ONCAlert | Upfront Therapy for mRCC

CLL: The Current and Future Paradigms of BCL2 Inhibition

Targeted Oncology
Published Online:12:00 PM, Tue August 13, 2019

Harry Erba, MD, PhD: It makes sense with BCL2 inhibition that we’re going to see this strategy being used in other cancers. And we know that it’s already been approved in AML [acute myeloid leukemia], and we can talk a little about that and other hematologic malignancies and maybe someday outside that. But before we get to the future of BCL2 inhibition, in CLL [chronic lymphocytic leukemia], what do you think are some of the challenging issues and unmet needs that remain out there? You keep mentioning older patients, but what else?

Javier Pinilla-Ibarz, MD, PhD: Absolutely. Harry, no doubt, I think the next frontier in the treatment of patients with CLL—as you know we can really improve their survival as we speak—is how to restore the immune system. Because those patients are still maybe vulnerable to infections and secondary cancer. Recently, there was another publication about the incidence of secondary cancer with these new therapies, now those patients per se have a high tendency to have a secondary cancer.

Those drugs can increase that or just really allow them to live a very long period of time in which the disease still produces severe immunosuppression, which predisposes them to have infections and cancers. I think it’s the next frontier: how to restore the immune system of these patients, so they can have a better life and continue to enjoy these prolonged periods of remission but without this complication that unfortunately happens often in this older population.

Harry Erba, MD, PhD: I think we’re all excited about looking at BCL2 inhibition in other malignancies and what we do, hematologic malignancies specifically. But there was a recent safety signal noted in our myeloma trial. Can you tell us more about that?

Javier Pinilla-Ibarz, MD, PhD: What we read from the news obviously is that in the trials, we heard about and we have seen the tremendous efficacy in subgroups of myeloma with venetoclax. However, it seems as if the FDA really saw some safety information or safety data and decided to put on hold these trials until more information is generated. I think it’s something that needs to be evolved. Obviously, patients with multiple myeloma have many other options. But as I definitely heard and I saw in our practice, some of my colleagues see that the drug is quite efficacious. So how to use it and how to avoid these safety things are some things that obviously have to be studied very well to make sure that patients are safely treated.

Harry Erba, MD, PhD: As I remember the survival curves that were presented that led to the FDA hold, they continued to diverge, so it doesn’t appear to be a tumor lysis event right at the beginning. It’s something that’s happening later.

Javier Pinilla-Ibarz, MD, PhD: Absolutely. And this may also be related to complications, infections, or many other things that need to be taken into consideration. Because we know, as we discussed, neutropenia can predispose to infection. And it’s something we need to be aware of and really deal with.

Harry Erba, MD, PhD: Any other BCL2 inhibitors coming forward that you know of?

Javier Pinilla-Ibarz, MD, PhD: I think the next generation may come with the MCL1 inhibitors. I think it’s fascinating. We believe that these drugs are coming and don’t have any problem. For sure we know that BCL2—in this case, venetoclax—may fail in the long run. Because there are BCL2 mutations that were described at the last ASH [American Society of Hematology Annual Meeting & Exposition]—and I had the opportunity to check a couple of cases—as well as the upregulation in the lymph nodes of MCL1 and BCL-XL. All other antiapoptotic protein that can really compensate block BCL2. So I think in the future we’re going to see lymdifferent combinations, even with other antiapoptotic protein blockades.

Harry Erba, MD, PhD: You’re the section chief for lymphoma. For other lymphomas, B-cell lymphomas, where this is being used?

Javier Pinilla-Ibarz, MD, PhD: It’s very interesting because everyone was predicting the high efficacy in follicular lymphoma. As you know, the data have not been as striking as we thought, considering the BCL2 is upregulated. There are different reasons that we still don’t understand very well. Definitely there is a role. We know, for example, in mantle cell lymphoma, it is studied very well in combination and alone. I think it still needs to be said how the BCL2 are going to be used, maybe in combination with chemotherapy. There are many trials that are addressing that. And maybe in different subtypes—who specifically sees benefit—as happens with the BTK or BCR inhibitors. We know ABC subtype may work more. But maybe in lymphomas we need to understand who are the patients who may be better candidates for these drugs.

