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Aaron Gerds, MD, MS, a hematologist in Cleveland Clinic Cancer Center’s Leukemia and Myeloid Disorders Program and Deputy Director for Clinical Research at the Taussig Cancer Institute joins the Cancer Advances podcast to talk about the MOMENTUM trial that was presented at the American Society of Hematology (ASH) 2022 annual meeting. Listen as Dr. Gerds discusses myelofibrosis, the differences between the trial results from 24 to 48 weeks, and the exciting new approaches that are coming to the field.

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Insights into the MOMENTUM Trial

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one and sarcoma programs. Today I'm happy to be joined by Dr. Aaron Gerds, Deputy Director for clinical research at the Taussig Cancer Institute, and a hematologist in Cleveland Clinic Cancer Center's Leukemia and Myeloid Disorders Program. Aaron previously joined us on this podcast to discuss the mortality risk associated with less intensive therapies for acute myeloid leukemia. He's here today to talk to us about the MOMENTUM Trial, so welcome back.

Aaron Gerds, MD, MS: Thanks a lot, Dr. Shepard. It's a pleasure to be here.

Dale Shepard, MD, PhD: There you go. So, remind us of a little bit about what you do here at Cleveland Clinic.

Aaron Gerds, MD, MS: Well, lots of different things, of course.

Dale Shepard, MD, PhD: I like the chuckle. That means a lot of things,

Aaron Gerds, MD, MS: I've got a hand in a lot of pots, certainly everything ranging from caring for patients with myeloid disorders and leukemia to trying to be as involved as I can with VeloSano, our philanthropy arm to support research funding for cancer medicine as well as cancer medicine and clinical trial infrastructure. So, heading up kind of the way we think about clinical trials and what trials we should have in our portfolio, how should we manage these, and how do we partnership with folks across the street at University Hospitals and Case Western Reserve University under the guise of our comprehensive cancer center.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to talk about myelofibrosis. So as an overview, give us a broad picture of what myelofibrosis is.

Aaron Gerds, MD, MS: So, myelofibrosis is one of these Ph-negative or Philadelphia chromosome negative myeloproliferative neoplasms, so kind of a slim section of leukemias, if you will. There are chronic leukemias, meaning that people can live many years even without treatment. And so often patients are diagnosed with myelofibrosis in kind of an insidious way. They had some symptoms that kind of brew up. Maybe they get a little bit of night sweats, maybe their spleen gets big, and they have some early satiety. Maybe their doc notices that their blood counts are going down or up and refers them to a hematologist for further workup.

Dale Shepard, MD, PhD: Excellent. And so, what are the current therapies for this? When you said this can be going on for a long period of time. What do we use to treat? What are the triggers to treat?

Aaron Gerds, MD, MS: Well, the treatment of myelofibrosis is a great historical story, too. In the 1950s, Dr. William Dameshek, who was a past President of the American Society of Hematology and first editor of the Journal of Blood said, you know what? These diseases, polycythemia vera, essential thrombocythemia and myelofibrosis have a lot in common clinically. And he said, "you know what? I bet there's some sort of pathobiology that's unique to this set of diseases. And sure, as schnitzel. Several years later, in 2004, 2005, four groups independently identify recurrent mutations in a gene called JAK2 in patients with MPNs. And that launched this whole C-change in the way we think about this disease.

On the tail end of that, were the development of JAK inhibitors. So, the first JAK inhibitor approved for the treatment of myelofibrosis was Ruxolitinib, and that was approved in 2011. And there were other ME2 JAK inhibitors being developed in this time. A lot fell away due to toxicities or a lack of efficacy. But ultimately in 2019, we had Fedratinib that was approved. And then about a year ago, we had Pacritinib that was approved. Each of these JAK inhibitors are slightly different and do slightly different things within the field, but really JAK inhibitors have been the mainstay of treatment up and through the current moment.

