Adding a FLT3 Inhibitor May Improve Chemo Efficacy for Newly Diagnosed AML | Musa Yilmaz, MD | #ASH24

I'm Dr. Yilmaz from MD Anderson Cancer Center Leukemia Department. So I'll be giving you a brief summary of the abstract that I'm going to be presenting today in ASH 2024. So in this abstract, we studied and will be reporting on phase one and two study of the triplet combination, which consists of three drugs, decidabine, venetoclax, which is the backbone chemotherapy for acute myeloid leukemia patients who are newly diagnosed and who are not eligible for intensive chemotherapy in combination with a drug called kuzartinib. Kuzartinib is a flip three inhibitor, and it has been recently approved by the FDA for that indication for younger patients, but with combination with intensive chemotherapy. In this abstract, though, we are looking at the role of the same flip three inhibitor, which is kuzartinib, in combination with a low intensity chemotherapy, kind of chemotherapy that we know that our older AML patients that cannot tolerate the intensive. That's why we use low intensity chemotherapy. That's the center of care. Now we are trying to answer the question whether adding a flip three inhibitor to this backbone would make the things better, would make the response rates better, would make the patients live longer, would cure more patients than otherwise. So this is not the first report. We have reported the outcomes in previous years, but now we have more patients. So I'll be giving you the summary on the newly diagnosed patients, which makes things a lot simpler. So we treated 23 patients, median age of 70 years old. So these are older, newly diagnosed AML patients. And on those patients, they all have a mutation called flip three ITD mutation. So flip three is one of the common mutations in AML. About 30% of AML patients do present with this mutation. And we know that the flip three mutations are prognostic, meaning if a patient presents with a flip three mutation, they are, although response rates are similar, these diseases tend to come back quickly. So we incorporated an inhibitor of that flip three mutation into this clinical trial. So right now we are in the phase two portion of the study. So the earlier phases completed. Now we know which dose to use and we are going to be using this optimal dose in a larger cohort of patients. So so far we have treated 23 patients. They are newly diagnosed patients. And out of these 23 patients, 22 achieve remission. So that's spectacular results. So that's normally the expectation with the chemotherapy backbone only, which is the decider been venetoclax is about 70%, perhaps 80%. Now we are pushing it to the 90% plus. So also not only morphological response, morphological means we are looking under the microscope and see elimination of the leukemia cells. This combination, this triplet combination generated deeper remissions. Let me do a test called flow cytometry, which tells us about the minimal residual disease status. 80% of these responders achieve this MRD negativity, meaning undetectable disease in the bone marrow. So this trial is still ongoing, although the trial started about three years ago. Right now we have a median follow up about 20 months, more than 20 months. And the median oral survival was not reached. So what that means is that we follow about 20 months till more than 50% of the patients are alive. Actually to be specific, two year oral survival is 65%. To give the comparison though, obviously not 100%, but to give the comparison and understanding, with the standard of care treatment with the cytobin and venetoclax or HMA venetoclax for the FLIT3 ITD mutated disease, the median overall survival is only 12 months. So now we are pushing it, perhaps doubling it soon with this small study, keviat is a small cell, we need more patients, we need to enroll more patients so we can gather better results. And so far out of these 23, four patients relapsed, meaning their disease came back. And when we look at specifically which patients relapsed, these are the patients with the high risk disease, these are the patients that has a mutation called RAS mutations in their leukemia cells, two of them, and one had a TP3 mutation which is also a high risk mutation and another called MECOM rearrangement which is a high risk. And then with high risk disease, all four relapses were the ones who had high risk disease. So yeah, this is pretty much the bottom line summary of the study which still continues. And so far, patients in terms of side effects, let's touch on that as well. So in general, the main side effects are not different from the backbone chemotherapy that we typically give. The one unique side effect that we pay attention is the QTC prolongation. So what that means is that the quesartanib is a drug that can cause written problems in some patients and a specific EKG abnormality called QTC prolongation. That's why we check our patients' EKGs multiple times in a week when they start on treatment to make sure that the QTC doesn't get prolonged so our patients doesn't get into a big arrhythmia. So far we have seen none but this is because we are doing vigorous monitoring and so far though it's manageable side effect. And the other to keep in mind is the prolonged cytopenia. So what that means is we start the chemotherapy typically with the backbone chemo only patients recover their counts between day 30 to 35 of the induction but when we give the triplet, recovery happens between day 35 to 40 range. So let's say about five days later. So that's the one noticeable side effect but other than that not any major toxicity signal with this program. The drug that we are using is a drug called quesartanib and again this is a drug that has been approved by the FDA recently and it's a second generation FLIT3 inhibitor. It's a more potent FLIT3 inhibitor. It specifically targets the ITD mutation. So what happens is in patients with FLIT3 ITD mutated AML the mutation occurs on a receptor called FLIT3. We all have this FLIT3 receptor in our bone marrow cell in the earlier life of the bone marrow cells. We all have it. When this mutates normally the receptor itself has a mechanism to switch on and off. And there is an auto inhibitory function of this receptor is there. But when there is a mutation this function gets disturbed. So that receptor becomes constantly active. It just constantly sends signals to the downstream pathways and makes cells to proliferate, proliferate and proliferate. And then that's why leukemia happens. And that medicine blocks that signal. That's how it works. It's pretty false within the standard. We don't make our patients to stay in the hospital longer because they are receiving triplet. No, it really doesn't change the way we admit discharge or monitor. So it's pretty much the same. It doesn't add anything. And what it adds is just patients need to take one additional pill. So part of this treatment perhaps patients will wonder is that the transplant. Bonemare transplant. So obviously as I mentioned the median age is 70 years old. So this study designed for patients, older patients. But there are some older patients we can do transplant. So with the philitary ITD disease once patients achieve remission the current as of 2024, current consensus is that patients should go to transplant. If they have a donor, they're eligible, they're performance status, physically fit, no organ dysfunction that would be the recommendation. But there are some patients they are old, they may not have donor. There might be some other reasons that they cannot go to transplant. Where this actually study comes in. So those patients who couldn't go transplant in our study doing relatively well. Because we keep them on the triplet regimen and perhaps they are how we call maintenance treatments so they start the drug with the triplet drug and we continue. After a year of therapy we continue therapy more depending on how patient tolerates. So we look at two things. As long as the leukemia is in remission and as long as the treatment we give is not harming by any means and tolerable, we continue. And we dose adjust down the way meaning we dose reduce the hydro of the drugs depending on patient tolerance but we make sure that it doesn't affect patient quality of life. Otherwise it's going to defeat the purpose, right?