Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 8

Management of AML: FLT3 Inhibitors and BCL2 Inhibitors

February 1, 2021
Harry P. Erba, MD, PhD, Duke University School of Medicine

Alexander E. Perl, MD, University of Pennsylvania

Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

Adam Bagg, MD, University of Pennsylvania

Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute

Harry P. Erba, MD, PhD: Eunice, why don’t you discuss the data that you presented on gilteritinib?

Eunice S. Wang, MD: At the 2020 ASH [American Society of Hematology] Annual Meeting, we at Roswell Park Comprehensive Cancer Center presented the updated safety cohort data from the LACEWING study, which is a phase 3 randomized controlled trial of gilteritinib plus azacitidine vs azacitidine alone in individuals with AML [acute myeloid leukemia], FLT3 mutant, who are considered unfit for intensive chemotherapy.

The original trial was a 3-arm cohort trial in which patients with FLT3-mutated AML were unfit, and they were supposed to be randomized to receive gilteritinib alone, azacitidine alone, or the combination approach. Patients were to be randomized after a lead-in safety cohort to determine the best dose of gilteritinib, either 80 or 120 mg. Data presented at the meeting included the safety cohort, of which there were 15 patients. The dose of gilteritinib was determined to be 120 mg. Of those 15 patients, some of whom got 80 mg and some of whom got 120 mg, 10 of 15 had a response. There was about a 33% CR [complete response] rate and a total CR/CRc [composite CR] rate of 67%, and the median overall survival with the long follow-up was 10.8 months, with 1 patient making it all the way to 36 months on therapy.

Based on that result, we have moved into the randomized component. There was a protocol amendment in which the company decided not to enroll patients further on the gilteritinib-alone arm, and that was based on data suggesting that there was potentially a low response rate with monotherapy and increased risk of developing further resistance down the line, as well as the data from studies like the VIALE-A trial suggesting that combinatorial approaches might be better. That study is about half accrued; it is a trial in progress, so they are anticipating to finish accrual within the next year or so and hope to have future results at another meeting. What I would like to highlight is the high response rates, which are similar to the response rates they were seeing with the VIALE-A trial with about two-thirds of patients achieving a CR/CRc. It is a well-tolerated drug in the outpatient setting.

Harry P. Erba, MD, PhD: Let me get in the middle of this duel between the 2 of you on this topic because I thought it was interesting. Eunice, I agree with you. As Sasha pointed out, the hazard ratio for survival in the VIALE-A study was not significantly different from 1 for patients azacitidine-venetoclax vs azacitidine-placebo. Here is the issue: It is the sequencing issue, and it is also the response rate because when these patients present, they are sick and need a response. What you could say of both studies is that azacitidine-venetoclax and azacitidine-gilteritinib can control the disease in these patients with FLT3 mutations on chemotherapy.

Eunice S. Wang, MD: I would agree with that, yes.

Harry P. Erba, MD, PhD: You are on solid ground choosing either of them. I will let you comment about triplet combinations in a second, but what I will mention what I find interesting here: In Courtney DiNardo’s presentation at EHA [the European Hematology Association 2020 Congress] of azacitidine vs azacitidine-enasidenib, there was no difference in overall survival. And the overall survival in those patients with IDH2 mutations was remarkable: 22 months, median overall survival. I cannot help but believe that it is because the patients who got azacitidine alone or azacitidine with enasidenib could then receive some other therapy once they relapsed: venetoclax-based therapy or another IDH2 inhibitor. It is the sequencing issue that is going to confound some of these survival studies. I am going to turn it back to you to comment on those things.

Alexander E. Perl, MD, MS: Whom would you like to go first?

Harry P. Erba, MD, PhD: You go first, Sasha.

Alexander E. Perl, MD, MS: Most of what we have learned about giving drugs that target FLT3 mutations potently—the current second-generation drugs—has been done in the relapsed/refractory setting. That is where we enrich for the leukemia that grows most rapidly and is most FLT3 driven, and there is no test that can say, “This is FLT3 driven and this is not” that we have so we can discriminate these. That is where we have seen the benefit of a potent selective FLT3 inhibitor: the relapsed and refractory setting.