Dale Shepard, MD, PhD: And I guess maybe we'll cover a little bit more about this, but you've mentioned that there's toxicity differences. Some of them quite honestly just didn't work. Are there other things in play, do you think, in terms of other genetic abnormalities we just haven't uncovered yet?

Aaron Gerds, MD, MS: No doubt. Yeah. I always say when I give these talks about myelofibrosis, that myelofibrosis is not CML. Everyone's very familiar with chronic myeloid leukemia. It's a one hit wonder as a singular mutation. If you hit that mutation, if you will, you can obliterate disease with just a pill and you put people in effective cures. So, there are clearly other pathways involved. Most patients will have not just a mutation in the JAK-stat pathway, but in other pathways that are key in developing this disease. And so really going forward, the future is a multi-drug, multi kind of targeted approach that is being developed in a large number of randomized phase three trials that are ongoing right now.

Dale Shepard, MD, PhD: Of course, the CML story has spurned thousands of efforts to find the magic bullet.

Aaron Gerds, MD, MS: I mean, we shot for the moon, hit it, and have never been able to do it since.

Dale Shepard, MD, PhD: Yeah. Excellent. So, we are going to talk about something called the Momentum Trial. So, tell me a little bit about the origin of this trial and what we're trying to find out here.

Aaron Gerds, MD, MS: Yeah, so Momentum study is really focusing on this new JAK inhibitor called Momelotinib. And you might ask yourself, well gee, you already have three JAK inhibitors. Why do you need a fourth? Well, there's a big problem in myelofibrosis, it's anemia. So roughly 40 percent of patients will be anemic at the time of diagnosis. In fact, it is a diagnostic criterion and as a criterion we often use in our prognostic scoring systems. So, anemia is incredibly common and is associated with a worse prognosis.

Virtually every patient at some point in time will become anemic over the course of their disease's span. So again, a really big issue. Our main stage JAK inhibitor Ruxolitinib, has a common side effect of worsening anemia. So, it can take this problem and potentially make it worse. Fedratinib does likewise as well. Pacritinib is kind of weird. It works in cytopenia myelofibrosis, so it may not affect anemia as much, but it has a very narrow label indication just for patients with platelet counts less than 50,000. So, it's kind of a subpopulation of myelofibrosis.

So, new ways to impact anemia are desperately needed. And Momelotinib turns out in some of the earlier studies, we've noticed that patients who were anemic or transfusion dependent became transfusion independent unexpectedly. That was seen in phase two trials. It was seen in two previous randomized phase three trials. And subsequently in this phase two trial, which we helped lead here at the Cleveland Clinic, we saw that roughly 40 percent of patients who were transfusion dependent became transfusion independent on Momelotinib. These are patients who were previously treated with other JAK inhibitors.

And through that work in that phase two trial, we identified a catnip for hematologists, if you will, hepcidin as the main reason. So, it turns out Momelotinib inhibits this molecule called ACVR1, which is a regulatory factor for hepcidin. Hepcidin is the master iron regulator in our body. It can block or allow for the transport of iron in and out of the reticular endothelial system. So, in effect, what it's doing with this drug is it's treating the anemia in inflammatory block by allowing iron to be shuttled throughout the reticular endothelial system improving erythropoiesis.

And so, the Momentum Study said, okay, well let's really focus in on these anemic patients with myelofibrosis and see if it does a better job than other available drugs. And of course, for this trial, Danazol was picked as a comparator because it is an active agent in treating anemia in myelofibrosis. And one of the kinds of common tools that we use in our toolbox to treat anemia. Although some may argue that it is the chlorambucil of myelofibrosis, it doesn't do a lot to shrink spleens or treat symptoms, but definitely is an active agent in treating anemia. And so that's kind of the origin of momentum study.

Dale Shepard, MD, PhD: And patients had already received JAK two inhibitors?