Harry Erba, MD, PhD: As you know, there’s been a recent update to the label of venetoclax to include AML, very exciting data from the phase Ib studies of older patients with infirmities and comorbidities that lead to them not tolerating chemotherapy. The combination of HMAs [hypomethylating agents] with venetoclax or low-dose ara-C [cytarabine] and venetoclax have produced very rapid and very high response rates. HMA/venetoclax, 61% CR/CRh [complete remission or CR with partial hematologic recovery], 70% CR/CRi [CR with incomplete hematologic recovery]. Very rapid time to response, and the duration of response seems significant, on the order of a year and median survivals of over a year, 15 to 18 months, depending on the analysis that’s been there. As you know, those combinations are in randomized clinical trials. We’re awaiting the results. They finished accrual.

Javier Pinilla-Ibarz, MD, PhD: Very exciting data for sure. A really, really a great alternative for our older population of patients that may increase the quality of life just to really put them in remission in a very, very nice way without necessarily time to be in the hospital.

Harry Erba, MD, PhD: Well, we’re appreciative to our colleagues in CLL who have prepared us for some of the issues that we are going to be seeing, like monitoring and prophylaxis for TLS [tumor lysis syndrome], neutropenia. I think these are things that we are going to have to deal with as we treat these patients with AML with a very effective regimen. Clearly, there’s a very active way of improving the outcomes of patients with hematologic malignancies; CML [chronic myeloid leukemia] and now AML. Before we close, anything you want to leave our audience with?

Javier Pinilla-Ibarz, MD, PhD: Well, I think the future is extremely exciting for patients with CLL these days. We have more alternatives for treatment in the frontline and the second line. And I think really blocking these important mechanisms for which CLL persist, survive, and proliferate are going to be crucial to really continuing to conquer the cure, or at least long-term control of these conditions.

Transcript edited for clarity.

Harry Erba, MD, PhD: It makes sense with BCL2 inhibition that we’re going to see this strategy being used in other cancers. And we know that it’s already been approved in AML [acute myeloid leukemia], and we can talk a little about that and other hematologic malignancies and maybe someday outside that. But before we get to the future of BCL2 inhibition, in CLL [chronic lymphocytic leukemia], what do you think are some of the challenging issues and unmet needs that remain out there? You keep mentioning older patients, but what else?

Javier Pinilla-Ibarz, MD, PhD: Absolutely. Harry, no doubt, I think the next frontier in the treatment of patients with CLL—as you know we can really improve their survival as we speak—is how to restore the immune system. Because those patients are still maybe vulnerable to infections and secondary cancer. Recently, there was another publication about the incidence of secondary cancer with these new therapies, now those patients per se have a high tendency to have a secondary cancer.

Those drugs can increase that or just really allow them to live a very long period of time in which the disease still produces severe immunosuppression, which predisposes them to have infections and cancers. I think it’s the next frontier: how to restore the immune system of these patients, so they can have a better life and continue to enjoy these prolonged periods of remission but without this complication that unfortunately happens often in this older population.

Harry Erba, MD, PhD: I think we’re all excited about looking at BCL2 inhibition in other malignancies and what we do, hematologic malignancies specifically. But there was a recent safety signal noted in our myeloma trial. Can you tell us more about that?

Javier Pinilla-Ibarz, MD, PhD: What we read from the news obviously is that in the trials, we heard about and we have seen the tremendous efficacy in subgroups of myeloma with venetoclax. However, it seems as if the FDA really saw some safety information or safety data and decided to put on hold these trials until more information is generated. I think it’s something that needs to be evolved. Obviously, patients with multiple myeloma have many other options. But as I definitely heard and I saw in our practice, some of my colleagues see that the drug is quite efficacious. So how to use it and how to avoid these safety things are some things that obviously have to be studied very well to make sure that patients are safely treated.