To me personally, as much as I want to bring these drugs to the frontline setting to suppress those clones early, we do not know that that is critical. That is why we are doing studies in the frontline intensive setting asking whether a drug like midostaurin or a drug like gilteritinib proves to be the better frontline drug, and we do not know the answer. Midostaurin is a weaker, less selective FLT3 inhibitor, but it may be a better FLT3 inhibitor because it hits all these other targets.

When you get to patients not getting intensive chemotherapy where they see less of the backbone treatment that could suppress the growth of all the clones, what is the best approach? I do not think anybody knows. What we need is a study that randomizes patients between 1 of these 2 approaches, either an HMA [hypomethylating agent]–plus–venetoclax approach—you could even argue an HMA only, like the study that Eunice is describing—vs a combination that includes a FLT3 inhibitor. That LACEWING study is important to define this. It is a randomized trial, and I hope we learn from this what the right answer is. It could be that there is no big difference in part because you are treating patients in the frontline setting. You may select for a growth of leukemia that has nothing to do with FLT3 through that approach.

What the data do show in the frontline setting is that, when patients get venetoclax plus an HMA, they do better than a patient who got an HMA alone in a study that was appropriately powered to answer that question. It was not powered to answer the question of the subgroup of FLT3 mutations, so I have trouble using a subgroup analysis to say that I should not use what has been proven to be a better drug if I had the option of HMA alone. I personally would have trouble enrolling to a study that had an HMA-only backbone based on the trial results of the VIALE-A study. I have been giving venetoclax plus azacitidine, but I freely admit that I do not know if this is the right thing to do, and we should be doing a randomized controlled trial.

Harry P. Erba, MD, PhD: Eunice?

Eunice S. Wang, MD: I would agree with the points that you made, Harry, that getting a response is the most important first goal: getting a CR or a CRc. There is no doubt that using venetoclax and azacitidine leads to 67% CR/CRc rate as opposed to 20% to 30% with azacitidine alone. In fact, that is the same rationale that I use to treat patients with TP53 mutations with venetoclax-azacitidine. Even though the survival data are not necessarily better, I can get a response, and if I can get a response in those patients, whether they are a patient with FLT3 mutations or TP53 mutations, you know what I can do? I can take them to transplant. If I can take them to transplant with little treatment-related mortality going into that transplant, that is the best approach for some of these poor prognostic subtypes of AML.

I have also heard the argument that patients should receive venetoclax-azacitidine, get that into that CR, and do what you mentioned briefly: sequencing. Go ahead and give them venetoclax-azacitidine, and then if they relapse, give them gilteritinib subsequently as a salvage maneuver.

The concern I have somewhat with venetoclax-azacitidine is mostly a theoretical 1. I do not disagree with Sasha, and I would not want to disagree with Sasha, but there are a lot of data coming out from Courtney DiNardo and Andrew Wei showing that FLT3 mutation is a major mechanism of resistance to venetoclax long term. When they looked at patients and looked at their mutational profiles, having a FLT3 mutation or the development, acquisition, or selection for a FLT3 mutation was a primary mechanism by which patients failed venetoclax-azacitidine. This again supports the triplet studies that are being done or at least the 2 double-targeted therapies, which we will talk about in a bit, by Naval Daver and Alexander Perl looking at the venetoclax-gilteritinib combination.

We are lucky to have many options. Whether you want to start with the FLT3 inhibitor azacitidine or you want to start with venetoclax-azacitidine and then switch, there are some data suggesting that venetoclax-azacitidine works best when you use it in the up-front setting. We know that venetoclax-azacitidine in the relapsed/refractory setting can only result in response rates as low as 20% to 30%. For that reason, people also do the venetoclax-azacitidine combination first and save the FLT3 inhibitor. We do not know. Either of these is a great topic for discussion, and we will be trying to sort out these data.

It is the same thing with IDH inhibitors. Are they better? Are they worse? Do they add anything? Is there a survival benefit? We do not know, but I do not think that we have to know. If we can use all these drugs in some sort of combination, and patients can make it 22 to 28 months or make it to a transplant, I do not think people will care how we got to that point.

Harry P. Erba, MD, PhD: I agree. My patients want to spend as much time in remission as possible.

Eunice S. Wang, MD: Exactly.

Harry P. Erba, MD, PhD: It is about getting in remission and staying in remission on drugs they can tolerate. What we do not know is the combinations vs sequencing and what the best way to do that is.

Transcript Edited for Clarity