This video features Michael Styler, MD presenting on Myeloproliferative Neoplasm. This presentation was given at our April 11th New Directions in the Diagnosis and Treatment of Hematologic Cancers Symposium in 2023.
Hello, everyone. I'm Doctor Mike Steer, a member of the bone marrow transplant and cellular therapy department here at Fox Chase. Uh This evening, I'm going to present um some recent data sets presented at the ash meeting from December on mylo proliferative neoplasms. Most of the focus will be on myelofibrosis and I'm going to present uh four uh five studies, uh two on the relatively new Jack inhibitors, Maloni and Parini as well as some combination studies which combine Jack inhibitors with uh ABC L two inhibitor in vila and a bet inhibitor aggressive as well as um a, a very early presentation of a new anti mutant CAL or antibody, which um may be a, a game changer for patients with uh cow mutated mylo fibrosis. So this is the the current uh set of available Jack inhibitors. Uh Rux lib was the first Jack inhibitor uh approved and uh it it's been effective at decreasing splenomegaly and uh improving symptoms though it has little impact on disease course and is uh has significant hematologic toxicity. So it's contraindicated in patients with severe thrombocytopenia. The next approved agent was the DR which is effective in some patients who progressed on Ruxin but also has the same hematologic toxicity as well as uh some G I toxicity and neurologic toxicity uh in the form of war against encephalopathy due to an acquired thin uh deficiency. The latest Jack two inhibitor that was FDA approved is Parini um which is exciting, it's a multi kinase inhibitor and has significantly less hematologic toxicity. So it's safe for patients with platelet counts less than 50,000. And uh today, I'll review AAA study uh showing that it may actually improve anemia in these patients. The last one we'll discuss is Maloni. Um this is not yet FDA approved, although it's anticipated that it likely will be shortly. It also has significantly less hematologic toxicity and may be useful in treating the anemia of patients with myelofibrosis. So, the first study we'll discuss is the momentum study, which uh is a multi armm study. But what was presented at Ash was um uh a group of patients who previously um were treated with the Jack inhibitor um and progressed and then received either maloni or danazol. So as most of the Jack inhibitors malot, it inhibits Jack two as well as Jack one. But interestingly, it also inhibits something called a CV R one or act in a receptor type one, active in receptor type A type one. Um and this is thought to be important because the uh when the active in receptor type one is activated, it turns on an inflammatory response that among other things leads to increased levels of pepsin. This results in decreased iron absorption and utilization and leads to uh anemia of chronic disease. So, because mama Latin, it inhibits that receptor, it's hoped that it will decrease hein and help ameliorate. The anemia seen in patients with myelofibrosis. And indeed, in the momentum uh study, uh they evaluated patients uh rate of becoming transfusion independent at 24 weeks. And in the malot arm arm, 30.8% achieved this outcome. Whereas with danazol, only 20% achieved uh the same outcome. So, while those are uh small numbers, we're hopeful that that uh this can be a useful agent for treating patients with anemia and myelofibrosis. It appears to be a well tolerated uh jack inhibitor. Early studies suggested that there was a an increased incidence of peripheral neuropathy. However, in this study, um it was quite minimal. There were also a uh there was also a presentation of ribs use for patients with um anemia and myelo fibrosis. Interestingly, Parini is an even more potent AC B R one inhibitor about four times more potent than maloni. So Britain has already approved um can be used in patients with platelet counts less than 50,000 at full dose regardless of cyto penia without increased toxicity. And uh study persists too um was updated at the recent ash meeting and they looked at clinical improvement in hemoglobin in 24 weeks similar to the Latin of study. Um Here, 25% of patients either became transfusion independent or had a two greater than two g increase in their hemoglobin compared to their baseline. This was compared to only 12% in patients receiving best available therapy. So we have a couple of agents now that, that appear to be useful in in helping the anemia of myelofibrosis. However, none of the jack inhibitors are really effective at controlling the natural history of the disease. They don't affect fibrosis and they don't decrease the incidence of uh transition to acute leukemia. So, there's been a lot of interest in combining other agents with Jack inhibitors to see if we can achieve disease modification. One of the agents that was discussed at ash is Nola and