Transcript:Harry Erba, MD, PhD: I think we have to be careful about how we use these drugs. For example, in those studies, both of them, the patients typically had nonproliferative disease. Only 10% received hydroxyurea. You couldn’t have a white count over 25,000. One-third of the patients had what we used to call RAEB-T [refractory anemia with excess blasts in transformation] with 20% to 30% blasts. So although it’s reassuring that they didn’t see any clinical evidence of tumor lysis syndrome, I think we need to be very careful as we move these drugs now out into practice, that we select patients who are best fit to receive it and also watch them closely.

Mark J. Levis, MD, PhD: That’s a great point because that’s exactly the patients who were recruited in the trial that got the drug approved, these low indolent cases. I think we are seeing tumor lysis with the more chemosensitive leukemias as these extend.

Naval G. Daver, MD: The good thing with the trial was actually about 90% of the people we saw—elderly patients with AML [acute myeloid leukemia]—went on this. This was our backbone, so it fits and these were kind of real-life situations. But we’ve actually seen tumor lysis in 2 patients, and whenever I present this or talk about this at advisory meetings, people don’t like it because really what we’re saying is we should still admit these people and hydrate them. We’ve had 1 case of a patient who was IDH [isocitrate dehydrogenase]-mutated and the white count was actually low, it was 20,000; it was not very high. Got one dose of AZA [azacitidine]/venetoclax, had creatinine go up in next 4 to 5 days, ended up on dialysis, had dialysis 2 to 3 weeks, got off it, never got venetoclax again, was in MRD [minimal residual disease]-negative remission and then eventually he was on 50 mg venetoclax and has maintained. Then we had another one with extramedullary disease, etcetera.

I think what’s happened is that the CLL [chronic lymphocytic leukemia] group got hit really hard and there was a whiplash effect, and they said, “OK, tumor lysis occurs, let’s do all of this.” And so we’ve done all these precautions. From the beginning, this whole trial was always admit, hydrate, use allopurinol, monitor labs twice a day. And so we didn’t see tumor lysis. I think if we had done the same for CLL, we would not have seen tumor lysis there. Now we’re going to remove that effect, hopefully not, but it will happen in the community. We’re going to go back to, OK, let’s give 400 mg VEN [venetoclax], because I’ve heard people say I’m going to start 400 mg VEN with AZA day 1 outpatient. I’m sure you’re going to see tumor lysis. It may be the same or more than CLL.

Raajit K. Rampal, MD, PhD: I think that’s an important point because one of the challenges in oncology in general is that the patients that we have on study are not necessarily always the patients that we see on a day-to-day basis. And so we have to be very careful about who we select for what therapy, particularly with this drug with which we have also seen tumor lysis. And so just because it is an oral therapy does not mean it is necessarily an outpatient therapy. And I think also part of the general discussion, as we talk about other therapies, is how do we incorporate this? Who are the right patients for which therapies? Which I think we don’t have a clear sense of that right now.

Naval G. Daver, MD: The other thing about neutropenia is very important, too, because that’s the other thing in the community I feel is going to be taking years for people to start realizing. There is very clear neutropenia. This is not AZA or DAC [decitabine] alone, not even close. There is much more neutropenia in that way, and what Sasha said is kind of what we’re doing. We do a bone marrow on day 21 to 28, whatever, end of cycle. If they’re ablated or in remission, which ends up being about 90%, 95% of the people, we actually just hold the venetoclax, let their counts recover, 10, 14 days. And then for subsequent cycles, and we presented from our institutional data and oral presentation, we go to 14 or 21 days.

And what we actually saw was with the DAC/VEN, I mean these are amazing, it was like 95% response rates frontline, but the CR [complete response] rate actually was 55%. So I think if you actually give to count recovery time, you’re actually seeing more people, which is different from FLT3 [fms-like tyrosine kinase 3] and IDH, where we actually do want more continuous suppressive therapy with venetoclax. Dan Pollyea [MD] and others had some suggestions why.

Harry Erba, MD, PhD: You mentioned your 10-day decitabine plus venetoclax study, and you’re right, you had virtually no early mortality. In fact, there was no early mortality, it was zero and we saw a 95% CR rate. But an important point to keep in mind was what you alluded to earlier. At The University of Texas MD Anderson Cancer Center, these patients, even though they’re getting less intensive therapy, are admitted for the entire time. And so we really need to pay attention to safety.

Naval G. Daver, MD: To the details.

Harry Erba, MD, PhD: Now, venetoclax has been given an accelerated approval in combination with HMA [hypomethylating agent] and low-dose ara-C [cytarabine] for older or unfit patients with acute myeloid leukemia who were previously untreated, based on this response rate. It was CR CRh [complete response with partial hematologic recovery] which I think is a very clinically meaningful outcome for patients, getting the platelets over 50 and ANC [absolute neutrophil count] over 500 with a CRh. But we all know that there are these phase III studies ongoing that are looking for survival benefit. So let me ask you, if those studies are negative and don’t show survival benefit, is there still a benefit with venetoclax? Is there something that we could point to?

Alexander Perl, MD: I think clinically one big difference with venetoclax is the speed of response. That is something that’s different from a hypomethylating agent. So when we start patients on hypomethylating agents, we say, “OK, we’ll get you on this therapy and we’ll see a response as we go.” But that as we go could be 4 to 6 months later before we really know something’s happening or something’s not happening. And that could be a hard time if the patient needs a lot of supportive care. That’s not to say the patients getting VEN and AZA are not needing supportive care, they absolutely are. But if it’s working or not working, you know very quickly. The question then is, how much benefit do you get in terms of quality of life by responding fast versus responding later?

Mark J. Levis, MD, PhD: And I think that’s what they responded to in the FDA. They said these are high quality responses. The CRh that we joke about is in fact what some people said is the CR Bahamas. You can go to the Bahamas if you have a CRh. It’s clinical benefit.

Harry Erba, MD, PhD: I do think that’s important, but let’s look at the survival that was seen. First it was a median of 18 months and now it’s been moved down to maybe a 15-, 16-month median survival. But what’s interesting about these reports of the combination is that the median time on therapy is only about 6 months. I mean, these are not durable remissions in many patients, and yet the survival is better. So one of the things I wonder about is with all of these new drugs that are being approved in AML and that are available, are we just getting more aggressive about supporting these patients in improving survival?

Naval G. Daver, MD: The duration of response that’s written in the label I think is 6 months, and this is really a statistical quirk. It was the way the cutoff was made. We reviewed our data, and it’s actually about 12 to 14 months, the duration of response. So I think the survival benefit is coming a lot from the duration, but I think there is a component of what you’re saying. Because we are having more options, even the elderly AMLs who fail, and they do. Even the 2-and-a-half-year survival is 45%.

There’s still the majority that in 2, 3 years are failing. I think we are treating them more, whether it’s with FLT3, whether it’s IDH, it’s Mylotarg, other approaches. I think your first question is really good about the phase III because I would not bet 90:1 that the phase III were always positive. We hope so. We’ve seen it with SGN-33; 74%, phase II, 10 centers and then you talk about toxicity. I think what that study will show if it’s negative is that AML really should be treated in big academic centers. That would be my takeaway.

Harry Erba, MD, PhD: Well, at least by groups that are comfortable treating these patients.

Naval G. Daver, MD: Or big community centers, yes.

Harry Erba, MD, PhD: Inpatient or outpatient, but you really need the resources to care for these patients.

Transcript edited for clarity.