ONCAlert | Upfront Therapy for mRCC

Venetoclax's Role in Frontline Management of CLL

Targeted Oncology
Published Online:12:00 PM, Thu August 1, 2019

Harry Erba, MD, PhD: I’ve been holding you back now for a few minutes on what we really would like to discuss that’s new at this year’s ASCO [American Society of Clinical Oncology Annual] Meeting here in Chicago, Illinois. And that is the use of venetoclax in combination with an anti-CD20 antibody in previously untreated patients. Why don’t you discuss a little bit about the use of venetoclax in those previously untreated patients?

Javier Pinilla-Ibarz, MD, PhD: We are very eagerly expecting the results from this trial because we knew that it was already finished, and we knew the results. And we didn’t have the opportunity to see them at the ASH [American Society of Hematology Annual] Meeting & Exposition, but now finally we’re going to be able to. Well, it was this morning when it was presented. There was an initiative from the German Chronic Lymphocytic Leukemia (CLL) Study Group. This is called the CLL14. The German group, as you know, has always been in the forefront for any kind of trial to address the needs of patients or the first trial that really starts to target the older population, as CLL14 does. It’s an older population, more than 65 years old, comorbid conditions, CR [complete response], Cumulative Illness Rating Scale score of more than 6 or younger with comorbid condition, so the classical patient that we really encounter in our practice.

The trial really tried to address the use of venetoclax in combination with a second-generation monoclonal antibody, such as obinutuzumab, against the classical combination of obinutuzumab-chlorambucil. It was very, very well studied and very well reported as good data in the older population.

Harry Erba, MD, PhD: It was the same population that led to the approval of chlorambucil with obinutuzumab.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, absolutely. I think it’s very, very important to point out that the goal of the study was in the classical CLL population, older patients. We note historically, at the very beginning, chemotherapy strategies and chemoimmunotherapy were applied to the general population. But we know that this is really only one-fourth of the patients. So the real patient with CLL is older with multiple comorbid conditions. And this is what really this trial is trying to address. And as you already read, these are extremely superior in terms of PFS [progression-free survival] when we compare really these 2 arms favoring the venetoclax-obinutuzumab arm. Once again, what has been reported by the German group obviously in this ASH is that very, very high levels of MRD [minimal residual disease] negativity down by many methods such as PCR [polymerase chain reaction] or even next-generation sequencing—with levels that really, really come almost to the 70% range—is something historically very, very important.

Once again, we start to define not only complete response and overall response, but now we’re introducing this MRD negativity in the bone marrow because it’s a very, very important predictor of long-term outcomes in terms of PFS. And this is what this trial is showing. The last thing that it’s showing obviously is limited therapy. And we are discussing 1 year of therapy in both arms, but I want a patient to stop therapy and be followed until progression.

Harry Erba, MD, PhD: Help me understand something. I remember some of the earlier venetoclax data with rituximab, and the rituximab was added after venetoclax. In this study, obinutuzumab started first and then venetoclax. Why is that?

Javier Pinilla-Ibarz, MD, PhD: Excellent point. What you’re referring to is that in the MURANO study, they used Rituxan and venetoclax at the same time. Again, we were discussing the myth of the TLS [tumor lysis syndrome] that is not really very well seen in real life but that was reported in the early, early studies. I think with this trial, in order to really make people more comfortable, their plan was to really debulk the disease with antibody as obinutuzumab, to really lower the amount of circulating CLL cells or even large lymphadenopathy. And then after 3 doses, they started to really do the ramp-up of the venetoclax. Again, we’ll discuss if it’s necessary or not. You can do it at the same time, but definitely it really, really downgrades most of the patients who have high or intermediate risk to really lower risk of TLS, which has these important consequences because we know intermediate and low-risk patients can be managed as outpatients. Whereas high-risk patients need to be monitored more closely.

Harry Erba, MD, PhD: In fact, in the CLL14 trial, if I remember in the presentation or the abstract, the TLS was actually seen during the obinutuzumab phase and not afterward when venetoclax was introduced.

Javier Pinilla-Ibarz, MD, PhD: That’s correct. That’s very, very important. We always talk about TLS, and we are doctors and we love to really see TLS.

Harry Erba, MD, PhD: It has to be managed, but we want to see it.

Javier Pinilla-Ibarz, MD, PhD: But we want to see that. What’s really very interesting is that we knew for years that obinutuzumab produced TLS, but no one looked at that. I have a patient who had 400,000 microliters, only with the first dose of 100 mg, go to nothing. It’s impossible that those patients don’t have TLS or have TLS that is being managed. I think what this trial is showing is that obviously you can see some evidence of TLS. It’s relatively easy to truly manage with hydration and with prophylactic measure in the first phase. Because it’s what these patients need to be debulked.

Harry Erba, MD, PhD: Ancient history with rituximab as single agent, it was like 5% TLS.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, absolutely.

