Ruben Mesa:

Hello, my name is Ruben Mesa and I’m the president of Atrium Health Levine Cancer and the executive director of the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. And joined here today by my wonderful decade-long friends and global MPN experts, Professor Claire Harrison from Guy’s and St. Thomas. Welcome, Claire.

Claire Harrison:

Thank you.

Ruben Mesa:

And of course, Professor Jean-Jacques Kiladjian from Hospital St. Louis in Paris. Jean-Jacques, welcome.

Jean-Jacques Kiladjian:

Hi, Ruben.

Ruben Mesa:

Well, we’re coming to you live from ASH 2023 here in San Diego, and this really is the aggregate meeting for true MPN updates, really on an international basis. This and the European Hematology Association meeting really being key ones. Let’s jump right into it. Claire, let’s first start kind of more with ET. Anything that struck you, something interesting that folks that are watching this that may be impacting their practice or changing the landscape for ET in the near future?

Claire Harrison:

Well, I think there’s a couple of things. One is a young person’s analysis, but I’m going to leave Jean-Jacques to talk about that because that’s really his brainchild. And I suppose the most important thing for ET is that we are on the verge of doing some very large Phase III studies with bomedemstat, the LSD1 inhibitor, which has been tested quite extensively in myelofibrosis and in a Phase I/II study with ET. And what’s been presented here is an update on that study showing durability of responses, but also an emerging key theme in our field is about molecular responses. We’ll be seeing an oral presentation on that and then we’ll be rolling into some large Phase III upfront and second line studies. I think that’s the main positive aspect for ET at this meeting.

Ruben Mesa:

I think it’s going to be key as we see more options evolving for ET. Bomedemstat, I had the pleasure of having an investigator initiated study for that in ET when I was in San Antonio. And clearly active, so it’ll be great to see that go through the Phase III process to kind of quantify that benefit. We have the ropepeginterferon studies in ET that continue to mature, one fully accrued with the SURPASS-ET study. Excited to see those data as well as we hopefully expand our armamentarium a little further.

Claire Harrison:

It’s certainly a long time since we had a new drug for ET patients, right?

Ruben Mesa:

Yeah.

Claire Harrison:

Ruxolitinib not looking so positive in the MAJIC ET data probably because it’s causing anemia as we expect. Good for symptoms but not approved in that setting. It’d be really exciting if we can get to delivering a new agent for those patients.

Ruben Mesa:

No, without question. And Jean-Jacques, more continues to evolve in PV. Obviously you’ve helped to lead this field for so long. What struck you this ASH about PV?

Jean-Jacques Kiladjian:

Well, we have asked, as Claire mentioned, we could collect a large number of young patients, younger than 25 years of age when they were diagnosed with ET or PV and most of them were PV. And we could study based on that large number of patients, the impact of drugs on their outcome and found, and that will be presented today here at ASH that treatment with interferon alpha could have an impact, a very positive impact on progression-free survival with less transformation, less evolution to fibrosis. Really important information for this particular population of young patients. We also have new data showing that molecular response can be achieved with ruxolitinib also, this was found in the MAJIC PV study that was presented last year, but here we see again with ruxolitinib an impact of this drug for reducing the mutant allele burden and hopefully helping to modify the disease history.

Ruben Mesa:

Wonderful. Well, it’s got to be so gratifying for you building on the work of Dick Silver and Harriett Gilbert and all the work that you had done. As we continue to learn more about the impact of interferon, it’s so important to really have an individual patient view as you manage these patients. And again, younger patients, I think just really bringing more data to what we’ve always expected, more impact on the disease, good control. We clearly have learned appropriate dosing and managing the patients is really key for that.

Claire Harrison:

I think as we’ve learned actually, Jean-Jacques, from that cohort, the risk of progression is not small for these young patients in the cohort that we pulled together across the EHA group. It’s 20% of patients at 20 years. And so really doing these kind of retrospective data analysis is a really important way of understanding that and understanding the impacts of the decisions we’ve made today. And it runs in line with Professor Barbui’s data about low-risk PV not really being so low-risk and needing to think about intervening. I wonder if you agree?

Jean-Jacques Kiladjian:

Yes, absolutely. Although we don’t have really new drugs this year in the field of PV coming out, we learn more about how to treat these patients and maybe change our way of treating them from the beginning. And especially young patients as you mentioned, because probably phlebotomy only is not the solution. It reduces the risk of vascular events, thrombotic events on the short-term but the disease is still there. And we saw with this cohort of young patients that after 20 years, the risk of evolution is really high and we need probably to assess now new strategies and with these new drugs to see how we can introduce them maybe earlier in the disease evolution to prevent such transformation.

