You use it for a period of time to see if someone responds and if they’re not responding, then we add that other drug in after three months or four months.

Or the final approach, you’ve been on a JAK inhibitor. You’ve been on one for a while. You’re no longer on a JAK inhibitor, and now you’re on a different drug.

As you might imagine, 10 to 15 drugs and three different ways you can use them, so many different potential combinations. None that at the moment are ones that people go out or able to have their doctors prescribe.

Promising clinical trials in myelofibrosis

But there are an unprecedented number of clinical trials that, again, if a patient is out there and has myelofibrosis and things are not doing well, or their spleen is too large, or they’re not feeling well, or they’re having side effects from medicines, one or more of these clinical trials may be an option for them.

I highlight just a couple that are probably the closest to the approval process.

Pelabresib

There is an ongoing clinical trial of the addition of a drug called pelabresib. These names are always so awkward. Pelabresib, which is working on the bone marrow in a slightly different way than JAK inhibition that is being combined.

Pelabresib, which is a BET inhibitor. It’s a type of protein that’s inhibited plus a JAK inhibitor from the beginning to see whether that is more effective than using a JAK inhibitor alone to improve spleen, to improve symptoms, anemia, fibrosis, and other things.

So that is an ongoing accruing study called the MANIFEST 2 study. There’s also some key similar approaches going on with a drug called navitoclax, parsaclisib, amongst others.

But the key takeaway: many things under investigation. Likely everyone will be on a JAK inhibitor either alone or with a possible combination. But the data from these studies will be very important to help us determine for one individual in front of us what might be the best approach based on their age, the genetic changes with their disease, or other features of the disease.

What are the determining factors in the sequence of treatment?

The Patient Story: When you have novel drugs, they have to be studied in a particular way. There are so many studies going on parallel, but with the data, I know this is patient dependent but how do you know if someone should start right away with just the one or if should be ruxolitinib and then wait until after or if the ruxolitinib plus the new one right off the bat? What are the determining factors?

Dr. Ruben Mesa: I think at this point we don’t yet know. I think the data from the Phase 3 clinical trials will be ones where we’ll have to look at it very carefully to see, are there subgroups, should it be everyone?

The downsides of being on a combination, it one might be more expensive. But two, there may be more side effects. So I think we’ll get a better sense from looking at subgroups of patients within the Phase 3 studies to get a sense. 

The current data that we used to before the Phase 3’s, the numbers of patients treated were enough to suggest that the combination was helpful, but not enough yet to answer that question.

It’s a natural question, but really a key one, we view these Phase 3 studies. The data are really going to have multiple important things that we’ll look at. Phase 3 studies are just to confirm what was seen in the Phase 2 study. This confirms is two drugs better than one? But the other question, in whom? Is that everybody? Or is it a subset?

Pelabresib side effects

The Patient Story: You had mentioned side effects. Do we know with pelabresib, what the major ones are – if it’s a lot more or less than the ruxolitinib?

Dr. Ruben Mesa: For most of these drugs, they have a tendency to potentially lower the platelets and the blood counts, which sometimes, depending upon the situation, is helpful if the counts were high. But sometimes, if the counts are low, it can be a limiter. Second, it can have some gastrointestinal side effects.

So for most of these drugs, those are the two biggest culprits that we look at, and there are for each drug. There can be some exceptions, but:

• blood counts
• GI side effects
• liver function

Those tend to be the main ones across these different treatments.

Pacritnib: better for patients with low platelet counts?

The Patient Story: I had a question for you in terms of they had one with pacritinib head to head with ruxolitinib for a patient population with low platelets. Did you have a strong opinion one way or the other of those results? And would it impact the way you deal with your patients who might be dealing with more severe low platelets?

Dr. Ruben Mesa: That was a study where I was a coauthor. It was looking back on several of the trials we’ve completed with pacritinib.

And I think, yes, very convincing data that for individuals with a low platelet count with pacritinib. We may be able to treat them with full dose of a pacritinib, versus frequently where there’s a modified dose of ruxolitinib or a lower dose. And that difference makes an impact in terms of its effectiveness for:

• control of spleen
• control of symptoms
• even safety

So yes, I think, a very compelling data. That’s why I think it most likely of all of those things we’re discussing. The most likely was a doctor is going to be able to prescribe it in 2022 to likely would be pacritinib.

Is there anything else that you want to cover, whether it’s in MF or PV for patients and their families?

Dr. Ruben Mesa: I would just share that in parallel again, not getting into great detail, but there were multiple different abstracts really looking at the most basic biological questions.

None of these change how we’re treating patients today but they will inform things moving forward, potentially.

