Welcome to The MPN Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Ruben Mesa & Naveen Pemmaraju, who discuss key updates in the treatment and management of MPNs at the 2022 Texas MPN Workshop. The experts cover several topics, including advances in the treatment of essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), ongoing clinical trials in the field, and future outlooks.
“We are seeing some movement very nicely, in both the research aspects and for the patient care… A couple of new topics that are coming out in ET is looking at new mechanisms of action, new drug pathways, such as the LSD-1 pathway, for example, and also looking at which patients may be more high-risk than we thought before.”
– Naveen Pemmaraju
Polycythemia vera: treatment updates
“You mentioned some of the other agents in clinical trial, the hepcidin mimetic, rusfertide (PTG300), now completing Phase II and heading into a multinational Phase III. So again, lots of movement in our earlier MPNs, whereas maybe before there wasn’t.”
– Naveen Pemmaraju
Myelofibrosis: treatment updates
“Momelotinib, showing great activity as a JAK inhibitor, improved spleen, symptoms and the potential of anemia. Pacritinib, particularly useful for individuals with thrombocytopenia, fedratinib and ruxolotinib, two real cornerstones.”
– Ruben Mesa
“The other concept is how we pair the JAK inhibitors with other chemo drugs, adjunct agents, growth factors. It’s just a whole new era for our patients.”
– Naveen Pemmaraju
Upcoming trials and sequencing of therapies
“There are three current… combinations with JAK inhibitor plus a novel agent in Phase III global multinational studies. One of them features inhibiting BCLxL… the navitoclax adding onto ruxolitinib. Then there’s pelabresib… and then even PI3 kinase combining with the rux JAK inhibitor.”
– Naveen Pemmaraju
“Great progress, ET, PV, MF… and benefits that really result from the research into these diseases…So the whole body’s connected, but it all starts with the blood.”
– Ruben Mesa
Watch the full session
Ruben Mesa: Hello. My name is Ruben Mesa. I’m the executive director of the Mays Cancer Center, UT Health San Antonio MD Anderson, and delighted to be at this third and the first in-person Texas MPN Workshop with my good friend and co-organizer, Dr Naveen Pemmaraju. Naveen, welcome.
Naveen Pemmaraju: Ruben. Thank you so much. Hi, everyone. I’m Naveen Pemmaraju, associate professor of leukemia in Houston at MD Anderson, and it’s my great privilege to be here with my friend Ruben Mesa and our colleague Dr Serge Verstovsek, and the three of us co-founded this auspicious occasion, Ruben, together, the Texas MPN Workshop.
Ruben Mesa: So we had this concept several years ago of really trying to bring together the MPN community in a unique workshop here in our home state of Texas to be able to dive deeper into some of the key issues in terms of the biology of MPNs, inflammation, clonal hematopoiesis, implications for prognosis, and really take a deep dive in terms of therapy where therapies are evolving, unmet needs in key parts. We’re excited to be here in-person. So let’s share with you just a little bit of the summary of that, particularly as it relates to how therapies are evolving. So first, I mean, why don’t we start with ET? You know, where do you see that we are now? And where is that cutting edge in ET?
Naveen Pemmaraju: Ruben, thank you so much. So I think for everyone out there in essential thrombocytosis, we are actually seeing some movement very nicely in both the research aspects and for the patient care. I think the traditional standards of ET have been this concept of either hydroxyurea or interferon, but a couple of new topics that are coming out in ET is looking at new mechanisms of action, new drug pathways, such as the LSD1 pathway, for example, and also looking at which patients may be more higher-risk than we thought before, molecular marker incorporation, etcetera. And then I think, also Ruben, trying to calculate and understand the JAK2 mutation versus say, the CALR, the MPL, is there a prognostic significance? And then finally, as you have talked about very nicely before our colleagues Ann Mullally in the United States in Boston, Professor Kralovics in Europe, starting to look at seeing if there’s unique targets, including immunotherapy, such as with the CALR mutation frequent in ET. So kind of a lot of development in our field of ET when maybe before there wasn’t.
Ruben Mesa: You know, it’s something I’m very excited about. These patients are heterogeneous. There clearly are some, not all, who really have significant suffering from their symptoms, recurring vascular events. They’re all concerned about risk of progression. So I’m excited about both there being some new drugs as well as some, perhaps unique capabilities to target CALR in the future.