Harry Erba, MD, PhD: Is P53 really an issue in the frontline setting, though? It’s only like 5% to 10% of the patients who have it. Is that correct?

Javier Pinilla-Ibarz, MD, PhD: It’s 10% by FISH [fluorescence in situ hybridization], but you can add 4% by sequencing. So around 15% if we can really put together both things.

Harry Erba, MD, PhD: In terms of the future, tell us a little bit about combinations. Can venetoclax be added to BTK inhibitors and PI3 kinase delta inhibitors?

Javier Pinilla-Ibarz, MD, PhD: That, for sure, is the future. You may have heard recently about a publication in the New England Journal of Medicine by The University of Texas MD Anderson group that really already incorporated this concept. A concept that has been studied in Europe, in the UK group, and also in a randomized trial that using ibrutinib-venetoclax against obinutuzumab-chlorambucil. A trial has already been enrolled, and now we’re going to start to watch. I think it’s bringing the next frontier of how we’re going to use these targeted drugs. I was mentioning to you in the beginning that we really characterize BCR signaling and BCL2 upregulation as the 2 main reasons why cells proliferate and survive. So it makes sense to combine both things to really achieve very high rates of MRD and responses, as the MD Anderson group show in this paper.

I think it’s something that we’re going to really see more and more in the future because we always say that the medicine is always divided between the people who want to use the best drug in the frontline or the people who want to save something in the back of their pocket. But there’s no doubt that I think it’s a great opportunity to investigate this trial that has very remarkable data in the frontline in so many groups. But we still need to really see how these data are going to pan out in randomized clinical trials.

Harry Erba, MD, PhD: And then in the NCI [National Cancer Institute]–sponsored Intergroup trials, Alliance, ECOG, we are looking at triple combinations.

Javier Pinilla-Ibarz, MD, PhD: Triple combination.

Harry Erba, MD, PhD: Yes, with anti-CD20, BTK inhibition, BCL2.

Javier Pinilla-Ibarz, MD, PhD: The triple combination is something that has also been studied and is very interesting. I just wonder how much we need to do to really eradicate it and how much damage we’re going to really produce in terms of infections, neutropenias, and things like that. It’s something that we should be very careful about, because obviously we have the best of the world, right—the anti-CD20, BCR inhibitors, and BCL2, and BTK inhibitors. But we need to really be very, very careful how we stratify, how we really sequence these drugs in the way that we don’t produce too much toxicity for patients who have really, really great outcomes.

Transcript edited for clarity.

Harry Erba, MD, PhD: I’ve been holding you back now for a few minutes on what we really would like to discuss that’s new at this year’s ASCO [American Society of Clinical Oncology Annual] Meeting here in Chicago, Illinois. And that is the use of venetoclax in combination with an anti-CD20 antibody in previously untreated patients. Why don’t you discuss a little bit about the use of venetoclax in those previously untreated patients?

Javier Pinilla-Ibarz, MD, PhD: We are very eagerly expecting the results from this trial because we knew that it was already finished, and we knew the results. And we didn’t have the opportunity to see them at the ASH [American Society of Hematology Annual] Meeting & Exposition, but now finally we’re going to be able to. Well, it was this morning when it was presented. There was an initiative from the German Chronic Lymphocytic Leukemia (CLL) Study Group. This is called the CLL14. The German group, as you know, has always been in the forefront for any kind of trial to address the needs of patients or the first trial that really starts to target the older population, as CLL14 does. It’s an older population, more than 65 years old, comorbid conditions, CR [complete response], Cumulative Illness Rating Scale score of more than 6 or younger with comorbid condition, so the classical patient that we really encounter in our practice.

The trial really tried to address the use of venetoclax in combination with a second-generation monoclonal antibody, such as obinutuzumab, against the classical combination of obinutuzumab-chlorambucil. It was very, very well studied and very well reported as good data in the older population.

Harry Erba, MD, PhD: It was the same population that led to the approval of chlorambucil with obinutuzumab.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, absolutely. I think it’s very, very important to point out that the goal of the study was in the classical CLL population, older patients. We note historically, at the very beginning, chemotherapy strategies and chemoimmunotherapy were applied to the general population. But we know that this is really only one-fourth of the patients. So the real patient with CLL is older with multiple comorbid conditions. And this is what really this trial is trying to address. And as you already read, these are extremely superior in terms of PFS [progression-free survival] when we compare really these 2 arms favoring the venetoclax-obinutuzumab arm. Once again, what has been reported by the German group obviously in this ASH is that very, very high levels of MRD [minimal residual disease] negativity down by many methods such as PCR [polymerase chain reaction] or even next-generation sequencing—with levels that really, really come almost to the 70% range—is something historically very, very important.