• Why do people with ET and PV progress to myelofibrosis?
• And the role of various proteins and cytokines such as interleukin 13?
• In that process or two, are there specific genetic changes that may be more involved with the process of progressing to acute myeloid leukemia? Whether that be a very impactful study that was presented as a plenary study.

Looking ahead on MPNs and treatments

Questions for MPNs specialists in patient care

This is one of the most impactful studies across the entire meeting that looked at that TP53 and its potential role in progression to AML or the USP6—another mutation that was more associated with progression. So none of these change how we’re treating patients today (December 2021). But they will inform things moving forward, potentially.

• Might we treat people in a slightly different way?
• Might we choose stem cell transplantation earlier?
• Might we develop other therapies that are specific for some of these things in one way or the other?

So very impactful as they really helped to inform the next wave of clinical testing.

How much longer until the next checkpoint where we can find the next thing about this study?

The Patient Story:  You brought up the studies going on to figure out this progression from myelofibrosis into AML. I know it’s early days, but I think people will be very eager to understand what comes out of it. So how much longer until the next checkpoint where we can maybe find the next thing about this study?

Dr. Ruben Mesa: I think we learn more about the main kind of milestones where we really gather as a scientific community tend to be twice a year.

That’s why these meetings are so important, because they really bring people together and allows the brainstorming to be at a much broader level.

In the summer, both the American Society of Clinical Oncology, the European Hematology Association. They both meet at the beginning of June. And then this ASH (American Society of Hematology) meeting in December are really the two key touch points.

When a dramatic scientific breakthrough that can be published at any time of the year, of course. But this is really where we come together. We try to synthesize everything that is going on, but we also collaborate where again, someone’s in the audience and says, I’m studying something that might have an impact on some studying something different, but maybe we could use it against TP53, and maybe it would help prevent AML.

So that’s why these meetings are so important, because they really bring people together and allows the brainstorming to be at a much broader level.

Is cure a part of the conversation right now?

The Patient Story: As we wrap this, any last message to patients and their families about I know we don’t like using cure as a word, because right now it’s taking time just focusing on making sure that we treat people where they are before you jump too far ahead. But, people wonder, and so is that part of the conversation right now?

Dr. Ruben Mesa: Without question, our goal is to cure the MPN. Now short of cure, our goal is to control them indefinitely so that individuals can live out their normal life span with as near a normal quality of life as possible.

So we shoot for a cure, but we don’t let perfect be enemy of the good. So we really work on both. I do think that future state, we hope that other approaches, whether they be vaccines against the abnormal cells and some studies like that are being planned against calreticulin or particular mutation, or whether some of the advances that have been impactful in other diseases with immune therapies, cellular-based therapies such as CAR-T or others, may have different or complementary impacts.

It may not be one or the other. It may be you start with one, you get the disease more control then you come with a different therapy. So clearly, our goal is to cure the diseases. But short of that, we work in parallel to see how we can control them as well.

Without question, our goal is to cure the MPN. Now short of cure, our goal is to control them indefinitely so that individuals can live out their normal life span with as near normal quality of life as possible. We shoot for a cure, but we don’t let perfect be the enemy of the good.

When and how to look for options

The Patient Story: And a lot of this being done in clinical trials. For people who maybe we talk about, for some time, but if people are looking for options, they can ask their providers about clinical trials that might be right for them.

Dr. Ruben Mesa: It’s critical. Two key things. So one, if you’re on a therapy, you’re doing well. You and your doctor think things are stable.

Although there’s all these things evolving, it may still make the most sense to just stay on what you’re on, it’s working for you. All of this will percolate.

In general, clinical trials are for those individuals where the current state is not working. You’re on a therapy, or we know if we start the therapy, it’s not going to have a high likelihood of success, or you’ve tried it in. It either has side effects, or it works completely.

So if you’re doing well, don’t worry, this is going to progress in parallel. I tell patients the best case scenario is you’re stable until we find a therapy that is so much better that even without you being worse, we replace it. That’s the best-case scenario.

But if you’re on a therapy and it isn’t really working, you should listen to our conversation and get the sense, well, maybe there is a trial I might benefit from.

Again, there are centers doing research around the country that, clearly, if you’re in South Texas, we’re happy to see you. But, likely for other parts of the country, there’s a center closer to you that may have some of these trials as an option for you.

»MORE: Read more on FDA approvals of clinical trials

The Patient Story: And if people are in the community setting, we know many are, can their doctor work with a specialist like you? If they can’t travel.

Dr. Ruben Mesa: Without question. Maybe particularly for diseases that are less common like this. Many patients, particularly with more complicated diseases, visit with an MPN specialist. They work along with their doctor and coming up with a plan, whether it be around the use of therapies like ropegylated interferon or others or a clinical trial.