Now in polycythemia vera, we had an exciting approval last year, November of 2021 in the United States with ropeginterferon alfa-2b, or BESREMi, previously approved in Europe. Some exciting things going on with PV, first, how do you think that rollout is going, and two, we’ve got some exciting new things, some hepcidin mimetics coming up on board. Where do you think they’re going to fit?
Naveen Pemmaraju: Ruben, you’re right. Again, just like we were mentioning in ET, but even more so in PV for our patients, lots of excitement. Not just in the research, but in the clinical space. Ruben just mentioned this ropegylated interferon, which amazingly led by our colleagues, Professor Hasselbach, Kiladjian, Gisslinger, and others, 7.5 years. So 7.5 year long-term data comparing the BESREMi ropeginterferon agent versus hydroxyurea really showing clinical benefit for patients specifically with p-vera. And I think also for you and me, what’s impressive is that the drug is now US FDA approved on the basis of that robust European data. So you and I, and others have already started to prescribe the agent as standard of care in the clinic. It’s very nice for our patients in that it’s only every two weeks injection in the beginning and then spaces out to one month, so we’ll see how that goes. But it’s it’s really great to be able to have another tool, if you will. And then you mentioned some of the other agents in clinical trial. The hepcidin mimetic, rusfertide, PTG-300, now completing Phase II and heading into a multinational Phase III. So again, lots of movement in our earlier MPNs, whereas maybe before there wasn’t.
Ruben Mesa: You know it truly is an exciting time, I think one for physicians to kind of come back to interferon. You know, community physicians really remember their father’s interferon, short acting, high-dose for CML or melanoma or renal cell. That was very toxic. This is a totally different deal. Individuals who use pegylated interferon alfa-2b, this is really quite helpful. So in new patients who need cytoreductive therapy in PV, I’m putting them on the ropegylated interferon. Individuals that are on pegylated interferon alfa-2a, if they’re having issues, I will consider absolutely a switch and have done so well. The new hepcidin mimetic, interesting, we also have a new one in our clinic by Ionis, a slightly different mechanism of action. But the same idea: re-create kind of a pseudo-state of anemia, of chronic disease to create hematocrit control without iron deficiency and the resulting toxicity.
Ruben Mesa: Now myelofibrosis tends to be the proven ground for drugs. Although it’s the smallest group of patients, it’s really the greatest unmet need. Now, we had ruxolitinib in 2011, fedratinib in 2019, and now pacritinib in February of 2022. And now some others coming up behind, momelotinib, which Serge Verstovsek presented at EHA, I presented at ASCO, showing great activity as a JAK inhibitor, improved spleen, symptoms and the potential of anemia. Pacritinib, particularly useful for individuals with thrombocytopenia first or second-line. Fedratinib and ruxolitinib, two real cornerstones, very active spleen and symptoms and good drugs. So first, in terms of JAK inhibitors, how do you see them kind of fitting together in your patients at the current time?
Naveen Pemmaraju: Right, Ruben and you and Serge and others have really been, and Claire Harrison, our colleague in the UK, have been at the cutting edge of all of these JAK inhibitors. So it’s great for our patients to know that in the US there’s now three approved JAK inhibitors, as Ruben mentioned with the fourth one, momelotinib, in the advanced stages of clinical development. I think this is the big question of our time. Just like you and I saw in the CML era when there were multiple drugs post-imatinib. What you said is correct. How are we going to sequence these drugs? How are we going to pick the right drug for the right patient in the absence of biomarkers or molecular guidance? And then what are the unique, shall we say, non-JAK inhibitor or beyond JAK inhibitor pathways that each of these drugs hits? And what are the benefits of that and the toxicity? So, I think you and I agree that it’s a good thing that we have more options for our patients. The FDA and regulatory agencies will give us the guidance on the particular niche areas, but a big win for our patients. I think also, the other concept is how we pair the JAK inhibitors with other chemo drugs, adjunct agents, growth factors. It’s just a whole new era for our patients with myelofibrosis, and as you and I know, stem cell transplant remains the only curative modality. So how do these drugs interact for the patient, pre-stem cell transplant and even post, if they need it?
