Harry Erba, MD, PhD: We’ve had a number, like 8 different FDA-approved drugs in AML [acute myeloid leukemia] since April of 2017. And our challenge really has been how to incorporate all of these new drugs into our algorithms for treating AML and where do they fit best. What I’d like to talk about first is venetoclax. Why don’t we start with you, Sasha. Give us some background on the data for venetoclax, that led to the FDA approval, in terms of combinations with HMAs and low-dose cytarabine in older and unfit patients.

Alexander Perl, MD: Venetoclax is an antagonist of BCL2 that’s been FDA approved for CLL [chronic lymphocytic leukemia] and lymphoid malignancies for some time now, and I think the community has gotten pretty familiar with it as a single agent in that context. What’s different in AML is, when the drug was tested in relapsed/refractory patients, activity was seen but it was really quite modest. As a single agent, it really didn’t go very far. However, when it was added to low-intensity chemotherapy, there was much more substantial activity, so much so that studies have largely been focused on frontline therapy of unfit, older patients or really the more extremes of age—either patients over the age of 65 with comorbidity or patients over the age of 75 without regard to comorbidity—to see whether the improvement in activity in that setting would just lead to transformative outcomes.

And I must say the data have been really eye-opening in a few ways. One is it’s not really new that you can add a drug to low-dose chemotherapy and get much better response rates. But what’s been really hard is the ability to do that with durability of that response. So, for example, in Britain there has been 1 study that added a number of agents to low-dose ara-C, and none of them had led to better survival, despite many of them improving remission rate, sometimes even doubling the remission rate and yet not improving survival.

What’s very interesting here is the reason that happened was there was not durability of the responses that were seen. Now, there’s not randomized data with venetoclax plus hypomethylating agents or venetoclax plus low-dose ara-C yet, but those data have been collected and we should have those soon. In spite of that not being at our fingertips, the FDA has looked at the data and found it convincing enough to approve either the combination of low-dose ara-C plus venetoclax, or either azacitidine or decitabine obviously can be used in this setting. The approval is for combination of a hypomethylating agent with venetoclax. The doses are actually different. The dose is 400 mg with a hypomethylating agent, dose of 600 mg with low-dose ara-C, and the results were updated at ASH [American Society of Hematology] in terms of longer-term follow-up, but basically show the same thing.

The response rates with these combinations are in the range of 60% to 70% for CR or CRI. The durability of these responses is in the range of about a year on average. And the overall survival I think was 17 months with the hypomethylating agent combination, which is really quite good. And despite that, there’s not a big increase in terms of toxicity by this in comparison to what might be expected with a hypomethylating agent alone, with 1 important exception—which is these drugs are really quite myelosuppressive.

And the approach to treating the patient with the combination really is different. You don’t just start this therapy and keep it going until you see response. You need to look for response. On the studies, they looked a month in, and if the patients had an aplastic bone marrow, which many of them had, that actually was a predictor of people going into response. If there was resistant leukemia, you could continue therapy at that point. But if your bone marrow was empty, you could stop therapy, hold, wait for count recovery, and that led to better safety. And the early death rate on these studies was actually quite low, which is encouraging. So, again, looking at really high-risk patients who didn’t have great options, now we’re seeing much longer median survivals, granted on single-arm studies, but quite promising and much better than what’s been seen historically.

Transcript Edited for Clarity