Recent Advances in Treatment of Acute Myeloid Leukemia - Episode 8

Managing Venetoclax-Associated Toxicity in AML


Harry Erba, MD, PhD: Rami, talk to us about your experience with managing the toxicities associated with venetoclax.

Rami Komrokji, MD: That is something we are now doing on a daily basis. In our practice, a lot of the patients we see are treated by our colleagues in the community, and they come back and forth. We deal with this a lot. We’ve treated, by this time, more than 150 patients off studies with the combination. One thing first: I tried to do some of what was done in the study. We don’t de-escalate the dose anymore, and we don’t admit the patients. If a patient’s white blood cell count was high, we try to bring the count lower: below 25,000 or 30,000 to start the treatment. We put them on tumor lysis prophylaxis, hydration, and all that before starting the treatment.

The key is that this is a regimen that’s been used by community colleagues and can be done near home with the caveat that we are much more used to using azacitidine alone in MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia], so we used to start the patient and say we’re going to see the response in 3 to 4 months. You cannot do that with this. The dosing of the venetoclax is the tricky part, and you have to find the sweet spot of the dose. We start patients at 400 mg, but if they were on prophylactic antibiotics, we reduce the dose accordingly, sometimes even down to 100 mg. At the end of the first cycle, we repeat the bone marrow, and we assess. If there is myelosuppression in the hypocellular bone marrow, we hold both treatments, and we wait for some recovery. Then we may do a little bit of dosage modification for 2 or 3 weeks out of 4 weeks. The key is reassessing the disease early on and modifying the dosage, because if we don’t, you will see profound myelosuppression, neutropenia, and infection. That has been my approach.

Mark Levis, MD, PhD: For the drug interaction problems, you’ve got to have some experience recognizing them. We want to use 8 mold-active azoles in our patients, but there are huge drug-drug interactions. You have to know to reduce that dose quite dramatically.

Harry Erba, MD, PhD: It’s not just that; it’s actually MDR inhibitors. Carvedilol, which is very frequent prescribed for older patients, will also raise levels.

Mark Levis, MD, PhD: A lot of people don’t know that about Coreg [carvedilol]. You better watch out.

Harry Erba, MD, PhD: Yeah, you have to be careful with that. I would just add that, even with cytoreduction to a white count that would have gotten a patient on the study, I have seen tumor lysis syndrome, and I’ve seen cytokine release syndrome with this, very abruptly, within the first day. If you’re not set up—like you probably are at Moffitt Cancer Center and The University of Texas MD Anderson Cancer Center—to see these patients in clinic, to check tumor lysis labs at the end of the day before they go home. If you’re not set up to do that, I’d be very careful and admit them. Dan?

Dan Pollyea, MD, MS: I completely agree. In fact, we continue to admit patients—high risk and low risk, regardless of counts. We continue to do the dose escalation. At this point, it’s probably out of habit. We’ve also treated close to 175 patients, and we still do things the same way we’ve become accustomed to doing them from what we’ve learned in the clinical trial. I don’t necessarily think that the way we do it is the only way or the right way, but it’s the way that works for us. It’s long been a concern of mine if the tumor lysis incidence was so low because of the biology of the disease. I believe that is true: this is not CLL [chronic lymphocytic leukemia]. Was it as low as it was because of the mitigation techniques? I’m hesitant to abandon those until I have more experience or similar to the rules for CLL with venetoclax. Someone can tell me, “These are the high-risk patients, this is how you handle them, these are the lower-risk patients.” Until that comes out, I’m more comfortable keeping them inpatient and being really conservative. But I don’t think that’s necessarily the right thing.

Naval Daver, MD: This is a very important point. The key, though, is doing end-of-cycle-1 marrow early evaluation. Of all of this, in the community, if we had to give a message, that’s the 1 thing: do not do continuous HMA [hypomethylating agent]—VEN [venetoclax], 2 or 3 cycles until neutropenia…

Mark Levis, MD, PhD: I’ve had patients spend an entire summer without a neutrophil when they didn’t need to.

Dan Pollyea, MD, MS: Early bone marrow, Naval—the other part of that, which Rami got to, is to take breaks. When patients achieve remission, which most of them do, they need breaks between cycles.

Naval Daver, MD: This is not HMA alone.

Dan Pollyea, MD, MS: Right, exactly.

Naval Daver, MD: That’s the whole point.

Transcript Edited for Clarity