Aaron Gerds, MD, MS: Yeah. So, in the trial it was patients who were previously treated with a JAK inhibitor who were anemic and symptomatic from their myelofibrosis and had a platelet count of at least 25,000.

Dale Shepard, MD, PhD: And so, could anemia be disease related anemia or treatment related anemia?

Aaron Gerds, MD, MS: Yeah. To throw out a common medical term, it is multifactorial in patients with myelofibrosis, it's due to the dysfunction inherent in the bone marrow. It's due to splenomegaly sequestering red cells. It's due to potentially JAK inhibitors making the anemia worse, and anemia of inflammatory block, as well as some patients are actually truly iron deficient as well.

Dale Shepard, MD, PhD: Gotcha. So, what kind of responses were seen in the trial?

Aaron Gerds, MD, MS: Yeah, so the top line results were reported at the ASCO meeting this past year and later published in The Lancet. So, what we saw was that compared to Danazol, Momelotinib had a non-inferior transfusion independence rate. Roughly 30 percent of patients remain transfusion independent on treatment. We saw that it had a better spleen volume response, so the proportion of patients had at least a 35 percent reduction in their spleen volume and a better symptom response. The proportion of patients that had at least a 50 percent reduction in their total symptom scores as measured by the MPN SAF, the Myeloproliferative Neoplasm Symptom Assessment Form for myelofibrosis. So clearly better than Danazol at shrinking spleens and improving symptoms and just as good, if not a little better. If you just kind of eyeball the numbers, it looks a little bit better. But it was a non-inferiority measure, so we can't officially say that it was better at preventing a transfusion dependency from occurring. So clear in all those marks at week 24, it hit everything. Hit all of its primary and key secondary endpoints.

Probably the most important bit of information that gets overlooked from this trial is the toxicity side. And early in the development of Momelotinib, there was concern over peripheral neuropathy. In fact, we did not participate in one of the earlier trials in the frontline setting because of the concerns of peripheral neuropathy. After a couple of studies, it was quite significant and not totally reversible. The rates of peripheral neuropathy in this study, and actually the previous two studies with Momelotinib didn't show very high rates of neuropathy. It's less than 3 percent, which was actually the same rates we saw in the Danazol arm, so it may be something inherent in the disease in fact. And with the week 48 data that was reported out at the ASH annual meeting here in December, we saw that even with extended duration of treatment, the rates of peripheral neuropathy remained very low.

Dale Shepard, MD, PhD: Do we have any idea why the discrepancy between the early studies and is this just better management of use of the drug?

Aaron Gerds, MD, MS: It's all speculatory, there was no clear mechanism action to cause the neuropathies. I suspect it probably was a combination of patients who were incredibly sick and had other medical issues, perhaps malnutrition played a role in it as well.

Dale Shepard, MD, PhD: I'm going to step back a second for us, non-hematologists. Spleen volume?

Aaron Gerds, MD, MS: Yeah.

Dale Shepard, MD, PhD: And the change in spleen volume, is this primarily a concern for symptoms like abdominal pain or anemia and cytopenias as a result? A little of both?

Aaron Gerds, MD, MS: A little of both. In the myelofibrosis world, splenomegaly has become the thing because for regulatory approval, it's something easy to measure. You get a CAT scan, you get a volume, it's a black and white number, and regulatory authorities love that kind of stuff. When you're talking about symptoms and quality of life, that's really hard to capture and measure in a very granular way. So, spleen volume has become the thing to do in myelofibrosis studies. And yes, we generally classify symptoms in the two categories. One is cytokine mediated symptoms, and the others are spleen mediated symptoms. So early satiety, weight loss, abdominal pain, kind of being the key factors there. Where cytokine mediated symptoms, we think more about night sweats, fevers, bone pain, itchy skin, and the like.

Dale Shepard, MD, PhD: Excellent. This is of course being used as a regulatory approval trial. If this gets approved, how's this going to change the treatment landscape?