Ruben Mesa:

And from my end, I’m hopeful that we’ll continue to learn more about the biology of why patients transform so we can better monitor that therapy in between. I know it’s been a frustration for myself is I’m never really quite sure if I’m at the right dose.

Jean-Jacques Kiladjian:

Mm-hmm.

Ruben Mesa:

I can control the counts, but is that dose sufficient for controlling counts really equivalent to avoiding progression? I don’t think we know, but I think it’ll be great as we learn more about that biology. Is that molecular markers, is that some cytokine profile, is that something else that tells us that?

Claire Harrison:

I think it’s the molecular marker, but my personal bet would be on that it’s the 50% or 25% reduction or even better, the phenomenal responses you’ve seen in some patients.

Jean-Jacques Kiladjian:

Yes, and I think the more we study these patients in depth, I mean, for example, by next-generation sequencing, we collect more and more information and we see that in fact these patients have sometimes additional mutations to the driver mutation that completely can change the outcome of the disease and detecting them early may probably lead in the future to more personalized or precision medicine. I don’t know how we can call that, but this is really a field I think MPNs and PV and MF in particular where these molecular markers will help us in the future to better tailor the treatment to an individual patient.

Ruben Mesa:

I know I’ve been evolving in my practice to try to get the NGS myeloid panels more really across the board, particularly at baseline. I think the data will become more and more important over time to give us really a window into that. Well, let’s pivot finally to myelofibrosis. In many ways, the energy around new drug development frequently begins with myelofibrosis, greatest unmet need, greatest threat to mortality. We have here in the US approved now four JAK inhibitors, ruxolitinib, fedratinib, pacritinib and most recently in September, momelotinib with an indication for myelofibrosis with anemia. And again, anticipate that those will be evolving in terms of availability in different parts of the world in different timeframes. But clearly the energy in this meeting was really around the first Phase III combination studies that were reported out in the frontline setting for myelofibrosis and what those mean. Claire, what was your takeaway? We had Phase III of both ruxolitinib plus pelabresib versus rux alone and then ruxolitinib plus navitoclax versus rux alone.

Claire Harrison:

Well, it’s a big tease, isn’t it?

Ruben Mesa:

Yeah.

Claire Harrison:

But it’s also probably quite a little bit confusing for our listeners because much as we were just discussing learning more about biology, the problem in myelofibrosis is we haven’t evolved our endpoints. Competing sessions, strong data, large studies. Let’s talk first about pelabresib maybe.

Ruben Mesa:

Mm-hmm.

Claire Harrison:

This is a really big study, 430 patients randomized just by one is the second-biggest study we’ve ever-

Ruben Mesa:

After SIMPLIFY-1, yeah.

Claire Harrison:

After SIMPLIFY-1, but we know that JAK inhibitors have changed the way we think about the disease. We’re just over a decade, maybe 12, 13 years now, but we know that there are limitations. Striving to do more is important. Thinking about the impacts of these therapies on the hallmarks of disease, but then having these studies talking first about pelabresib, strong signal on spleen, good signal on toxicity. Actually more grade three events strikingly in the ruxolitinib monotherapy arm, but missing on the symptom aspect. And I think it makes us reflect that actually, should we really be aiming to drive down the symptom burden further or is it enough to say we add another drug, it has side effects, but the patient’s symptom benefit is the same. And I guess you’re the guru on that, Ruben. Let’s hear what your thoughts are.

Ruben Mesa:

Well, I think the near doubling of spleen volume response rate with both trials, I think very, very meaningful. In the pelabresib study, we did analysis to show when one looks at it by absolute change in total symptom score, it was nearing statistical significance for the combination. And from my end, I think that’s very relevant. One is we look at the granularity of the data. I think there is a bit of a ceiling effect in terms of how much symptoms can improve because again, this was frontline, patients had a significant improvement in symptoms. You start to get down to that range where again, you’re bumping up against kind of the maximum amount that you can improve the symptoms. There really may not have been enough really kind of space in terms of the residual symptoms to really prove superiority. I view it as very positive. I look at the symptoms also to confirm that patients are not really feeling worse by being on combination, which clearly they were not. Now Jean-Jacques, Claire and I, they had them in two different rooms.

