Case 4: Observations of HMA/Venetoclax in Trials

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD:I’m going to go ahead and do some of the data slides on the venetoclax, and then we’ll have any additional discussion points that may emerge after that.

There were 2 studies. Both of them are phase II. There are 2 phase III studies, actually, both near completion. One is completed, and one is near completion, but we don’t have any data to show from those. Of those 2 phase II studies, the one I’m going to discuss is the azacitidine or decitabine. It was basically an HMA [hypomethylating agent] combination with venetoclax. The study started about 4 years ago, and this was a study that was designed for elderly patients, but also those who are not fit or considered not fit for your traditional induction using a cytarabine/anthracycline-based approach. The phase II study did not have extremely strict criteria. It was left more to the treating physician considering them as the expert to make that decision on who they thought was a good candidate. The phase III does have more strict criteria to select patients who really would be considered unfit.

The other exclusion criteria, and something that I think was mentioned by Drs Rizzieri and McCloskey is that the white count is important. You don’t want to give venetoclax to somebody with 50,000 and test the waters, because we actually have seen tumor lysis in a couple of patients when you treat large numbers. It’s rare; it’s not the frequency that’s been shown in CLL [chronic lymphocytic leukemia], but it can occur, so I would be very careful. The doses of [azacitidine] and decitabine were standard doses. Venetoclax was given in a ramp-up here—100, 200, 400 [mg]. This was in the phase I/II, so azoles were not really allowed on that study. I think most people are now using azoles, and capping it at 100 [mg] with POSA [posaconazole] is reasonable and 200 with VORI [voriconazole] or Cresemba are probably reasonable options.

Here, we have the slide that has generated, rightly so, a lot of excitement. You see response rates in this population of 60-plus in the range of 70% to 75% with a large number of those being true CRs [complete responses]. To put this in perspective, if you look at single agent azacitidine phase III data and the single-agent decitabine phase III data from Dr Hagop Kantarjian, MD, published many years ago, the CR/CRi [complete remission with incomplete hematologic recovery] rates are 20% to 28%. This was not really double. It was almost triple the response rate. People were quite excited about this, even before we knew the survival. These are the data showing only the people who got 400 [mg] [venetoclax]. There are actually more patients on the study. There are 220, but these are the 115 who got the FDA-approved dose of 400 [mg] with the HMA, whether it was azacitidine or decitabine.

As you can see, most of these responses occur early. This was the second thing that people were excited about after seeing the response rate; it was happening within 29 days. All of you who have used hypomethylating agents know that it takes usually 2, 3, 4 cycles. Here, the median time was actually 1 cycle, so there was definitely a qualitative difference in the response.

On the next slide, we see the responses across molecular and cytogenetic groups and de novo and secondary. Basically, a 10,000-foot view here is that it didn’t really matter. Response rates were quite similar, between 60% and 80% in different cytogenetic and molecular groups. Even in secondary AML [acute myeloid leukemia], numbers are small now, but you have a pretty good response rate. With time, there’s more data that we’re not going to go into detail about, but it does appear thatTP53andFLT3patients don’t seem to do as well when it comes to survival and duration of response. With theTP53, although the response rates were not bad, at 60% or 80%, the survival is about 8 to 9 months. WithFLT3, both Dr Andrew Wei, MBBS, PhD, as well as our group, have shown analysis that the duration seems to be shorter. The high-risk groups are still difficult. They do better than with azacitidine and decitabine alone, but were not really anywhere close to a home run in those populations, so more research is definitely needed.

The survival curve, of course, came later, and people were still holding their breath because we’ve had a lot of experience with azacitidine plus drug ABC. We’ve done it with Revlimid, Vorinostat, and Mylotarg, and everything looked very good in the beginning, but the survival didn’t pan out. There have been multiple phase IIIs that actually fell after this approach. Here, it was nice to see the survival panning out at about 16 to 18 months, depending on the azacitidine or decitabine combo that was used. Of course, the tail of the curve is what patients and clinicians are more concerned about, rather than the medians. Here, you see a 2-to-3-year follow-up, and now this has been updated. We have about 45% to 50%. Again, if you look at azacitidine or decitabine alone, it was about 15% to 18%, so still not randomized, but very encouraging. I think in the United States, at least, this has become something that’s used very frequently in this particular population of patients.

Now, the next slide, I think is important, and we were discussing this in the break. This is not low-intensity therapy like azacitidine alone. This is not the therapy that you can give and bring somebody back in 4 weeks. You already heard the discussion from the panel, so 1) You start it inpatient. I think if you don’t have a very big setup that can do laboratory tests daily twice a day, like in the community, my recommendation will be to consider admitting that patient for a few days. Second is you need laboratory tests at least 2-3 times a day. These people do get cytopenic. They do need platelets. They do need neutrophil support, and you do see febrile neutropenia, as you can see in this slide, in 50% to 60% of the patients. It’s not as severe as 3+7 [cytarabine/daunoribicin]. It’s manageable, but you do need to be aware of that. We actually recommend dose interruptions once you’re in remission. You can do 14 or 21 days out of a 28- or 35-day cycle, and it seems to be quite efficacious in that approach.

Transcript edited for clarity.