Aaron Gerds, MD, MS: I'm struggling with this quite a bit as I take off my investigator hat and I put on my NCCN Chair hat, because we're going to have to put this in guidelines, and where are we going to stick it? I think independent of guidelines, it's quite clear that anyone who has anemia, who has myelofibrosis, who has a platelet count over 25,000, this drug could certainly be used because that was the basis of this trial. I think there's going to be tougher questions of do we use it in the frontline or second line setting? So, in the frontline setting, there was a prior randomized phase three trial, the simplified study that did show some efficacy, but maybe not better efficacy than Ruxolitinib. It was kind of plus minus compared to Rux where momentum was done in patients previously exposed to a JAK inhibitor. So, to me, a question is do you use it in frontline?

Personally, I think it has a lot of utility in the frontline. Looking at the simplified trials, it was on par with Ruxolitinib. So, if you get this on spleen and symptom benefit, but yet you get this added anemia benefit, it only makes sense to use it in a very broad way. I think it will have a clear indication in the second line. And it all ultimately depends on what the label looks like. So, if the label makes a line in the sand with a platelet count of a certain degree, it will somewhat limit what we can do with the drug. If it is frontline or second line, is it going to be just for anemic patients or any patient with myelofibrosis? I think that's the big question mark in all our minds thinking about how are we going to incorporate this drug?

Dale Shepard, MD, PhD: And of course, there's always an unpredictable factor what that label's going to look like.

Aaron Gerds, MD, MS: Totally. Who knows?

Dale Shepard, MD, PhD: When we think about, you mentioned at the beginning things about multiple pathways and other approaches. What's most exciting looking forward to?

Aaron Gerds, MD, MS: The way I kind of see it is there's kind of three waves in myelofibrosis. There's the wave we're on right now, which is clearly going to be Momelotinib. Is this drug going to get approved this June or not? And then the next wave is upfront combinatory therapies. So, combining a JAK inhibitor like Ruxolitinib, which has a pretty favorable side effect profile, not a lot of toxicities there outside of bone marrow suppression, combining that with other agents that can hit other pathways. So, there's a couple of really exciting lead candidates moving through that. One is Pelabresib, it's a BET inhibitor. BET is a key dysregulated pathway in myelofibrosis. We led a clinical trial here, a randomized phase three trial, which is another regulatory focused study comparing the combination of Ruxolitinib and Pelabresib versus Ruxolitinib plus placebo in patients with myelofibrosis in the frontline setting. That study is completed enrollment, and the patients are in their initial follow up.

So hopefully within the next six to 10 months, we'll get some frontline data from that study. There's another combination with ruxolitinib and Navitoclax in the frontline setting that's being studied. Both things are being studied in the second line setting as well to rescue responses, if you will. And to me that's kind of the next big wave is upfront combination therapy.

The wave after that I think is incredibly exciting. So, the big splash of the annual meeting for the American Society of Hematology this year was a plenary abstract of a monoclonal antibody against calreticulin, which is a mutated protein in myelofibrosis cells. So roughly a third of patients with myelofibrosis will have this cal reticular mutation. And it acts in this kind of paracrine fashion where it's secreted from the cell and goes and activates the cytokine pathways that leads to the disease. And you could think, well, if you just get an antibody in there to neutralize it, you've effectively eliminated the disease, or you might cause cellular or immune system killing of those cells. So just a naked antibody could have a huge impact. You think about Rituximab for lymphomas and lymphoid mil, this could be our Rituximab potentially.

And then beyond that, you think about, well, if we have a monoclonal antibody, we can then produce bispecific antibodies or even engineered cellular therapies like CAR T-cells in the near future. So that's kind of the third wave that's coming down. That's super, super exciting.

Dale Shepard, MD, PhD: Well, so lots of exciting things and even more problems from a guideline standpoint about when you use what?