Claire and I were in the room for the pelabresib study, although we were listening to the navitoclax study on the virtual platform. Very high-tech. You got the phone open, have the AirPod in for one abstract, listening to the other. But you were in the room for the discussion around navitoclax study. What was your takeaways?

Jean-Jacques Kiladjian:

Yeah, it was very close. As you mentioned, the two studies provided almost similar results in terms of spleen volume reduction, doubling compared to ruxolitinib alone, missing for the further improvement in symptom response. But as you said, is it really the aim? The first aim is not to harm the patient and to keep the response there, that is already wonderful on rux. We must say that the vast majority of patients is doing well on rux, and it’s nice to see that adding another drug doesn’t impair that response. Then what is the aim of adding another drug on first line therapy? Probably not just for the symptoms, but you want probably to alter again, deeply the disease history, the risk of transformation to acute leukemia, et cetera. I think to fully appreciate the impact of these two combinations, we need to wait for more biological information in terms of biomarkers, is the fibrosis better on these drugs? Is the mutant allele burden lower with these drugs?

Does the cytokine profile move in the right way? I think this will bring us more information to see if really adding something to rux has a meaningful impact on the outcome of patients on the long-term as first-line therapy.

Ruben Mesa:

I think timing is going to be very important. I’m mindful, we were reminiscing that we were here in San Diego 12 years ago exactly when the matured COMFORT data was being presented. It had been approved in the US just in November of 2011, and that I think some of these benefits will take time. I think part of the challenge of large Phase III studies is you want to read out those results as early as you can, but time really is important for progression-free survival and these other benefits. Before we conclude, what are things you guys are excited about as we’re moving forward? I know from my end, there remains a lot of buzz around both monoclonal antibodies and vaccine therapies around calreticulin. Those will be moving into clinical trials. I think a couple patients have already been dosed, but obviously very, very early at this point. Claire, things that you’re really looking forward to in this next year or two for us to learn on?

Claire Harrison:

Well, I think many of the things we’ve already discussed, clearly super excited about calreticulin, but we need to understand a lot more about that. How’s it going to work, toxicity, et cetera. And we’ve got at least three different modalities there. Bispecific, vaccination, antibody, and maybe more than one antibody. I think seeing the maturity of these Phase III trials is going to be really important for me. And we have the little teaser for pelabresib on fibrosis responses, cytokine responses and anemia responses. We didn’t see that for navitoclax. I’m looking forward to more data evolving from that perspective. And I’m looking forward to a study that Jean-Jacques and I are working on together in PV, the frontline PV study MITHRIDATE, soon to open in France. Fingers crossed. Yeah.

Ruben Mesa:

Excellent. And Jean-Jacques, how about yourself? Something you’re excited about for MPNs for 2024?

Jean-Jacques Kiladjian:

What’s exciting in this field, I think compared to other maybe, is that the more we study them, the more the complexity occurs and it’s getting more and more complex. Patients are more and more individual rather than a very homogenous group. And there’s room for many, many new studies as well in terms of biology and understanding the disease, but also for the therapy of these patients. As Claire said, we are happy to see that some of these combinations that we hear about for many years are now maturing and the data are coming out. Probably next year we will have more of the results of these combos. And I think probably there will be room for almost all of them because each patient is different and each patient need is different, and these drugs target different aspects of the disease. Exciting times, I think.

Ruben Mesa:

Wonderful. No, agree. I think the more drugs the better for our patients. We clearly learn that there’s a lot of differences. The more options we have, the better off we are. They clearly end up having other secondary uses. In ruxolitinib down the States, they’ll use that for everything from vitiligo to other conditions. It’s all good, all very beneficial. Well, we’ll leave it there. Hopefully this leaves folks with a sense of a lot of movement in the MPN field, a lot of new therapies, important trials being done, excited by the progress. And as always, just any time to spend time with my good friends, Claire and Jean-Jacques, is time well spent. Thank you.

Ruben Mesa – AbbVie, CTI, Incyte, Sierra: Consultancy, Honoraria, Research Funding; Leukemia & Lymphoma Society: Membership on an entity’s Board of Directors or advisory committees; PharmaEssentia: Research Funding; Blueprint, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Novartis: Consultancy, Honoraria.

Claire Harrison – Morphosys: Honoraria, Speakers Bureau; AOP: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Galecto: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Jean-Jacques Kiladjian – Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; AbbVie, AOP Health, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, Novartis, Pharmaessentia.: Consultancy.