Venetoclax Combination Therapy for IDH-mutated AML


Key opinion leader in the management of acute myeloid leukemia, Harry Erba, MD PhD, builds a conversation on the use of venetoclax as a part of combination therapy in patients with IDH mutations.

Harry Erba, MD, PhD: We need to talk about these combinations still, and so, Courtney, the study that your group led is with the combination of ivosidenib and venetoclax. Do you want to talk about that?

Courtney DiNardo, MD: I will; I think the main question is that most people in the United States, at least, are using azacitidine with venetoclax for frontline treatment. For me, the question is, for patients with IDH (isocitrate dehydrogenases) mutations, they do really well with HMA (hypomethylating agents) and venetoclax , but can you do better with incorporating an IDH inhibitor, and doing that triplet strategy? We have updated data that 1 of our fellows presented at EHA (The European Hematology Association) looking at that triplet, Azacitidine-Venetoclax-Ivosidenib in a small number of patients, just about a dozen, and that we treated both patients who were newly diagnosed and who had relapsed refractory disease. Not surprisingly, the remission rate is great, as we are seeing in patients who are newly diagnosed; there was composite remission rates above 90%, and then in patients with relapsed refractory disease, those rates were above 60%. The question is really going be, how durable are those responses? Are we seeing patients who are losing their IDH mutation, as well as others? We did also look at the oral doublet, of Ivosidenib and Venetoclax , and I think it is a nice combination. It is oral, it is outpatient, and those were cohorts that we treated earlier; we are starting to see relapses. I am not so sure that Ivosidenib-Venetoclax is going to be the be-all-end-all for patients with IDH-mutations.

Harry Erba, MD, PhD: In thinking about the use of HMA-Venetoclax for your previously untreated patient, we know what the approved label is in the population, but if I have a patient with a PCR (A polymerase chain reaction) who is positive for IDH1 (isocitrate dehydrogenase 1) or IDH2 (isocitrate dehydrogenase 1), and they're 60, I look for a reason, actually, not to give them intensive chemotherapy, given that there is an 85% response rate with HMA-Venetoclax . Then, we think about getting them in remission, and then maybe transplanting them after that. Vinod, what would you say about that practice?

Vinod Pullarkat, MD: That is what I would do. I would not do intensive chemotherapy if there is an IDH mutation and the patient is even younger; I think those trials have not been done, but I think the tolerability and the responses would be much better with the HMA-Venetoclax regimen. That is 1 area where getting the mutation back would be useful upfront to make that decision, especially for the patients in that age group, who are between 50 and 65. My choice would be to go straight to HMA- Venetoclax.

Dan Pollyea, MD, MS: Here, I think what we, as a community, need to do—because I think you are hearing all of us say that that would be a very reasonable thing—is to publish our experiences of venetoclax remission to transplant. That has not been published. There has been 1 presentation at last year's ASH (American Society of Hematology) conference by Keith W. Pratz, MD, wherein for something like 30 patients, the outcomes were phenomenal, but that is really early follow up. I think that is the piece of the puzzle that is missing, because what you are saying, I think, is that a lot of people would initially ask, "How can you deny these patients a curative option?" Well, that is not at all what you are doing because you are getting them into a remission, ideally, in a safer way for these patients, and perhaps a more reliable manner of getting into remission. Then, you are taking them to a transplant. That is what you are proposing for your early or mid-60 year old patient. I think that is a great strategy. We have to prove that that is viable.

Mark Levis, MD, PhD: The problem with that approach—well, it is very appealing. You do usually need next gen back, and so you have a 62 year old with a white count of 20k and they are sitting in your inpatient service area. Are you really going to hold 7 and 3 for the night? Maybe you have PCR for IDH and you get it quicker? Most do not.

