Combinations are the Future in FLT3-Mutated AML - Episode 11

BCL2 Inhibitor Combinations in FLT3-Mutated AML


A discussion on the use of venetoclax combinations with FLT3 inhibitors, especially in older patients with FLT3-mutated acute myeloid leukemia.

Naval G. Daver, MD: Let’s talk about some of these ongoing therapies. We’ve talked a lot about younger patients, but for older patients with FLT3-mutated AML [acute myeloid leukemia] what would you do? This is something that comes up at every ad board, and during every steering committee argument.

Let’s say you have a 75-year-old FLT3-ITD [internal tandem duplication] case and the patient is reasonably fit. Do you use azacitidine and venetoclax, do you use azacitidine with a FLT3 inhibitor, do you use azacitidine/venetoclax/FLT3, or do you use venetoclax with a FLT3 inhibitor? What are your thoughts?

Jessica K. Altman, MD: As you well know, FLT3-mutated disease is not always the same. There are some patients who have characteristic proliferative FLT3-ITD–driven disease, who come to the hospital with all sorts of excitement—a high white blood cell count, and we’re concerned about tumor lysis, and leukostasis, and all sorts of things. Then there’s an individual who has a prior MDS [myelodysplastic syndrome] and low burden of disease and has acquired a FLT3 mutation. Those patients are different. By all means, we need to wrap our heads around these folks. But for now, we can count them all as having FLT3-mutated disease.

So for an older individual with FLT3-mutated acute myeloid leukemia, whether that be a proliferative patient or a more indolent patient, in the absence of a clinical trial, I am treating them with azacitidine/venetoclax, if that’s the appropriate therapy for them. I think you were alluding to the recent report on the LACEWING data, which looks at azacitidine versus azacitidine and gilteritinib in adults with FLT3-mutated disease. We don’t know much yet, but we do know the trial did not reach its primary end point of overall survival. There was not an overall survival advantage. We can hypothesize all sorts of reasons of why that might be, but based on those data I am not utilizing azacitidine/gilteritinib for my patients with newly diagnosed FLT3-mutated disease. That doesn’t mean I won’t use gilteritinib later in their course, or even gilteritinib in combination, but that’s my approach right now until we acquire more information.

Naval G. Daver, MD: Yes, and I have to say that was one of the surprises. We had a previous study here of azacitidine/quizartinib, and the response and survival were dramatic. So as you say, the devil is in the details, and we’ll have to see what all happens. But I agree. The randomized data, the FDA label, the NCCN [National Comprehensive Cancer Network] guidelines are in favor of azacitidine/venetoclax. So that’s what I would use.

There may be unique circumstances, like a situation where somebody is highly proliferative. Then you may need to move to gilteritinib earlier, or incorporate gilteritinib into treatment. But I think this is where, in the trial setting, you and I and other friends of ours are working very intensely on the combination of venetoclax with a FLT3 inhibitor. It doesn’t have to be gilteritinib. Although that’s where the clinical data are, it could be quizartinib or sorafenib. This is one of the times when there are very powerful preclinical data published by 3 different groups showing high sensitivity and synergy. And so, we put this into clinic—venetoclax/gilteritinib—and as we have shown at ASH [American Society of Hematology] and EHA [European Hematology Association] and other meetings, and will update on, this combination is very potent but is also very myelosuppressive. This is a theme we’re seeing with all of these venetoclax combinations, and maybe we are giving too much venetoclax across the board. How can we adjust that? I think in the frontline setting, my hope is that these triplets, if we can optimize them in a way—azacitidine/venetoclax with a FLT3 inhibitor, and maybe much less venetoclax and maybe even less FLT3—could almost serve as an initial induction. These are older patients, so we don’t use that word. But to get debulking molecular flow clearance, 1 or 2 cycles, and then we could probably go on to azacitidine/gilteritinib or azacitidine/venetoclax. I think with that approach, some of the early signals look very promising. They’re getting very high molecular flow clearances. Hopefully we can move that forward.

I know you’ve co-led the trial and treated people with venetoclax/gilteritinib. What are your thoughts on that combination, and what are your thoughts on frontline development of these triplets? How do you see this happening?

Jessica K. Altman, MD: I am very impressed with the venetoclax/gilteritinib data. When we first designed that study, it was based on preclinical musings from the laboratory. We thought about putting that protocol forward well before gilteritinib or venetoclax were approved.

As you know, it takes a long time to get these trials up and running. The response rate has exceeded my expectations from what I thought when we first planned out this study. And also, the myelosuppression has exceeded my expectations. That’s the biggest downside. The response rate, as you can correct me, in this patient population was about 80%, 85%. I think about 60% or so of the patients we treated on that study had received a prior tyrosine kinase inhibitor [TKI]. So that response rate is not just due to lack of exposure to a prior TKI. There is clearly synergy that we’re seeing and a really nice response to that regimen. But I think we need to figure out how to optimize that. I also believe that the patients we treated on that study were probably pretty FLT3-addicted patients. They had relapsed disease. I don’t know that we would see the same response in newly diagnosed patients. Only time will tell.

For a newly diagnosed patient, my goal in thinking about these patients moving forward is to allow for some chemotherapy in combination with these targeted agents. And with time, hopefully we will have an all-oral backbone for patients—oral HMA [hypomethylating agent], oral FLT3 inhibitors, oral BCL2 inhibitors—and be able to treat these patients. That doesn’t mean, however, that the patients can just go home and hide for a week or month and then come back. They’re still going to need significant monitoring. But at least they can spend a little less time in our medical centers.

Naval G. Daver, MD: Yes, absolutely. I think these combinations with BCL2 inhibitors and FLT3, as you said, we were all very excited to see this 85% clearance. These are not even the same population of patients as we saw in the ADMIRAL or QuANTUM-R studies. These are much worse patients. As we discussed, only 5%, 10% had received a prior TKI in ADMIRAL or QuANTUM-R. Here, 65% had, and in fact, the median was 3 salvages. Both of those other trials were predominantly first salvage. So, very impressive. But as you said, and again with all venetoclax combinations, I think that’s a common theme emerging—that 28, 21 days of venetoclax is too much and may not be needed, and we’re adding more myelosuppression. Slowly, we’re trying to come down, in a cautious way, to 14 days. And we are looking at what is tolerable. But I do think that a combination, whether it’s a doublet or triplet, will find an important role in the next couple of years. I’m looking forward to working on those trials.

Transcript Edited for Clarity