Ruben Mesa: And then the final thing that we cover, which is the key one is, now we have multiple drugs with alternative mechanisms of action that clearly are having a role, both alone or in combination. Agents that may help to improve anemia, like luspatercept, agents that are telomerase inhibitors, agents that are BET inhibitors, BCLxL inhibitors, PI3K inhibitors, or others. Naveen, which of these are you most excited about, what are some of the Phase III data that folks are expecting to see soonest? You know, we both have been intimately involved in all of this development. But what should folks know at this point?
Naveen Pemmaraju: That’s right, Ruben. That’s very exciting. And as everyone knows out there, Ruben and I are active clinical trialists, not meant to be a summary, but to give people a flavor. There are three current, if you guys can believe it, combinations with JAK inhibitor, plus a novel agent in Phase III global multinational studies. One of them features inhibiting BCLxL that you and I are part of, the navitoclax adding on to ruxolitinib. Then there’s the pelabresib, BET or bromodomain inhibitor, and then even PI3 kinase combining with the rux JAK inhibitor. So those three in particular just because they’re in the later stages. But as you and I know and our colleagues around the world have tried any number of different other strategies, including telomerase inhibition, as you mentioned, targeting CD123, heat shock 90, apoptotic proteins, etcetera. I think the key for us is two: one is for folks to know out there no matter how rare these diseases are that we have people all over the world, labs, a lot of whom are collaborating together to look at new pathways. That’s what you’re mentioning to us, beyond JAK, and then working on the side effects and problems that people have, so thrombocytopenia, anemia. So how to deliver the JAK inhibitor, but then to improve the counts, I think those are the exciting areas for people to keep their eye on.
Ruben Mesa: Well, wonderful. I hope that we really left you with a sense of tremendous progress. You know, both exciting discussions here at this Texas MPN Worksop. But great progress, ET, PV, MF, and benefits that really result from the research into these diseases will impact not only MPN patients, but those with MDS, MPN-MDS overlap, hopefully have implications in terms of less patients progressing to acute leukemia. Might even have implications in terms of broader issues of health with clonal hematopoiesis, cardiovascular mortality. There’s even discussion on intersections of how clonal hematopoiesis interferes or has an impact on cognitive health, brain health and the risk of development of Alzheimer’s. So the whole body is connected, but it all starts with the blood. So we’re excited by what we do. Naveen, any final thoughts?
Naveen Pemmaraju: Well, I just really love any time I talked to Ruben, I get even more excited about what we’re doing. I think for you and me, as we’ve always said before, it’s all about our patients. So it’s a patient-centered approach, this Texas MPN Workshop, despite 2.5 years of pandemic, we’ve been able to bring folks together. Professor Barbui is here from Italy in-person. We’ve got folks here from all over the world connecting about MPNs here in San Antonio, and on behalf of Ruben, Serge Verstovsek, and myself, wer’e honored to be on this journey with all of you. And we just want people to know that they’re not alone. We’re here for them.
Ruben Mesa: Great, thank you.
The MPN Channel on VJHemOnc is supported by Constellation Pharmaceuticals, Kartos Therapeutics, Inc. and Sierra Oncology.
These supporters have no influence over the production of the content.
Ruben Mesa, MD, has participated in a consultancy role with Novartis, Sierra Onc, La Jolla, Pharma and Constellation; and has received research support from Celgene, Incyte, AbbVie, Samus Therapeutics, Genotech, Promedior, CTI and Constellation.
Naveen Pemmaraju, MD, is a member of the ASH Communications Committee and the ASCO Leukemia Advisory panel; has participated in consultancy work for Pacylex Pharmaceuticals, ImmunoGen, Bristol Myers Squibb, Blueprint Medicines, Clearview Healthcare Partners, Astellas Pharma US Inc., Triptych Health Partners and CTI Biopharma; has received grants from Affymetrix and SagerStrong Foundation; has received honoraria from Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Diagnostics, Blueprint Medicines, DAVA Oncology, Springer Science + Business Media LLC, Aptitude Health, NeoPharm Israel and CareDx, Inc., has received research support from Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix, Daiichi Sankyo and Plexxikon; and has received travel reimbursement from Stemline Therapeutics, Celgene, MustangBio, DAVA Oncology and AbbVie.
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