Once again, we start to define not only complete response and overall response, but now we’re introducing this MRD negativity in the bone marrow because it’s a very, very important predictor of long-term outcomes in terms of PFS. And this is what this trial is showing. The last thing that it’s showing obviously is limited therapy. And we are discussing 1 year of therapy in both arms, but I want a patient to stop therapy and be followed until progression.

Harry Erba, MD, PhD: Help me understand something. I remember some of the earlier venetoclax data with rituximab, and the rituximab was added after venetoclax. In this study, obinutuzumab started first and then venetoclax. Why is that?

Javier Pinilla-Ibarz, MD, PhD: Excellent point. What you’re referring to is that in the MURANO study, they used Rituxan and venetoclax at the same time. Again, we were discussing the myth of the TLS [tumor lysis syndrome] that is not really very well seen in real life but that was reported in the early, early studies. I think with this trial, in order to really make people more comfortable, their plan was to really debulk the disease with antibody as obinutuzumab, to really lower the amount of circulating CLL cells or even large lymphadenopathy. And then after 3 doses, they started to really do the ramp-up of the venetoclax. Again, we’ll discuss if it’s necessary or not. You can do it at the same time, but definitely it really, really downgrades most of the patients who have high or intermediate risk to really lower risk of TLS, which has these important consequences because we know intermediate and low-risk patients can be managed as outpatients. Whereas high-risk patients need to be monitored more closely.

Harry Erba, MD, PhD: In fact, in the CLL14 trial, if I remember in the presentation or the abstract, the TLS was actually seen during the obinutuzumab phase and not afterward when venetoclax was introduced.

Javier Pinilla-Ibarz, MD, PhD: That’s correct. That’s very, very important. We always talk about TLS, and we are doctors and we love to really see TLS.

Harry Erba, MD, PhD: It has to be managed, but we want to see it.

Javier Pinilla-Ibarz, MD, PhD: But we want to see that. What’s really very interesting is that we knew for years that obinutuzumab produced TLS, but no one looked at that. I have a patient who had 400,000 microliters, only with the first dose of 100 mg, go to nothing. It’s impossible that those patients don’t have TLS or have TLS that is being managed. I think what this trial is showing is that obviously you can see some evidence of TLS. It’s relatively easy to truly manage with hydration and with prophylactic measure in the first phase. Because it’s what these patients need to be debulked.

Harry Erba, MD, PhD: Ancient history with rituximab as single agent, it was like 5% TLS.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, absolutely.

Harry Erba, MD, PhD: Is P53 really an issue in the frontline setting, though? It’s only like 5% to 10% of the patients who have it. Is that correct?

Javier Pinilla-Ibarz, MD, PhD: It’s 10% by FISH [fluorescence in situ hybridization], but you can add 4% by sequencing. So around 15% if we can really put together both things.

Harry Erba, MD, PhD: In terms of the future, tell us a little bit about combinations. Can venetoclax be added to BTK inhibitors and PI3 kinase delta inhibitors?

Javier Pinilla-Ibarz, MD, PhD: That, for sure, is the future. You may have heard recently about a publication in the New England Journal of Medicine by The University of Texas MD Anderson group that really already incorporated this concept. A concept that has been studied in Europe, in the UK group, and also in a randomized trial that using ibrutinib-venetoclax against obinutuzumab-chlorambucil. A trial has already been enrolled, and now we’re going to start to watch. I think it’s bringing the next frontier of how we’re going to use these targeted drugs. I was mentioning to you in the beginning that we really characterize BCR signaling and BCL2 upregulation as the 2 main reasons why cells proliferate and survive. So it makes sense to combine both things to really achieve very high rates of MRD and responses, as the MD Anderson group show in this paper.

I think it’s something that we’re going to really see more and more in the future because we always say that the medicine is always divided between the people who want to use the best drug in the frontline or the people who want to save something in the back of their pocket. But there’s no doubt that I think it’s a great opportunity to investigate this trial that has very remarkable data in the frontline in so many groups. But we still need to really see how these data are going to pan out in randomized clinical trials.

Harry Erba, MD, PhD: And then in the NCI [National Cancer Institute]–sponsored Intergroup trials, Alliance, ECOG, we are looking at triple combinations.

Javier Pinilla-Ibarz, MD, PhD: Triple combination.

Harry Erba, MD, PhD: Yes, with anti-CD20, BTK inhibition, BCL2.

Javier Pinilla-Ibarz, MD, PhD: The triple combination is something that has also been studied and is very interesting. I just wonder how much we need to do to really eradicate it and how much damage we’re going to really produce in terms of infections, neutropenias, and things like that. It’s something that we should be very careful about, because obviously we have the best of the world, right—the anti-CD20, BCR inhibitors, and BCL2, and BTK inhibitors. But we need to really be very, very careful how we stratify, how we really sequence these drugs in the way that we don’t produce too much toxicity for patients who have really, really great outcomes.

Transcript edited for clarity.
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