Jorge E. Cortes, MD: Let’s move on to unfit patients. We’ve been talking about the issue of fitness and how we approach it. Historically, we’ve done 7+3 and had high mortalities, or palliative care and then all those are received for a long time…. Everything changed with venetoclax. Brian, beyond what we heard from the initial studies, what’s your experience with azacytidine-venetoclax? Is that what you do as standard? Did you use azacytidine or decitabine, and does it make a difference?

Brian Andrew Jonas, MD, PhD: Thanks for that question. With the azacitidine-venetoclax data, everyone knows them very well from the VIALE-A trial. Keith Pratz showed the long-term follow-up at ASH [American Society of Hematology Annual Meeting], where the survival curves remain separated the tail intriguingly stays around 20%. Also, there seem to be particularly long survivals in the setting of the best responders; ie, those that maybe had MRD [minimal residual disease] negativity.

There have been many discussions about subsets—which might not be ideal for the regimen, which might be more ideal for the regimen—and I’m sure we’ll discuss IDH1 later, for example. The TP53 mutations are also a potential weakness for the regimen. But at least at our institution [University of California, Davis], it’s our standard of care for older patients, the ones who would be induction ineligible. It’s fairly straightforward to use the VIALE-A entry criteria when you first meet somebody. Of course, a lot of nuances go into these discussions about whether they’re fit biologically, as well as patient factors that make that decision not so cut and dried. If they’re ECOG [performance status] 3, they’re a candidate; that’s a more complicated discussion.

The emergence of triplets is interesting. They’re mostly still investigational at this point. There are other doublets that could be considered in lieu of azacytidine-venetoclax, but it still has productivity and there’s clear evidence in a randomized placebo-controlled trial that it’s superior to azacitidine in this population. To me, it’s the standard. It’s potentially the backbone, the new 7+3, where we have new agents being added to it.

We’re discussing induction-ineligible patients, but there are important trials. One is looking at the randomization of 7+3 vs azacytidine-venetoclax in younger patients, which starts to ask the question: could this be a drug combination that’s used in younger populations? Of course, it has many issues, but lots of emerging retrospective data suggest it has a role in patients outside the VIALE-A population. There’s a lot to learn, about how to use it. That’s a separate discussion—how to make it better. But it’s changed how we treat older patients.

Jorge E. Cortes, MD: I always hesitate about calling these nonintensive chemotherapies. From the myelosuppressive point of view, that’s intensive. Margaret, you told us a few pearls of wisdom under this leaf, tricks that you had for the outpatients with CPX-351 [liposomal cytarabine-daunorubicin]. Tell us about your tricks for making azacytidine-venetoclax doable. There’s this 28-day thing with venetoclax. Is that what you do? Tell us your tricks.

Margaret T. Kasner, MD: Some of them are the same. And those aren’t tricks—that’s my amazing team taking the calls and supporting the patients. You’re right: this is very intense. They can be very myelosuppressive for longer than 7+3 in a lot of patients. Do we need 28 days of venetoclax in the first cycle? Those are the data. There’s a lot of management of how long and how much in future cycles, but from a first-cycle perspective, we try to give patients 28 days. Some centers and practices that do an earlier [bone] marrow [biopsy] at day 14 to decide about things like growth factor support. In general, it isn’t our practice, but that doesn’t mean it never happens.

It’s not like giving azacytidine separately from venetoclax in a patient with CLL [chronic lymphocytic leukemia], and understanding that is extremely important. This is going to make people’s blood counts 0 from the white blood cell perspective. We know it and expect it, and some centers are doing it as an inpatient [treatment] because of that. Understanding the intensity and not giving up early or being afraid of it is very important. For patients to benefit they must be well supported through the first cycle.

After that, or in the triplet setting, there are a lot of different data. As an example, the FLT3-azacytidine-venetoclax triplet is being studied pretty well. There are some good data that show all patients becoming plastic by day 14. If that’s the case, do they need more venetoclax? Maybe not. If every patient is going to become ... by day 14 with the triplet, that may be all they need. We’re gathering a lot of data about how much patients need, but we still follow VIALE-A in terms of the first cycle of 28 days.

Jorge E. Cortes, MD: That’s the label and VIALE-A, but I do a bone marrow [biopsy] on day 21. If they don’t have blasts, I stop there. I don’t go the 28 days.

Margaret T. Kasner, MD: That’s very reasonable.

Jorge E. Cortes, MD: That helps with the myelosuppressive a little. They’re still going to be myelosuppressive for a while, but it may shorten it. Remember, these patients need to receive prophylactic antimicrobials and all these things in the transfusion support.

Hetty E. Carraway, MD: I agree with that and with the comments from Dr Pratz at ASH. Patients whowere on more than 6 cycles of azacytidine-venetoclax ultimately ended up having 5 weeks in terms of the distance between cycles, and many of those patients were then modified to 14 or 21 days.

Jorge E. Cortes, MD: There was an interesting study at ASH using 7 days of venetoclax, and the outcomes were not that much inferior. I wouldn’t use it regularly, but there will probably be some patients [for whom that makes sense]. Because on the unfit you have the fit-unfit and the unfit-unfit. For the unfit-unfit, I’d try the 7 days if you know it’s going to be way too much for those patients.

Hetty E. Carraway, MD: That was a retrospective study, though.

Jorge E. Cortes, MD: It was, yes.

Transcript edited for clarity.