Harry Erba, MD, PhD: We do, and that is why I can do it. Your points are well taken, though, about turnaround times, and it is okay to wait, except if the bean counters and the financial people are wondering why you have not treated that patient. I think many of us have discharged a patient that got admitted from the outside just to wait for the data to come back. I would say—

Mark Levis, MD, PhD: 20,000 in the—

Harry Erba, MD, PhD: No, not that patient. No. The patient with pancytopenia—no, because Courtney made that point before. They have a white count and you want to stay on top of them.

Dan Pollyea, MD, MS: Well, let me ask you—

Harry Erba, MD, PhD: The next-gen panel can help because how about if you see now, not only the IDH1 or IDH2 but then you see a RUNX1 with it or you see a ASXL1 and you know the best outcome is likely to be due to transplant, long term. Getting them to transplant might be better. Now, I will get back to you, Dan. I want to make the point that you are all saying the same thing. We need the randomized phase 3 studies in these younger patients to prove the point. The NCI (National Cancer Institute)-sponsored MyeloMATCH program has written studies to look exactly at this question of using HMA-Venetoclax versus intensive chemotherapy regimens in younger patients who we would want to get to a transplant. We are not only looking at MRD (minimal residual disease) negative remissions—that is the primary endpoint of our studies that we have designed—but we are also looking at toxicities and how many patients can get to transplant. Those studies will be coming online in the next 6 months or so. Dan?

Dan Pollyea, MD, MS: Well, I do not want to believe her, but just to your theoretical question and Mark's response that you are going to have to wait around a long time. That same scenario that you propose—an early 60-year-old patient who is a potential candidate for intensive induction chemotherapy, you said you would, with an IDH, give them Venetoclax-Ivosidenib and a transplant, but what is the other data? What is the other subset, biologically, where you would not do that? Presumably, you would rule out a combining factor because I think that is a patient view at all, but then, what is the other biological subset that you would want to give? That is chemotherapy, too. If you would give that IDH positive patient Venetoclax-Ivosidenib, complex cytogenetics, and secondary AML (acute myeloid leukemia), I think both of those would push us to use Venetoclax. Someone at the beginning said that they would prefer for a patient who is FLT-3 positive to get intensive chemotherapy. I think that that is reasonable, so it may be something you would wait for, but what else are you waiting for, to not give?

Harry Erba, MD, PhD: It is a very rare situation. I love the challenge, but I just admitted someone who I was on the fence about. I could wait for the next-gen panel and she turned out to have a nucleophosmin (NPM1) mutation which we don't do PCR-4 testing for, and those with FLT3-TKD mutation, and nothing else. I struggle with this and with her because she is obese and I struggle with it, because I said, "You have potentially curable therapy, favorable risk disease by ELN (European LeukemiaNet) standards 2017." We ended up giving her 7 and 3 with Midostaurin for the FLT3-TKDd but we will have to see what happens. I do not know what the right answer is, but that is the other subset. If they had a biologic CDP-alpha—again, you have to wait for the next-gen sequencing to get that. I do not know. Does anyone else have a comment about that?

Courtney DiNardo, MD: I just think this is where MRD is going to become so important. As you said, that was your endpoint for MyeloMATCH, as we are trying to compare a regimen to another; there is a difference between a couple of cycles of induction consolidation and being done and continuous therapy with HMA-Venetoclax, but now that we are in the world of maintenance therapy, if we are not going to transplant or we are taking either of those regimens. We are getting patients into a deep remission and then going to transplant; these lines have blurred so much that I think seeing how deep our responses are and the tolerability and ability to survive the first 60 days of these therapies are more and more relevant.

Vinod Pullarkat, MD: I think we also need to look at the induction mortality of 7+3 versus HMA-Venetoclax, right? That has not really been compared in a formal manner; you do have some depths with neutropenia and infections, but I feel for the 50- to 65-year-old patients as it is less than 7+3.

Harry Erba, MD, PhD: Or there is patient who gets so beaten-up during induction that they cannot get to a transplant.

Vinod Pullarkat, MD: Yes.


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