Harry Erba, MD, PhD: As I remember the survival curves that were presented that led to the FDA hold, they continued to diverge, so it doesn’t appear to be a tumor lysis event right at the beginning. It’s something that’s happening later.

Javier Pinilla-Ibarz, MD, PhD: Absolutely. And this may also be related to complications, infections, or many other things that need to be taken into consideration. Because we know, as we discussed, neutropenia can predispose to infection. And it’s something we need to be aware of and really deal with.

Harry Erba, MD, PhD: Any other BCL2 inhibitors coming forward that you know of?

Javier Pinilla-Ibarz, MD, PhD: I think the next generation may come with the MCL1 inhibitors. I think it’s fascinating. We believe that these drugs are coming and don’t have any problem. For sure we know that BCL2—in this case, venetoclax—may fail in the long run. Because there are BCL2 mutations that were described at the last ASH [American Society of Hematology Annual Meeting & Exposition]—and I had the opportunity to check a couple of cases—as well as the upregulation in the lymph nodes of MCL1 and BCL-XL. All other antiapoptotic protein that can really compensate block BCL2. So I think in the future we’re going to see lymdifferent combinations, even with other antiapoptotic protein blockades.

Harry Erba, MD, PhD: You’re the section chief for lymphoma. For other lymphomas, B-cell lymphomas, where this is being used?

Javier Pinilla-Ibarz, MD, PhD: It’s very interesting because everyone was predicting the high efficacy in follicular lymphoma. As you know, the data have not been as striking as we thought, considering the BCL2 is upregulated. There are different reasons that we still don’t understand very well. Definitely there is a role. We know, for example, in mantle cell lymphoma, it is studied very well in combination and alone. I think it still needs to be said how the BCL2 are going to be used, maybe in combination with chemotherapy. There are many trials that are addressing that. And maybe in different subtypes—who specifically sees benefit—as happens with the BTK or BCR inhibitors. We know ABC subtype may work more. But maybe in lymphomas we need to understand who are the patients who may be better candidates for these drugs.

Harry Erba, MD, PhD: As you know, there’s been a recent update to the label of venetoclax to include AML, very exciting data from the phase Ib studies of older patients with infirmities and comorbidities that lead to them not tolerating chemotherapy. The combination of HMAs [hypomethylating agents] with venetoclax or low-dose ara-C [cytarabine] and venetoclax have produced very rapid and very high response rates. HMA/venetoclax, 61% CR/CRh [complete remission or CR with partial hematologic recovery], 70% CR/CRi [CR with incomplete hematologic recovery]. Very rapid time to response, and the duration of response seems significant, on the order of a year and median survivals of over a year, 15 to 18 months, depending on the analysis that’s been there. As you know, those combinations are in randomized clinical trials. We’re awaiting the results. They finished accrual.

Javier Pinilla-Ibarz, MD, PhD: Very exciting data for sure. A really, really a great alternative for our older population of patients that may increase the quality of life just to really put them in remission in a very, very nice way without necessarily time to be in the hospital.

Harry Erba, MD, PhD: Well, we’re appreciative to our colleagues in CLL who have prepared us for some of the issues that we are going to be seeing, like monitoring and prophylaxis for TLS [tumor lysis syndrome], neutropenia. I think these are things that we are going to have to deal with as we treat these patients with AML with a very effective regimen. Clearly, there’s a very active way of improving the outcomes of patients with hematologic malignancies; CML [chronic myeloid leukemia] and now AML. Before we close, anything you want to leave our audience with?

Javier Pinilla-Ibarz, MD, PhD: Well, I think the future is extremely exciting for patients with CLL these days. We have more alternatives for treatment in the frontline and the second line. And I think really blocking these important mechanisms for which CLL persist, survive, and proliferate are going to be crucial to really continuing to conquer the cure, or at least long-term control of these conditions.

Transcript edited for clarity.
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