Myeloproliferative Neoplasm Management: Future Directions in Care

EP: 1.Overview on Essential Thrombocythemia and Polycythemia Vera Management

EP: 2.Role of Symptom Burden in Thrombocythemia and Polycythemia Vera

EP: 3.Novel Therapy in Myelofibrosis: Momelotinib

EP: 4.Therapy in Myelofibrosis: Pacritinib

EP: 5.Myelofibrosis: Nuancing the Potential of Disease Modification

EP: 6.Therapy in Myelofibrosis: Fedratinib and Ruxolitinib Strategies

EP: 7.What is the Role of Transplant in Managing Patients With Myelofibrosis?

EP: 8.Myeloproliferative Neoplasms: Targeting CALR With Novel Therapy

EP: 9.An Expanding Armamentarium in MPNs: Therapeutic Strategies Under Investigation

EP: 10.Sequencing and Managing Combination Therapy in Myeloproliferative Neoplasms

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EP: 11.Myeloproliferative Neoplasm Management: Future Directions in Care

Transcript:

Naveen Pemmaraju, MD:So team, what I want to do is, I’m going to go to each of you and get some final comments, and ask you to give me 2 or 3 things. Maybe 1 is something that you learned, maybe at ASH [American Society of Hematology meeting] or in the last few months leading up to ASH, and then 2 and 3 is what’s your wish list? What do you want us as the field to think about and focus on in 2023, either in the setting of clinical trials, transplant symptom burden, to give folks out there a sense of what you are thinking about and what you’re excited about? Dr Palmer, we’ll start with you, and we’ll go down the panel.

Jeanne M. Palmer, MD: This year at ASH, it was great to hear some of the updated information and to try to understand the new drugs that are coming out and have discussions with people about where we think they’re going to fall into the landscape of the therapy. I look forward to exploring that further. Although I recognize it’s certainly going to be a goal for the next 5 years, probably more than the next year, I’m hopeful that we’ll be able to do that. One of the things that’s on my wish list is I think we need to better understand the response criteria we’re looking at, so what is the meaningful response that we have for a patient? Right now, we’ve been using spleen size, reduction, and symptom burden, which are very important factors that contribute to it, but what are the markers that are going to predict survival? Because it takes a long time to see survival. We must figure that out. What are the markers that are most meaningful to patients? What can we anchor with something like the Global Impression of Change that tells us this makes the patient feel a lot better. It doesn’t just make me feel better to look at their numbers or look at different things, but it makes them feel better also, more importantly, associated with survival. That’s my wish list is to come up with the best way to figure out what works.

Naveen Pemmaraju, MD:Wonderful. Dr Oh, your final thoughts?

Stephen Oh, MD, PhD:We are at a very exciting time for this field with more new agents becoming available, and many are now in phase 3 that may soon become approved. It continues to be an extremely exciting time for the field. In terms of specific things that I will highlight, I’ll be the broken record and keep coming back to inflammation and anemia, and more recognition that this is something important in terms of the clinical features of patients with mild fibrosis, anemia related to inflammation, targeting these pathways, hepcidin. It’s also something as far as updates on the lab side that is increasingly being investigated. What I continue to say as far as that’s concerned is, we all ask, can we more potently target the abnormal inflammation? But I think there is an opportunity to leverage these abnormal inflammatory signaling pathways in a way that not just reduces symptoms and improves bone marrow function, but can turn it on its head to target the malignant cone as well in a more effective way. That’s what I would highlight. The last thing I would say, we talked about this new monoclonal antibody for mutant calreticulin. The other obvious approach, and along those lines, is something specific for mutant JAK2 [Janus kinase 2]. We still don’t have that. There are obvious reasons why that has not been the case over the years, but I think there is a growing hope, maybe it’s the best way to say it, that a truly mutant selective JAK2 inhibitor may be here in the coming years.

Naveen Pemmaraju, MD:Wow. That’s exciting. I’ll share my thoughts with the panel. At this year’s ASH, the exciting thing for me was mainly in our myelofibrosis sessions, the emphasis on what all of you discussed here, which was the elucidation and understanding of disease biology and biomarkers that you can hang your hat on, or at least have a sense of what’s going on. The one that really captured that for me was what Dr Oh presented, which was the ACVR1 [activin A receptor type I] story in pacritinib [Vonjo], our third approved JAK inhibitor. We now have several JAK inhibitors, momelotinib and pacritinib, which can be not only delivered in the setting of cytopenias, but actually improving the cytopenias, including the holy grail of anemia. I want to see how the combination therapies do, not only in terms of overall survival, spleen and symptoms, but how they do with the anemia, and how durable that is. I thought that was an exciting finding. For the future, as you all know in our own discussions, I hope you’ll allow me to say a unified theory of disease modification, what we’ve all talked about, and I still think it’s an aspirational goal. It can be something like overall survival as the top most important thing for our patients and for us, coupled with the traditional factors that Ruben and Serge pioneered of spleen size reduction symptoms, and then coupled with some of the newer markers that Steve, Dr Angela Fleischman [University of California, Irvine] and our colleagues are working on, including VAF, variant allele fraction, cytokine state, and maybe even bone marrow fibrosis. Can we couple all those into something meaningful for our patients? John, let me turn it to you, and then Ruben for your final thoughts.

