Monitoring Response to Venetoclax Regimens in AML

Mark J. Levis, MD, PhD: It’s hard to imagine doing a trial to decide the best regimen. We are all applying our knowledge, our art, our experience. I’m curious, how would we design a trial to answer Amir’s question, how do we give this drug? Because every patient is different.

Gail J. Roboz, MD: This is a nightmare. Dan Pollyea and I have been together on a couple of meetings where the goal was to try to get an expert consensus. We were cracking up at the end. Not only can we not get an expert consensus; we can’t even decide what you want to have for lunch, let alone this. In Colorado, apparently there are no fungal organisms so they don’t use it; Dana-Farber Cancer Institute doesn’t use antifungal prophylaxis. I absolutely do. The University of Texas MD Anderson Cancer Center does. I do marrow on day 21.

You have a lot of people who treat a lot of AML [acute myeloid leukemia], and of think we know what we’re doing. We concluded at the end of this that we are all either a bunch of geniuses or a bunch of idiots, because we couldn’t agree on anything. The problem is that bespoke medicine is nice, so you want to take individual excellent care of your patients, but it’s nerve-racking not to be able to figure out some consistency.

I would say the closest we have—I mean, we’ve got the Bible and the Torah and we have Dan’s paper on leukemia. All the PAs [physician assistants], if they can’t at least tell me about that paper and exactly what it says, I don’t want to have a conversation. Because at least that gives you something to hang on to. Please check the marrow. Please don’t be on day 60 of venetoclax without a bone marrow biopsy. Please don’t add an antifungal. If you’re going to add it, you’ve got to down the dose. At least certain basic principles have to be absolutely applied, even if the subtleties of exactly what day you do the marrow and exactly which antifungal can’t be mandated.

Daniel Pollyea, MD, MS: I think it’s in the Talmud, Gail. It’s really far in there.

Gail J. Roboz, MD: I was sure of that, but I wanted it to come from you.

Harry Paul Erba, MD, PhD: I need to push back on Amir’s comment about patients who are pancytopenic and maybe sick with a fungal infection. You don’t want to give them venetoclax in the first cycle. I disagree.

Amir Fathi, MD: I didn’t say that if patients are very sick with their leukemia, I don’t want to give venetoclax.

Harry Paul Erba, MD, PhD: Oh, OK.

Amir Fathi, MD: I said there are some patients because of their functional limitations or their age, I may worry about significant marrow suppression with the combination, and I may choose to give HMA monotherapy. Again, everybody is different. Do I see 85- or 90-year-olds with AML who I want to treat? I do.

Mark J. Levis, MD, PhD: But you’ve actually seen deaths from AZA-VEN [azacitidine-venetoclax] in some of those patients.

Amir Fathi, MD: I have.

Mark J. Levis, MD, PhD: Right. Actually, we get very arrogant with this today for everybody. You’re 100 years old and this and that, and we’re going to do AZA-VEN [azacitidine-venetoclax]. Every now and then we get bit.

Gail J. Roboz, MD: This is a bad disease but having count recovery faster is better.

Mark J. Levis, MD, PhD: Oh, yeah.

Harry Paul Erba, MD, PhD: That’s the key here. The last patient I just treated—a 90-year-old man, hand fungal pneumonia but cleared his blast quickly—I did the marrow on day 14, and it was clear: Start him on GCSF. Counts came up. You’ve got to get the leukemia to go away for the counts to get better, and that’s the FISH [fluorescence in situ hybridization] regimen. But I think what Gail said is exactly right: There’s not 1 size fits all. And Mark said it, there’s an art to giving these regimens. The community needs to learn about how to do this with experience and reaching out to people.

Gail J. Roboz, MD: I also really worry, and I just want to emphasize this point: I worry that people got on the wrong bandwagon somehow with venetoclax because of the original CLL [chronic lymphocytic leukemia] approval. Obviously in practice settings there’s an awful lot more CLL than there is AML. Everybody knows the ramp-up, the TLS [tumor lysis syndrome], watching all that. That’s the stuff that we don’t care about in AML. Ramp up? I don’t even ramp up. I just get there. I think I’ve seen 1 laboratory TLS when I had to look for it.

These are the kinds of things I can say. I’m not advocating in any way not to be careful. I am very careful. I admit these patients unless they live within 3 feet of the hospital entrance. I treat them as induction. I watch them very carefully. But I don’t even know where to find the 20-mg dose of venetoclax or 50 mg. That’s for CLL doctors. It was a wrong focus of the toxicity, and it should be regarded differently. It should be regarded as intensive induction. My final point, which Harry and I love to talk about, is the end and death hopefully of fit and unfit. There are fit people and there are unfit people. You worry about everything. You want to give everybody this high response rate. You want to get them into remission. Whether you do a transplant or send them on a cruise after they get a remission, never mind. Just get them into remission. But the point is that you can’t. You can’t call somebody unfit forever and say, well, they’re not a candidate for a transplant because they might be a candidate later.

Similarly, you can’t necessarily call somebody fit forever because if they have a terrible time with induction and they blow up and have infections, that patient may actually want to go on or need to go on to some sort of maintenance. So flexibility in thinking.

Harry Paul Erba, MD, PhD: I agree. We’re coming to the end of this part of the discussion. I’m going to turn to Mark for that. But I want to quickly come to a few other end points from VIALE-A that were important. You know we talk about a CR [complete response], CRi [CR with incomplete hematologic recovery] rate of about two-thirds of patients in the study. But what’s really impressive to me is that they weren’t just CRis, almost all of them were also CRhs [CRs with partial hematologic recovery]. Mark, what’s a CRh?

The other thing was that patients who were transfusion dependent at baseline had a higher rate of transfusion independent after AZA-VEN [azacitidine-venetoclax] than after azacitidine. We’re still waiting to see the quality-of-life data. But it gets to the point that Gail just made about fitness, which is important. If you look at the hazard ratio for survival in patients under the age of 75 years old in VIALE-A, that actually is pretty close to unity. But remember, for the patients to be under 75 years old to get on the study, they had to have very poor performance status or comorbidities. So we really need to continue to take very close care of these patients, especially older patients who with infirmities who may make them at higher risk of infectious complications and bleeding.

Transcript Edited for Clarity