it was combined with Rox in, in this study. So Nala is ABC L two BC L X inhibitor and patients with myelofibrosis uniformly have increased levels of of BC L two and BC L X. Um So the hope was that adding Nevio claques would enable those mutated cells to uh undergo apoptosis and potentially change the natural history of the disease. So, this is called the refined study and it was uh uh looked at in patients who are jack inhibitor naive uh receiving uh plus, right. So the the standard evaluation points in patients receiving jack inhibitors um is significant reduction in spleen size and the Hallmark is 35% spleen size reduction it's questionable how clinically meaningful that is. But it is the the gold standard in evaluation of jack inhibitors. And in this study, 80% of patients achieved that goal. Interestingly, um nine of the 32 patients evaluated or 28% achieved at least one grade reduction in degree of ma ma fibrosis. And two of those nine achieved um complete remission, complete reduction of their myelofibrosis. It took about three months to achieve that. And in some of these patients, it appears to be a durable response. And so possibly the addition of novelas will change the natural history of my fibrose. The other agent that was uh evaluated at ash um was he which is a debt inhibitor and it too was combined with Roxy in treatment. I knew patients with my fibrosis and they evaluated uh responses at 24 weeks and beyond. So that uh receptors also uh mediate downstream inflammatory response and in particular um appear to stimulate cytokines that are significant in uh myelofibrosis. So this agent in particular is is hoped that um it will uh significantly decrease myelofibrosis. So this was the manifest study. And the 1st 48 patients were initially reported at ash in 2019 and this was an update of that uh study. Um Yeah, it spleen volume reduction observed um uh less than 35% reduction or less was 94% in this study. Um And they also observed an increase in hemoglobin by 1.5 mg per deciliter compared to baseline. Um And that was seen both when Ressa was used alone or combined with Jay. And it's thought the mechanism was a combination of decreased spleen size and decreased fibrosis. Moreover, they showed that um Marro fibrosis was improved in 58% of the valuable patients. So to dig into those uh data a little bit more, um the, the, the two primary end points of the study were um 50% total symptom score reduction um from baseline at 24 weeks. And then it was looked at again at 48 weeks. So over half of patients achieved that by 24 weeks and the majority of them sustained it at 48 weeks. Um 81% of patients achieved 50% reduction in their symptom burden at some point during the course of the study. Um Likewise, 35% or greater spleen volume reduction was seen in 68% at 24 weeks and 60% at 48 weeks. So the majority were able to sustain their, their response. And again, uh the percent who have achieved 35% reduction at any time during the study was 80% with 87% able to maintain their response at the time of the data cut-off. Um The more interesting part of the study is the bone marrow fibrosis response. Um Though these numbers are still kind of modest uh 28% achieved at least one grade reduction in in Marro fibrosis. There are three grades, grade 12 and three. Um overall uh 56% and about half of those maintained their um response at 48 weeks and 40% achieved um some degree of uh improvement in fibrosis at any time during the study. So, while these are small uh numbers and and early days, we're cautiously excited that adding uh one of these agents to uh one or more of these agents to Jack inhibitors uh may significantly alter the, the development and progression of fibrosis and hopefully reverse it in some patients. This is just a graphic of the same results. OK. There have been a number of other uh targets looked at in myelo proliferative disorders. One exciting one that that was briefly presented actually was presented as part of the plenary section at ash. But uh it's, it's a very early in its development is that an antibody directed against the mutated cow R um seed in my uh disorders. So it doesn't have a name yet. It's INC A 033989 and it uh is monoclonal humanized monoclonal antibody against the mutant cow reticulin uh scene in my neoplasms. So to, to clarify um the Jack inhibitors are not directed against the specific um Jack uh B 16 F mutation that's characteristic of my fibrosis and the other myg disorders. It's against wild type So this one is directed specifically against the mutated cat are sparing wild type and they were able to demonstrate that it selectively killed the mutated cells compared to wild type. Um And so the hope is that this will be uh sort of like the the Gleevec of that of, of uh my fibrosis and potentially have the ability to uh modify the the disease, the natural history of the disease without significant toxicity. But clinical trials