John Mascarenhas, MD:It’s difficult to be the fourth person in a row to do this. I thought that’d be Ruben, because he set all the right things you said all the top line.

Naveen Pemmaraju, MD:It’s all supervised here, OK.

John Mascarenhas, MD:I agree with you all, and I know you share this enthusiasm. As a clinician investigator in this field, this is a great time to be in it because the science is driving the medicine and translating directly into the clinic. What we learned in the clinic feeds back and then helps us understand how to refine and go about it the right way. I’m most impressed with beyond the things I’ve been talking about, is how we sit down and listen carefully to a lot of the scientific sessions. You start to realize that there’s so much interconnectivity here between the pathways, seemingly redundancy here, and what we end up often doing is trying to target 1 pathway that we think is relevant, not understanding that there’s so many other pathways that are activated, and that compensate and sometimes overcompensate for shutting down 1 pathway. There’s a lot of examples of this, one clear example is if you shut down BET [bromodomain and extraterminal] regulated transcription, you have a consequence of down regulating NF-kappaB [nuclear factor-kappa B] activity, and down regulating BCL-2 [B-cell lymphoma 2] expression, c-MYC expression, all relevant nodes in the pathobiology of myelofibrosis. It begs the question, is there 1 specific target? Or is what we’re looking at such a complex interplay that we need to be approaching this from various angles at the same time? Which I think reinforces the theme that we’ve been discussing, which is rational combination, mechanism-based combination. I’m excited that a lot of the scientific abstracts that were presented today will in 2 years, 3 years, translate into the next wave of clinical trials. I think that’s fabulous. That’s why we’re here.

Naveen Pemmaraju, MD:That’s fantastic. Ruben, take us home and give us your final thoughts.

Ruben Mesa, MD:One thing I’ve learned this year is don’t let the perfect be the enemy of the good. Meaning, when ruxolitinib [Jakafi] was first approved, there were many detractors saying, “This is supportive care. I could just give patients 10 milligrams of prednisone, and they’d be the same.” That is just pure nonsense. The rate at which patients pass away from myelofibrosis is clearly decreased significantly over the years. Is it perfect? No. I think the expansion we’ve had now to hopefully have 4 JAK inhibitors is important. These drugs make an important difference. They each have their own role. I still agree with John, I want to look at novel combinations, but a combo that includes a JAK inhibitor probably is logical, based on several things that we have learned. Although these are not perfect, these are good drugs that make a real impact on patients both in terms of length of life and quality of life. Now my wish list is, I envisioned the situation where we’re 18 months from now, and we have 6 phase 3 clinical trials that have data that looks similar, we improve spleen and symptoms more than singulation ruxolitinib, and we have a toxicity profile that includes diarrhea, nausea, and vomiting. That’s what we’re going to be stuck with. So how do we sort through which patient goes on which drug because they’re going to be patients that have a fabulous response to rux [ruxolitinib] and pelabresib, rux [ruxolitinib] and parsaclisib, rux [ruxolitinib] and navitoclax, rux [ruxolitinib] and HDM2 inhibitor, on and on, but not everyone. How do we sort through that? I think the correlative studies are going to be important. How do we sort through so that we have any science behind I’m going to give which drug just comes to top of mind because they have very different mechanisms of action, and the patients are different? Those that develop these trials hope that the patients are going to be eligible, of course, but we realize that a drug has a 20% response rate. It means it has 100% response rate for 20% of the patients and has a 0% response rate for the other 80%. That’s my wish list. Our work is not done when we have the top line data on those phase 3 studies, but a tremendous sense of progress and hope. As Naveen and I were talking earlier at ASH, when you think about what ASH looked like in MF [myelofibrosis] in 2002. In 2002, I gave the oral presentation on thalidomide [Thalomid] and prednisone, and it was like the Super Bowl. There were so many people there because we showed some improvement in anemia, but that was it, no spleen, no symptoms, no disease modification. There was a bouncer outside keeping people out, so the progress we’ve made is unbelievable.

Naveen Pemmaraju, MD:Well, I must tell you, team, we have lovely discussions. This was one of the best yet. On behalf of my colleagues Ruben, John, Steve, and Jeanne, I want to thank you all for this very rich and informative discussion. I want to thank our audience for taking time to view this, and we hope that you found this OncLive Peer Exchange discussion to be useful and informative for your practices. With that, I’m Naveen Pemmaraju. We will sign off for now and see you next time. Thank you all so much.

Transcript edited for clarity.