Unmet Needs and Future Directions in the Management of Myelofibrosis


Naveen Pemmaraju, MD, highlights unmet needs in the setting of myelofibrosis management and looks toward future evolutions in the treatment paradigm.


Naveen Pemmaraju, MD: As I survey the landscape of myelofibrosis [MF] as we enter 2023 and beyond, it’s an amazing, encouraging, and rapidly exploding field. Many of the agents we’re investigating were not available in the clinic 3 to 5 years ago. Just to review, we mentioned some of the combination approaches that are furthest along in development for review. That’s a JAK inhibitor plus BET, or bromodomain inhibitor, pelabresib which again, has already shown the phase 2 safety and efficacy, and is now in an ongoing phase 3 frontline approach. There is navitoclax, so ruxolitinib plus navitoclax, BCL-XL inhibition, as I just mentioned, the phase 2 REFINE study is ongoing, also with the phase 3 setting, TRANSFORM-1 and TRANSFORM-2. A third approach is ruxolitinib, a JAK inhibitor, plus PI3 kinase inhibitor parsaclisib, which is the same story, with phase 2 completed and now into the phase 3 setting.

Those are the three furthest along. In addition, you have many other combination studies, ruxolitinib plus selinexor for XPO1 inhibition, and so on and so forth. Before that, we did test combinations of ruxolitinib with other, older agents such as HDAC inhibitors, hypomethylating agents, IMiD [immunomodulatory] drugs, interferon, etc. Some of those are still in active phases of investigation. Now in the second category, for novel agents, there are quite a few. We won’t be able to list all of them in this interview, but certainly, these are available on ClinicalTrials.gov, which is a nice publicly maintained website for all of these. There are a couple to keep our eyes on, in terms of the JAK inhibitors, we mentioned the 3 that are approved and available as of this recording: ruxolitinib, fedratinib, and pacritinib. We have a fourth JAK inhibitor being evaluated now, which is called momelotinib, so we want to all keep our eyes on that, and hopefully, in the next year we’ll find out the status of this drug as it’s now completing the advanced phase of the trials, and other JAK inhibitors in development.

In terms of beyond JAK inhibitors and novel agents, we have several. One that’s getting a lot of attention is imetelstat, which is thought to be the first-in-class telomerase inhibitor, being actively investigated in myelodysplastic syndrome, MDS, as well as in our MPNs [myeloproliferative neoplasms] and the myelofibrosis field. It’s now in an ongoing phase 3 randomized study against the best available therapy, relapsed/refractory after JAK inhibitor therapy for patients with MF. And importantly, it marks the very first trial in our field at a phase 3 level that’s using overall survival as a primary end point. Again, to this disease modification story, trying to understand what the outcome for the patient is at that high level. So, we eagerly await those studies. In addition to imetelstat, several different pathways and drugs are out there, and again, people can get a sense of that by looking at the ASH [American Society of Hematology] abstracts or ClinicalTrials.gov.

We have a number of different approaches, epigenetic with LSD1, apoptotic modulators, CD123 microenvironment modulators, and so on. Some of these I’m personally involved in, some of them I’m not involved in. What I would say out of all these novel agents is, let’s see the data. Let’s let these go through phase 1, 2, if they qualify, phase 3 testing. Let’s really think about the end points in the relapsed setting, as I’ve kind of argued here, potentially we may want to look at separate end points. Once the frontline therapy has concluded, I would also argue that we need to be looking at overall survival. Let’s keep in mind that allogeneic stem cell transplant remains the only curative modality, but still, how to optimize allotransplant, make it available for more folks, less toxic, and durable responses after. Also, what’s the incorporation of novel combinations? Novel/novel agents, for example, so 2 non-JAK inhibitors combining, or a triple combination, or post-transplant novel agent administration. There are a lot of different, open-ended, ongoing research questions we’re all looking at.

I think the data, as always, should speak loudest and first, so that we continue to review these trials together as we have always done in the MPN field at the large congresses and also the smaller ones, debate and discuss. Let’s use modalities such as social media and online sources to make sure all stakeholders are involved. Let’s always keep the patient voice and patient experience front and center. As my colleague Ruben Mesa, [MD,] pioneered the MPN symptom burden, which is the ultimate sort of PRO, patient-reported outcome, and patient-centered approach that’s incorporated into all our clinical trials, let’s continue to think about the patient experience. As we go into doublets and triplets, let’s consider toxicities, so both overlapping toxicities of multiple agents, uncovering novel toxicities, which often is something that does come out in these clinical trials. Let’s think about the duration of therapy, and let’s think about financial toxicity to patients as we incorporate new drugs. What’s the cost to the health care system, to the patient, to the insurer? How do we provide access and availability all across the world with so many geographic barriers and issues? I think these are the active issues I want us to consider as a field.

On a personal note, I would say I’m very proud to be a part of this MPN field. Again, as I mentioned to you, with this renewed hope, with this nice meeting of everyone in person after 3 years of [the COVID-19] pandemic, I can report that there is a lot of momentum in our field, a lot of joy, and a lot of forward-looking optimism from scientists and investigators. They feel for the first time in 10, maybe 20, years that there is a wealth of actionable information from the laboratory to the clinic that we may hope to deliver a better future for our patients and their families with MPNs.

Transcript edited for clarity.

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