BCL2 Inhibition in Leukemia - Episode 11

Venetoclax's Role in Relapsed/Refractory CLL

Harry Erba, MD, PhD:Let’s turn now to the BCL2 inhibitor that we have: venetoclax. Discuss for us your experience and the clinical trial data for venetoclax in the relapsed-refractory setting.

Javier Pinilla-Ibarz, MD, PhD:In the relapsed-refractory setting, venetoclax use was very, very well documented in the MURANO study, which really compared Rituxan-venetoclax against bendamustine-Rituxan. It was a very, very classical study, and we already have at the last ASH [American Society of Hematology Annual Meeting & Exposition] a longer follow-up and very, very exciting and very, very remarkable data in terms of efficacy. What’s really, really important about the trial is that this is a time-limited therapy. It’s providing another alternative for a patient who, because of financial toxicity or preference, doesn’t want to stay on a drug for life.

We know that this trial decided to really provide 2 years of therapy and stop and wait until patients progressed. I think it’s really, really bringing the opportunity for patients—who for many, many reasons may not want to be on these long-term therapies—to have another alternative. Right now, I’m always very, very interested to follow those patients because I think the prediction is it’s very likely it’s going to happen as chemotherapy did in the past. So the high-risk population will start to relapse earlier than a less-high-risk population.

We already saw that in the last follow-up. Patients withTP53, very interestingly, as we predicted, were going to start to relapse shortly or in a lesser period of time compared with non-17p or non-TP53patients after they stop therapy. With those patients, will we be able to be rechallenged with these therapies? Maybe the answer is yes, but we still need to know. We know chemotherapies select clones. We don’t know very much about how venetoclax is going to behave in terms of selecting clones. We know that it’s equally effective in 17p, non-17p. We may really see that this is coming back in the same way that it was before. So it may be amenable to be re-treated with the same drugs.

Harry Erba, MD, PhD:Well, you and I have interacted in the past in the treatment and clinical trials for chronic myeloid leukemia [CML]. And there with the 4 agents that we now have for initial therapy, 1 of the deciding factors of how we pick 1 is patient comorbidities. Can you discuss, in the relapsed-refractory setting for CLL [chronic lymphocytic leukemia], how things like cardiovascular disease, bleeding tendencies, and being on anticoagulants might inform these decisions?

Javier Pinilla-Ibarz, MD, PhD:That’s a great, great point. As you know, Harry, we came from the era of CML. The more I really do see CLL, the more I remember all the same problems we had and we still have with CML: chronic AEs, adverse events, and really switching from 1 to another drug. There is no doubt it is coming to the same answer I was telling you. Each patient is different, and now with all these different alternatives of therapy, I think we are in an excellent position to start to really offer the best therapy with fewer potential adverse effects for each patient. You were bringing the story of the bleeding, of the anticoagulation. Of course those things were never really a contraindication. We have done that, but in certain situations, you may really try to look in another direction or at drugs that may not really have this risk. Again, the risk benefit should be discussed with the patient, and I think as part of this conversation that we have with patients at the time that they require therapy.

Harry Erba, MD, PhD:Just give me some idea. What is the response rate in PFS [progression-free survival] with venetoclax in the relapsed-refractory patients?

Javier Pinilla-Ibarz, MD, PhD:The relapsed-refractory data show very, very high rate of response. It’s less a response but rather like PFS. We are really talking about 60%, 70% PFS over time. And I think the important thing in those patients, obviously over time we’re very interested to really follow them. But the response rates or the progression-free survival is very, very related to the capacity of venetoclax to obtain a minimal residual disease [MRD] negativity in the bone marrow.

We know historically that from the time of FCR [fludarabine, cyclophosphamide, rituximab], the patients who really obtain MRD-negativity in the bone marrow were associated with a very prolonged PFS. The same thing is happening right now; the same thing starts to evolve with venetoclax. I always say that venetoclax is chemotherapy without chemotherapy, but at the same time, we are able to really eradicate to a very, very high level the cells in the bone marrow. And these MRD negatives in the bone marrow very likely are going to predict, as is happening right now and has been documented in the MURANO trial, very long progression-free survival for our patients.

Harry Erba, MD, PhD:Although venetoclax is clearly active in 17p-deleted patients, you don’t need to have a 17p deletion orP53mutation to use it.

Javier Pinilla-Ibarz, MD, PhD:Absolutely not. As you know, the initial indication for venetoclax was 17p, obviously. After that, it’s been expanded. Right now, in the recent label, the FDA is open for any frontline or second-line use, independently of the prognostic factors.

Transcript edited for clarity.