Aaron Gerds, MD, MS: I don't know. I think the guidelines, I sometimes don't stay up at night thinking about this, but I stay up at night thinking about this, that how are we going to do this? Because there's so many drugs now, I can't say that it's an embarrassment or enriches multiple myeloma or breast cancer, but it's certainly so different from when 10 years ago when I kind of started out where there was a drug that was just approved and that was it, that's all we had. And all we had to do was figure out how we can stretch this drug to infinity to take care of patients? And now we have three, potentially four JAK inhibitors, combination therapies, antibodies on the horizon, it's a wild time right now in this disease.

Dale Shepard, MD, PhD: And I guess it just gives us a sense, as we do research, we come up with new things, we come up with better therapies. From a patient standpoint, what does the world look like now compared to before as these first JAK inhibitors were in terms of either management of symptoms? Or essentially, how much longer are people living now?

Aaron Gerds, MD, MS: I think that is a fantastic question. There was a really nice analysis done a couple of years ago where quite simply we looked at the survival before Ruxolitinib's approval, so before 2011, and the survival of patients diagnosed with myelofibrosis after in a large kind of US Medicare database. And the survival effectively doubled. And that was almost independent of whether or not they received Ruxolitinib. So clearly, patients who had received Ruxolitinib did better than those who did not after approval, but even patients who didn't receive Ruxolitinib after approval survived longer. So, it's telling us that these advances have not only led to immediate effects and benefits for individual people, but it's helped the community out recognize this disease and manage this disease much better, thus improving survival for these patients.

Dale Shepard, MD, PhD: That's fantastic. And I guess that was, you mentioned recognize the disease. That was where I was going next. We've had all this discussion about how you treat it once you know it. And then how do you treat recurrences and things like that? Let's go back to the very beginning. What are the challenges in people even getting to your clinic with the diagnosis?

Aaron Gerds, MD, MS: Yeah, I think things can go round and round. I just met with a patient who had an elevated white count, and they saw their doc and they said, yep, your white counts. Oh, you must have cellulitis because they had a rash. Okay. Treat the cellulitis, it didn't get better. Okay, well, your white count's still high. Well, let's give you some more antibiotics. And you go through three or four rounds of antibiotics. And then you're like, wait, this can't be just a garden variety infection. It must be something else. And then the workup starts, or the common thing that we see a lot is anemia in older patients. So, anemia in older patients, or dare I say, geriatric patients, is not normal. It's not normal to be anemic. And people are like, oh, you're just a little anemic. No big deal. No big deal. No big deal. And then this goes on for years.

Dale Shepard, MD, PhD: And unfortunately, it's a mindset.

Aaron Gerds, MD, MS: It is totally a mindset.

Dale Shepard, MD, PhD: Oh, marrow doesn't work as well. You're old.

Aaron Gerds, MD, MS: Yeah. And it's not true. The marrow should work normally if you're older, yes, your cellularity is going to be down. Yes, you're more susceptible to flux and influences of cytokines and immune effects and stuff. But your marrow should still be producing plenty of red cells. And so, anemia in the elderly is not normal. And if I could say one point, that would be it.

Dale Shepard, MD, PhD: Yeah, that's important. And I think that in addition to this whole concept of new therapies, that's huge. Just getting people to the right therapy.

Aaron Gerds, MD, MS: Just something as simple as that. And again, the field is evolving so rapidly. So definitely encourage folks to partner with those people like me who do this all the time and help work through some of these subtleties and rapidly changing landscapes. I still get patients referred to me who've not been through any JAK inhibitors because maybe the referring doc just hasn't had experience or is familiar with them or doesn't know they're available or the mechanisms to get them. And so, we're always happy to partner with folks to help navigate the rapidly changing landscape for these diseases.

Dale Shepard, MD, PhD: Wow. Well, you've provided some great insights for us today. I appreciate you being with us.

Aaron Gerds, MD, MS: My pleasure. Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website, at consultqd.clevelandclinic.org/cancer.

Thank you for listening. Please join us again soon.

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