BCL2 Inhibition in Leukemia - Episode 10
Harry Erba, MD, PhD:This is probably going to be a difficult question, but I want to now focus on relapsed-refractory CLL [chronic lymphocytic leukemia]. In my mind, what makes it difficult is that we may be seeing patients in the modern era who have had long responses or received prior immunochemotherapy, and they’re progressing. On the other hand, we now have BTK [Bruton tyrosine kinase] inhibition as first-line therapy. How do you decide what to do for a patient who has relapsed-refractory disease, given that they’re coming at you from all different types of pretherapies?
Javier Pinilla-Ibarz, MD, PhD:I think it’s very important. I think we need to touch upon that historically, we went from short therapies, chemoimmunotherapy, a time-limited therapy. And the paradigm changed with the introduction of the BTK approvals. We change from a time-limited therapy to prolonged therapies, therapies until progression or unacceptable toxicity, which really completely changed the way that we really control CLL. Now with these new regimens, including venetoclax, we’re going back to the old paradigmit’s not so old—of the time-limited therapy. These days we really can move between these 2 paradigms, and in the future we’re going to maybe be able to combine them.
At the end of the day, when we really discuss relapsed-refractory CLL therapy with patients, we really encounter the same conversation. We have very, very good drugs that really maintain, or while patients are taking the drug can really, really have very long duration. We are presenting in this ASCO [American Society of Clinical Oncology Annual Meeting] the first clinical trial with a very, very long PFS [progression-free survival] of almost 44 months. But also we have the MURANO study that was reported at ASH [American Society of Hematology Annual Meeting], also with a very, very long time to progression. Which 1, we’re going to really elect.
Obviously, once again, it’s a decision I need to make for each patient. In my opinion, not every patient could be given the same medication becauseand what we’re discussing, Harry, is why we treat CLL—we don’t treat all CLL for the same reason. We have patients with very bulky lymphadenopathy who really do fantastically with ibrutinib or with any kind of BTK inhibition. But also we see patients with cytopenias where the goal is to really empty this bone marrow with very, very good drugs. I think we’re going to really define this in the near future and customize why we’re going to treat patients. Note in CLL that if it’s relapsed-refractory, what is the main issue, what is the problem that we’re going to really resolve? At the same time, we understand that some patients, because of the genetic feature, may require therapy for life while others may really require therapy for a short period of time and then wait until they progress and do it again.
Harry Erba, MD, PhD:Before we leave immunochemotherapy in the distant past, are there patients who have been treated with immunochemotherapy who have had a long remission, where you might be tempted to treat them again with the same agents? Do you think that’s dead?
Javier Pinilla-Ibarz, MD, PhD:That’s a great point. I think chemoimmunotherapy is going to be gone very, very soon. But you have a good point. In the old time, we said, “Well, if an FCR [fludarabine-cyclophosphamide-rituximab] patient has more than 3, 4 years, why we shouldn’t we do it again?” I think what we have learned is that when we do fludarabine and other agents like bendamustine, they really, really give us a good result in the short run. But I think what we always underestimate is the damage that we do to the genome of the CLL and how we’re going to likely change, although maybe we need more data and the natural history of this patient in the long run. I think it is the reason to try to avoid damage to the cells and also damage to the immune system. It’s going to be an important part of really looking forward regarding the therapy in the relapsed-refractory patients.
Harry Erba, MD, PhD:Let me provide a third nail in that coffin, OK? From my perspective as a myeloid leukemia doctor, you and I both know that these drugs are mutagenic and genotoxic and may lead to MDS [myelodysplastic syndrome] and AML [acute myeloid leukemia].
Javier Pinilla-Ibarz, MD, PhD:Absolutely. And I think, unfortunately, sometimes we see this consequence around 10, 15 years after these patients were exposed.
Harry Erba, MD, PhD:We are going to talk about, while in the relapsed-refractory setting, how we have BCL2 inhibition, we have the BTK inhibitors, we have PI3-kinase-delta inhibitors. Is there any assay that you can do that might help predict for response to 1 or the other? For example, do you test forBCL2orBH3expression?
Javier Pinilla-Ibarz, MD, PhD:That’s a great point. Right now we know this consistently in any trial that has been done with new drugs: with BTK, with BCL2, with PI3K-delta. There is not really a factor showing who is really predisposed to have a better response with 1 subtype of CLL versus another. So we know that the classical 1 is the example ofIGHV-mutated versus unmutated. We know with chemotherapy people will do well but they start to really separate, of course, in PFS. Now with BTK inhibitors, with BCL2 inhibitors, we don’t really see a difference. The efficacy is the same. The same happened withTP53, deletion of 17p. I’m very interested even in deletion of 11q. We even see better outcomes with these new drugs, though we still don’t understand, and we are really studying this very, very deeply. So I think right now, as far as I know, we don’t have any predictive factor in genetics or mutation who can tell us these patients are going to work better in this drug versus another drug.
Transcript edited for clarity.