Disease Modification in Myelofibrosis: The Current Treatment Paradigm


Shifting his focus to treatment strategies in myelofibrosis, Naveen Pemmaraju, MD, reviews the current drug armamentarium and explains how it ties into disease modification.


Naveen Pemmaraju, MD: In terms of available treatment options for patients with myelofibrosis [MF], I’m proud to report to you that there is a rapidly evolving, changing field happening in front of our eyes. In terms of standard of care, what’s available in the clinic now, you can look at 3 buckets or categories in treating our patients with myelofibrosis. No. 1, of course, is the JAK inhibitor class of drugs. These have been approved and available now for a decade plus. This is the category where you have a monotherapy, a single agent, usually a pill chemotherapy in the case of JAK inhibitors. You’re able to administer it to those patients with intermediate- to high-risk disease. Ruxolitinib was the first-in-class JAK inhibitor, followed by fedratinib, and now pacritinib, so three FDA-approved JAK inhibitors are already available on the market for various indications.

The second category, as we move into the near future, is combination therapy. These are all available in clinical trials right now; they’ve completed phase 2 and are now into phase 3 clinical trials, which represent a more advanced stage of development. There are many combinations there, but they’re all a JAK inhibitor plus another agent, so JAK inhibitor plus BET, or bromodomain inhibitors; JAK inhibitor plus BCL-XL inhibitors, navitoclax; JAK inhibitor plus PI3 kinase inhibitor parsaclisib, so on and so forth. You have a class of clinical trials that are combination therapies originally, usually tested as either a single agent or a combination in the relapsed or add-on setting, and now remarkably already being moved into the frontline setting, usually in a randomized trial against a JAK inhibitor alone.

The third and final category, which is very encouraging, sometimes very scientifically exciting, which needs to be tested and investigated in the clinic, is that of completely novel agents. We’ll call this third bucket non-JAK inhibitor, beyond JAK inhibitor, or different than JAK inhibitor therapy. You have a whole host of drugs, most of which are in what’s called phase 1 and phase 2 testing, so the earlier stages of clinical development. The concept here is fairly straight forward, which is outside of the JAK-STAT pathway, can a novel drug be designed, again, either to combine with a JAK inhibitor or to stand alone on itself to treat patients with MF? So, there are lots and lots of clinical trials. Many of these are available throughout the world, not just in the United States. We were able to meet in person at ASH [American Society of Hematology annual meeting] 2022. It was really heartwarming, all of us got together, investigators from America, South America, Europe, Asia, Africa, Australia, all over the world, to be able to discuss the exciting progress we have made in all the clinical trials that remain open despite 3 years of [the COVID-19] pandemic. I think in the coming 3 to 5 years, we will see a lot of these investigational approaches that I mentioned hopefully read out and have some data to discuss.

As we have this explosion, rapid improvement and augmentation of clinical trials, new science, and new pathways in myelofibrosis, I think what’s also being made clear to us as investigators is that we need to revisit, reevaluate, and maybe even have new definitions for what does it mean to have a response in myelofibrosis in these new settings. I’m talking about combination therapies where you have a JAK inhibitor plus a novel agent, novel agent-only settings, relapsed/refractory patients, or post-transplant. There are so many new scenarios as our patients nicely both live longer and have new and different sets of challenges, problems, barriers, and expectations once you get past the frontline setting.

To help understand and explain this unprecedented setting, I and others have come up with a phrase known as disease modification, something I’m very passionate about. It’s one of those areas we’re still aiming to define, much less trying to improve on. I think the concept here is 3-fold. One was that in the frontline setting, newly diagnosed myelofibrosis, JAK inhibitor alone, we very nicely had a field led by my friends and colleagues Ruben Mesa, [MD,] Claire Harrison, [MD, FRCP,] Srdan Verstovsek, [MD, PhD,] and others, with the COMFORT-I and II trials for the approval for ruxolitinib. In that frontline, untreated setting, with no other therapies available, it was deemed very nicely, you’d have the spleen size of the patient, reduction, and symptom burden, which really helped to understand the activity of JAK inhibitor monotherapies. That has stood the test of time nicely, and it helped lead to multiple JAK inhibitors, with more being evaluated.

However, the only thing I will say now, 10 years after the first JAK inhibitor approval, is that you have patients who are at advanced risk, with high-risk molecular findings, combination therapies, and patients who are being treated in the second-, third-, and fourth-line setting. In many of those patients, a chronic disease has now turned into an acute disease. What I mean by that is that many of these patients who have failed frontline therapy with JAK inhibitor may have markedly reduced overall survival, a very high chance to transform to an acute leukemia, and potential for early death. I think what we’re trying to think about is, whether there is another way or measure or marker to assess these patients when they have escaped the frontline setting. I would propose the term disease modification.

Now, the second part of this is what does that mean? That’s an active area of investigation in the coming year, and I’m sure we’ll define that together. Right now, we and others are using what you would call a working definition, one that’s meant to evolve, meant to change, meant to be contested because as we get new pathobiological information about the disease and how these new treatments affect it, it should change. When you get past the traditional, older spleen and symptoms, and now you’re in the second-, third-, fourth-line setting, we want to incorporate overall survival into the response criteria. But also, does this correlate biochemically with whatever the new drugs are doing? Is there a decrease in the variant allele fraction, for example, decrease in the bone marrow fibrosis, decrease in elevated aberrant cytokines and messenger proteins, etc? All of this is a work in progress, so anyone who’s trying to think about this with us in this field, it’s an active area of investigation. At least it puts a name to what we’re trying to say, which is, can we go beyond the clinical factors of spleen and symptoms and incorporate some of these patient-centered factors, such as overall survival, biochemical correlative factors, so we understand what these new drugs are doing?

Then of course, we have modalities such as allogeneic stem cell transplant, which remains the only curative modality for myelofibrosis, to measure what’s happening there in both the short and long term. I think this is an important factor, disease modification. We need to aim to further define it over time. We need to see how these novel agents, such as BET inhibitors, BCL-XL inhibitors, PI3 kinase inhibitors, XPO1, and all these new pathways that are coming out in combination with a JAK inhibitor, how do they modify the disease short, medium and long term? Are there other curative modalities out there outside of allogeneic stem cell transplant? In the case of allogeneic stem cell transplant, how do we define disease modification 3, 5, 7, 10 years out, in the long-term setting?

Transcript edited for clarity.

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