Venetoclax-Based Chemotherapy Combinations in AML

Transcript:

Harry Erba, MD, PhD: At this year’s ASH [American Society of Hematology Annual Meeting & Exposition], we heard a lot about combination studies. We’ll come to that, but there were 3 abstracts with venetoclax combinations I want to focus on before we move on. The first was the analysis of responses, but more important duration of response and survival, based on mutational analysis. As we know, the patient with nucleophosmin ideation mutations had very high response rates and very long duration remission. On the other hand, the TP53-mutant patients were 50% to 55% on response rates but had very short remissions and very short median survival of less than 6 months. We’ll talk later in this program about some new options for those patients. They showed that BCL2 family member expression did not correlate with response. The second important thing is that about 10% of patients on those phase I studies were allogeneic transplant. They weren’t supposed to be fit for allogeneic transplant when they went on the study, but they went on. They showed very good overall survival following transplant. That’s all I’ll say about it. The message is this: if you get an older patient with AML [acute myeloid leukemia] in remission, let’s not forget that the only curative option is allogeneic transplant. It may give them something that cures the disease as opposed to a prolonged maintenance.

The last thing I’ll say came from the University of Texas MD Anderson [Cancer Center], and it was the most sobering. We are seeing relapses and refractory disease with ACA [acalabrutinib]—venetoclax, and the median survival of those patients was less than 3 months. They could not be salvaged, and they often had high-risk mutations. The importance of that is in preparation for what’s coming this year: the survival data from the low-dose araC [cytarabine]–azacitidine combination studies.

We have to be prepared for the fact that maybe the survival benefit that we’re all expecting won’t be as great as we think. We must consider the toxicity of the combination but also the ability maybe to salvage an HMA [hypomethylating agent] failure better than with investigational therapies, IDH inhibitors versus salvaging an HMA-VEN [hypomethylating agent, venetoclax]. We’re going to need to think about whether that means that this regimen doesn’t have benefit, and I would argue that of course it has benefit. It has very high remission rates, and it is very quick. What we’ve heard here is that we need to think about how we manage the toxicity.

Naval Daver, MD: I was just going to make that point, and I reviewed this abstract that Abhishek Maiti presented a lot with our group with Marina Konopleva. We don’t want to give that message because we did that subsequent part of that abstract to show that, in the end, the survival was still higher with HMA-VEN [hypomethylating agent, venetoclax] than any other HMA combination. However, because you’re receiving a more effective therapy up front, the clones and the diseases that are emerging after that is just horrible. This is very similar to a paper that had been published by Christoph Röllig using [cytarabine, daunorubicin]—sorafenib versus 7+3 [cytarabine, daunorubicin] in non–FLT3-mutated cases. What they showed in that is that the RFS [relapse-free survival] was significantly improved with 7+3 [cytarabine, daunorubicin]—sorafenib. When they relapsed, they fell off the cliff. The goal here is that we need to restructure our clinical trial infrastructure because this is becoming the largest referral population to us: AZA-VEN [azacitidine, venetoclax] failure relapse. We need to find new drugs. If you have FLT3-IDH, those were the only ones we could salvage. For everything else, you have to develop new therapies.

Transcript Edited for Clarity