are just beginning. Ok. We'll switch gears a little bit for the, the last couple of presentations. Um In, in the last few years, there's been a resurgence of the use of alpha interferon in the my proliferative disorders. Um partly due to the development of heated forms of interferon which need to be given less frequently and seem to have significantly less uh side effects. So, an interesting study that was uh presented at this year's ash meeting um looked at its use in newly diagnosed patients with low risk polycythemia vera. So these are patients that ordinarily would only be treated with lobotomy and aspirin. But the idea of the study was to see whether interfering was more effective than, than uh phlebotomy and aspirin at uh maintaining inadequate, less than 45% and decreasing thrombosis. So, it was a one-to-one randomization with patients either being randomized to the standard arm um versus the addition of peg interferon Tole bot and aspirin. And the main endpoint was response at 12 months. OK. So this is AAA summary of the results that we're seeing at one year and two years. Um So phlebotomy alone, about half of the patients were able to, to maintain a hematic below 45%. And this, with the uh medium lobotomy requirement of 4.2 uh per year. Um complete complete hemologic response was not seen in, in any patients. However, at two years, about um um half of these patients maintained their response and their lobotomy requirements uh decreased significantly and about 3% had a complete hematologic response. In the Interferon arm, 81% responded to treatment and the lobotomy requirements were uh between a third and a half of that in the lobotomy only arm with complete hematological responses seen in 28% at two years. Um 83% maintained their response, the phlebotomy requirements decreased further and the hemologic complete response rate increased to 46%. So it's unclear what the long term benefit of this therapy is. However, the fact that some patients are achieving complete hemologic response leads one to believe that it, it may affect the natural history of the disease. This is a graphic of those results and you can see a very distinct difference in um the uh the two arms. The other thing that was looked at in this study is the, the mutant Jack two V 617 F uh variant to leal frequency. So this is sort of like the BC R able of, of my proliferative disorders. Uh we know in C M that if you can achieve deep molecular emissions, patients live longer and, and uh it, it clearly changes the natural course of the disease that's yet to be proven in the other Myer disorders. But to date, most of the agents available are unable to decrease the variant of little frequency here. Um there was a significant improvement in the patients receiving interfere. OK. The last step, um abstract, I'd like to present is one in chronic phase C M L. So there are six agents now approved for treatment for patients with C M L. Um And we now know that uh some patients who achieve very deep molecular responses are able to come off therapy. Um This is an important goal since despite the effectiveness of these therapies, they do carry side effects and significant toxicities including occasional severe vascular complications. So in the ask for more study, they looked at patients who received imaginative as their initial therapy and at one year had not yet achieved a deep molecular response. So that's defined as 4.5 log reduction in the BC R able transcripts from baseline. Um So patients that did not achieve that were randomized to either continue Matip because they'd had a good response and to see if, if longer treatment would lead to better uh deeper emissions or switch to a second generation uh T K I Nilo or add a semi a new um V C R able inhibitor that works at a different site on the V C R able molecule, not the tyrosine chima domain, but something called the metal domain just in way of background. First generation um therapies lead to 30 to 60% of patients not achieving uh deep molecular responses. So they evaluated responses at 24 weeks and 48 weeks. On the experimental arm, there were two doses of Aimin that were used. Um These are the two Aimin doses. This is uh staying on a map and this is switching to meloni. And what you can see is that the percentage of patients achieving M R 4.5 were uh 14.3 and 19% in the aim of arm, no patients in the continuation of the magni arm and only 9.5% in the environment developed M R 4.5 at 48 weeks. Um The numbers with as Sini steadily rose such that um 19% of the low dose and 28.6% achieved this goal uh with the the higher dose of Asim no patients on a mab achieved M R 4.5 and the rate um with the actually dropped to 4.8. So these are very intriguing data that show that that some of these patients are substantial number will achieve long term uh deep molecular emissions. And would be candidates for discontinuation therapy. He didn't answer any questions.
