Looking Ahead in Treating Myeloproliferative Neoplasms

EP: 1.Overview of MPNs

EP: 2.Systemic Treatment Options for Polycythemia Vera

EP: 3.Polycythemia Vera: Prognosis and Risk for Progression to Myelofibrosis

EP: 4.Myelofibrosis: Classification, Risk Factors, and Biomarkers

EP: 5.Myelofibrosis: Diagnosis and Prognostic Risk Assessment

EP: 6.Transplant Therapy in Myelofibrosis

EP: 7.JAK Inhibitors in Myelofibrosis

EP: 8.Monitoring Strategies in Myelofibrosis

EP: 9.Treatment Sequencing Approaches for Myelofibrosis

EP: 10.Novel Therapies Under Investigation for Myelofibrosis

EP: 11.Potential Combination Therapy Approaches with Ruxolitinib in Myelofibrosis

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EP: 12.Looking Ahead in Treating Myeloproliferative Neoplasms

Transcript:

Naveen Pemmaraju, MD: In this booming time of research for our patients with MPNs [myeloproliferative neoplasms], particularly myelofibrosis [MF], I'm energized by the worldwide community that has not only persisted during the time of the pandemic but has really augmented. I recently returned from presenting at the ESH [European Society of Hypertension] meeting in Berlin, Germany, for MPN and CML [chronic myelogenous leukemia]. And I was energized to talk to my fellow colleagues from around the world. I think we identified 3 major areas to focus on in terms of emerging trends and special considerations over the coming year. One, I believe, is the further investigation of these novel combinations. So far, we have focused on JAK inhibitors plus novel agents, but the discussions will be over the coming years together. What about different JAK inhibitors as the backbone beyond ruxolitinib? What about newer targets, and novel agents? And then, of course, novel, novel agents, as we call them, which is the combination of 2 beyond JAK inhibitor agents in a non-JAK inhibitor-containing regimen. So, I think those clinical trials would be of the highest importance to the field based hopefully on rational design and preclinical signals.

The number 2 concern I think is that of toxicity. I think as we introduce these novel agents and novel combinations, we, our patients, and scientists need to be thinking about what the new toxicities. What are the emerging toxicities? What are the unexpected ones that either result in longer-term follow-up or unexpected toxicities and side effects from combinations? What is the benefit to the patients in terms of adding a second and potentially even a third drug at some point vis-a-vis the toxicity, financial toxicity, the cost of these drugs, access to them, monitoring of them, and then the medical adverse effects.

Then I think the third area for us is the optimization of stem cell transplants. We know that transplant remains the only curative approach thus far in the myelofibrosis space, but with improvements in immune modulation, GVHD [graft-vs-host disease] monitoring, new medicines, pre-, and poststem cell transplant, can we optimize the transplant by offering it to more patients in a safe way, improving transplant access across the world, and reducing the short and long-term risks and mortality that are associated with transplant in some cases?

I think on that note of immune modulation, another exciting area to keep in mind is the development of immune therapies beyond interferon and stem cell transplants, which admittedly are the original immune therapies in our field. And so, entities such as CAR [chimeric antigen receptor] T-cell therapies, and monoclonal antibodies, we heard about the new mutant CalR-specific antibody, perhaps other immune approaches, combined vaccines against CalR with immune therapy drugs that are starting in clinical trials. So, an exciting area, we'll call that immune modulation. So, optimization of the existing forms, the interferons, the stem cell transplant, and then keeping an eye towards the new ones. I think those are some of the emerging areas to keep our eyes on for 2023 and beyond.

Aaron Gerds, MD: The treatment of MPNs is a field that is rapidly evolving, and it has rapidly evolved over the last 5 years. And it's exciting to see that we're moving past simply giving JAK inhibitors to patients and looking to combination therapies to better the outcomes of these patients. And certainly, that's the big next wave of therapy where we're not just giving JAK inhibitors, but we're giving combinatorial therapies to try to illicit a deeper effect on the disease. I think we need to continue to work to find better biomarkers of this disease modification, and we often look at changes in allele burden and changes in the scar tissue in the bone marrow, but this is often a biomarker of a biomarker or a reflection of a reflection. I think it doesn't really get to the true modification of the pathobiology of the disease.

