The Role of Venetoclax for Treatment of AML

Harry Erba, MD, PhD: Vinod, why don’t you give us a high-level view of this new standard of care for older, unfit patients?

Vinod Pullarkat, MD: We’ve already talked about it quite a bit. For our patients over 75 years old who are unfit for treatment, it’s the standard of care. The question is whether a triplet regimen in a patient who has an actionable mutation would add something more, but we must wait for those studies to be completed. At this point, as we said, the tolerability of this is excellent, provided we pay attention to the cytopenias. That’s a challenge in community practices where this is considered a low-intensity regimen, but it’s an intense regimen from the standpoint of hematologic toxicity. We also talked about the ability to take many patients who, up front, may not look like transplant candidates, but once they get a quick CR [complete remission], that’s the other advantage of this regimen. The median time to CR is a month, so once they get a quick CR and their counts bounce back, their performance status often improves. We’ve had patients who didn’t look like transplant candidates when they presented, and then they became transplant candidates, which is completely opposite to intensive chemotherapy, where sometimes you get a complication and now you cannot transplant them. Here, you have a patient who now becomes fit and can be transplanted, so in that population, this is the standard of care until something in addition to this backbone is established.

Harry Erba, MD, PhD: Do we have data about MRD [minimal residual disease] status after azacitidine-venetoclax and getting them to transplant, if that’s important to getting—especially an older patient— to a reduced-intensity preparative regimen?

Vinod Pullarkat, MD: That data were just presented, and you can see there was about a 30% MRD negativity using the 10+3 standard. The outcomes are significantly different among patients who are MRD negative going to transplant vs those who aren’t. With the MRD negativity, we know that patients can achieve deep remissions. The bigger question is, if somebody is not MRD negative, then do you do something before you transplant them? I don’t think we have the answer.

Mark Levis, MD, PhD: I will occasionally follow an HMA [hypomethylating agent]-venetoclax with a rounded height. In other words, the patient’s performance status improves so much. They can intensify a little. I’ve done that once or twice before, and then take the patient’s transparency.

Vinod Pullarkat, MD: I’ve done it the other way too. I’ve followed IDAC [intermediate-dose cytarabine] patients with a cycle of HMA when, before taking them, transplanting younger patients.

Harry Erba, MD, PhD: I love this discussion because we’re all off-study doing a lot of this. I agree with you, Mark. I wonder if 1 of the things we should look at is giving them an HMA-venetoclax again, get remission, and then they become more of a candidate for an intermediate to high dose, and that is what—

Mark Levis, MD, PhD: In the treatment of pediatric ALL [acute lymphoblastic leukemia], that was always used. There was poor drug induction that was gentle and put them in, and then you could intensify.

Harry Erba, MD, PhD: Exactly. We’re unbelievable. After 40 years, we’re rewriting the whole AML [acute myeloid leukemia] algorithm. We might be as smart as lung cancer doctors soon. That was a great discussion. I loved it.

Mark, I’m going to put you on the spot. You had an patient with MDS [myelodysplastic syndrome] on HMA responding who then progresses to AML. There’s no targetable therapy. You’re not at Johns Hopkins [University School of Medicine]. Do you add in venetoclax? Do you give them CPX-351 [cytarabine, daunorubicin] ?

Mark Levis, MD, PhD: I just thought—

Harry Erba, MD, PhD: LDAC [low-dose cytarabine] with glasdegib. I have to give you that 1 too.

Mark Levis, MD, PhD: I just saw somebody respond last week. My goodness, what do I do now because I’m diverter? Anyway, no, the frame would be, “Am I going to add venetoclax, or am I going to go to CPX-351?” I just saw a guy before running over here for this who got azacitidine for 3 cycles and was 15% blasts, and I casually pronounced him 20% and added venetoclax. He got a quick remission and was MRD positive, and this is a year after his transplant. Last week, there was also a young, fit patient who had progressed into a nastier AML. Yes, the guy had a remission transplant. I don’t know the answer to that. I tend to pull out CPX-351 [cytarabine, daunorubicin] when it’s really AML, and the case this morning was more sludging and slower, so I pulled out venetoclax. I have no idea what the answer is. Do both; you have options. That’s my practice. If cases are a little more indolent, I pull out venetoclax. If it’s a little more aggressive, I pull out CPX-351 [cytarabine, daunorubicin].

Courtney DiNardo, MD: One thing that I’ve noticed, as what Mark mentioned, is that by adding venetoclax, you can get patients who’ve lost their response to an HMA agent alone. Those patients were not eligible in the original trial. You had to switch them to low-dose cytarabine with venetoclax and, in the United States at least, we don’t use a lot of low-dose cytarabine. One of the things I do is exactly what Mark did: you have a patient who’s failing with azacytidine or decitabine and add the venetoclax. I’ve seen quick responses and a handful of people with that smoldering AML or progressing disease. CPX-351 [cytarabine, daunorubicin] is also very effective. You look at the forest plot of who responds and who doesn’t respond to CPX-351 [cytarabine, daunorubicin], though, and unfortunately, patients who’ve had prior HMA therapy really don’t gain a lot of benefits. We all have anecdotes, and it’s such a challenging population.

Harry Erba, MD, PhD: It’s a very heterogeneous population. There are those who Mark just described—who go through 2, 3 cycles of an HMA and they haven’t had the deep response you want. Maybe those patients will have a better outcome by adding venetoclax or take to CPX-351 [cytarabine, daunorubicin], and the patient who for 2 years has been on an HMA with cytopenias the whole time—they’re not going to do as well. It’s a very heterogeneous population of patients.

TRANSCRIPT EDITED FOR CLARITY