Adding Menin Inhibitors in Combination Therapy for AML Patients | Amir Fathi, MD | #ASH24

So, my name is Amir Fati. I'm a leukemia specialist. I work at Massachusetts General Hospital in Boston, Massachusetts. There I direct the leukemia program, and I'm also associate professor of medicine at Harvard Medical School. So, at this year's ASH meeting, I think a particularly interesting clinical trial that we presented was the COMET 007 study, which was the combination of standard conventional treatments for acute myeloid leukemia with the menin inhibitor, Cyftaminib. You know, intensive induction chemotherapy has been around for four to five decades. And it's hard. Patients come into the hospital, they receive about a week of treatment, they remain in the hospital because their marrow empties out, their blood counts go down, and they're generally vulnerable to episodes of infection and bleeding. And they have to stay in the hospital until they recover their blood counts. And that's a long time away from their families in the hospital, hospitalized, and suffering from the sundry side effects that you oftentimes get from intensive therapy. And as you can imagine, that type of intensive therapy is not for everybody. And particularly for older, frail patients, we for many years did not have much to offer them with a diagnosis of AML. In recent years, hypomethylating agents such as azacytidine and thecytabine have emerged. Initially, they were used as monotherapy because they were well tolerated, they didn't cause GI side effects, the degree of cytopenia, meaning low blood counts, was less than traditional intensive therapy. So we used that. And then I would say about five, six years ago, about, data started to emerge with the combination of Venetoclax, a BCL2 inhibitor plus these hypomethylating agents, that led to a much higher rate of response and a much better survival. So now the standard of care for older patients is a combination of these hypomethylating agents, either thecytabine or azacytidine, plus the BCL2 inhibitor Venetoclax as an oral agent. It is still marrow suppressive, it still causes low blood counts, still places patients at some degree of risk, but certainly not to the degree that you would get with intensive therapy. And so it can be given generally outpatient. We presented two sets of data. One was the combination of Zifton-Mennib with intensive chemotherapy for younger patients with KMT2A rearranged or MPM1 mutated AML, which are the two populations of patients who are thought to benefit from this Mennib inhibitor. And we also presented data with Zifton-Mennib in combination with azacytidine and Venetoclax for older patients who generally get that combination when they're diagnosed with acute myeloid leukemia. So I'll talk about the former first. So the combination of intensive induction chemotherapy with Zifton-Mennib was conducted in newly diagnosed AML patients. And in that patient population, we saw that the combination was well tolerated. There wasn't any new signal in terms of toxicity. We found a very high rate of complete remission, actually 100% complete remission for patients with MPM1 mutations and a very high rate of complete remission also in the more challenging KMT2A rearranged patient population. Now this is a small population of folks in a phase one study, but nevertheless promising and opens the door for additional larger, maybe placebo controlled studies in the future. As far as the combination of the azacytidine Venetoclax plus Zifton-Mennib, that was conducted in older induction ineligible patients or patients who had progressed beyond initial induction chemotherapy. These are relapsed refractory patients, not newly diagnosed, so a very different patient population and probably more heterogeneous and harder to treat patients. These folks received a combination of azacytidine and Venetoclax and on day eight were initiated also on the Mennon inhibitor, so a triplet combination therapy. So Mennon inhibitors interfere with the interaction of two key proteins that are thought to be essential for the process of leukemogenesis or the development of leukemia and those are Mennon and KMT2A. They interact with each other and in patients who have KMT2A rearrangements or MPM1 mutations, that interaction is leukemogenic, meaning it triggers the phenotype of AML and the aberrant blockage in the normal differentiation and maturation of blood cells. So it causes the development of AML. With these Mennon inhibitors and those particular subsets of patients that have those alterations, KMT2A and MPM1, it helps to release the block and differentiation, leading to normal maturation of myeloid cells into normal healthy cells and hopefully, as we have seen, clinical responses. So that's how they work or thought to work. We found that the combination at multiple dose levels that we looked at of Ziftaminib was well tolerated and generally safe and saw a composite remission rate of around 50% for the MPM1 mutated folks and slightly lower for the KMT2A rearranged patients. But nevertheless, this opens the door for additional study in the newly diagnosed setting of the same triplet regimen for patients that are not eligible for more intensive therapy. So I think overall a successful clinical trial to date and we look forward to additional hopefully promising results in the future. Because the combination of HMAs and Venetoclax have been so promising in older patients, leading to high rates of response, I'm leading a group of cancer centers and clinicians in a clinical trial that actually compares that, the more gentle outpatient treatment, to intensive therapy in younger patients to see if we can actually get very similar results but better quality of life, outpatient treatment, less time in the hospital with the more gentle treatment that has shown so much promise in older patients, perhaps in younger, formerly induction candidates, intensive induction candidates.