Many are looking at additional markers, like Dr Joseph Michael Scandura, MD, PhD, whom I mentioned earlier, who's looking at megakaryocyte density and spacing within the marrow it has a perhaps better predictor of disease modification, so better biomarkers are needed, better therapies are needed. And again, it's super exciting to see these combinatorial therapies as the next wave in drug development in therapy development in myelofibrosis. But we can look even further onto the horizon into some of the exciting things that might be coming in the future. The plenary session at this year's ASH [American Society of Hematology] Annual Meeting was a monoclonal antibody targeting calreticulin disease protein. And so, that's really exciting.

And this is a monoclonal antibody. You think about how much rituximab revolutionized the care of b-cell malignancies, and you can see that calreticulin may do the same for myelofibrosis. Not only could we use just the negative antibody, but you think about all this you can build bispecific antibodies or even modified cellular therapies like CAR T-cells or end-modified NK [natural killer] cells to really dramatically change the way we treat these patients. So, you can see that being the wave after the next wave, which is absolutely mind-blowing and exciting to think about.

Pankit Vachhani, MD: There are several areas that we are looking to improve upon and bring new options for our patients and also trying to sort out with all this new knowledge that is coming along in the field. Patients with cytopenic fibrosis, despite the numerous therapies that have come and are coming, continue to do worse than other patients. We need to improve their outcomes. It is tremendous that we have pacritinib [CPI-0610] now, whereby patients with thrombocytopenia have a good treatment option available for them to benefit from, but I think more agents like that and momelotinib [C23H22N6O2] for sure, is looking promising to deliver outcomes for thrombocytopenic and anemic patients, but I think we need some additional disease-modifying agents in this space, especially for cytopenic myelofibrosis patients. That is something that I'm definitely looking forward to coming about in the field over the next few years.

Along that same vein, we need to improve the survival outcomes of patients, more so than what we have already done with ruxolitinib. Many of these combination therapies which are ongoing are great, but I'm looking forward to seeing genuine, good survival outcomes happening from that. That would be the ultimate marker of a disease-modifying agent. While we are on the topic of combination therapies, should 1 or more of these combination therapies come out and there is a very high likelihood that that's going to happen, I think the very next question that will come about in the field, is sorting out what biomarkers can we identify either at baseline, or let's say, at 3 months, 6 months, or a year, to identify patients who are going to benefit or not going to benefit from one combination therapy vs the other, who may benefit on the initial half vs through continuous maintenance of a combination therapy. The field of biomarkers is going to evolve in line with the new therapies that are going to come out. After all, biomarkers have to be looked upon in the context of treatment as well.

While these are the 3 points that I think need to be answered and need to be looked into, there are some additional things that I do want to mention. JAK2 Keller vaccines are being developed and these hold tremendous promise. We are hoping that they work out. They may really help us down the line in thwarting the progression of a disease in its very early course and may serve as a brand-new way of treating our patients with myelofibrosis, PV [polycythemia vera], or ET [essential thrombocythaemia]. For polycythemia vera patients, there are many drugs that are currently being developed, which work on the iron homeostasis pathway. Should 1 or more of these drugs come out to the market, they may offer yet another option for our patients, and in doing so, they may help eliminate phlebotomies. While not directly a supportive care method, it may very well help in supporting patients on their other therapies as well. Not to mention, they may help in maintaining a target hematocrit of 45% or more on a long-term basis and in a consistent manner and therefore, also decrease the need for phlebotomies and prevent thrombotic episodes.

Last but not least, interferon-based therapies have always been talked about, but they're probably being talked about now more than ever before and these truly may slow the progression of myeloproliferative neoplasms speed that ET, PV, or maybe even profibrotic MF and in selected cases, even possibly overt myelofibrosis. But more studies need to be done and I think there is more and more emerging evidence suggesting the use of interferon as early as possible in patients with MPNs.

Transcript edited for clarity.