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Toxicity Management With Venetoclax for CLL

Panelists: William G Wierda, MD, University of Texas MD Anderson Cancer Center; Alexey V Danilov, MD, PhD, University School of Medicine in Portland, Oregon; Matthew S Davids, MD, MMSc, Dana-Farber Cancer Institute; Anthony R Mato, MD, Memorial Sloan Kettering Cancer Center; Susan M. OBrien, MD The University of California, Irvine Medical Center
Published: Friday, Jan 25, 2019



Transcript:

William G. Wierda, MD, PhD:
We had generated a lot of MRD [minimal residual disease] data when we were doing work with FCR [fludarabine/cyclophosphamide/rituximab] and FCR-based regimens, and then we had the small molecule inhibitors become available, particularly the BTK [Bruton tyrosine kinase] inhibitors, and weren’t seeing as deep of a remission. But, with venetoclax, it really has ushered in an era again of discussion of MRD. It’s a treatment that is tolerated well by patients, including older patients. And I think we’re able to have a discussion about depth of remission, including for patients who are older and had been less able to tolerate the more intensive chemoimmunotherapy regimens.

It’s probably important to have a little discussion about venetoclax and some of the features that are clinically relevant and important. With MURANO we started to see more usage. MURANO allowed, or enabled, or was the reason for approval of venetoclax, not only in relapsed CLL [chronic lymphocytic leukemia] with 17p, which was the initial indication for monotherapy, but now broadly for relapsed disease. But, Anthony, we can start with initiating treatment, and what’s the feature that concerns us most in terms of initiation of venetoclax, and as patients are on a stable dose, what are the other features that we need to look for?

Anthony R. Mato, MD: I feel like from an AE [adverse event] perspective, venetoclax is a relatively easy drug to understand. It has 2 major AEs that we think about. One is electrolyte abnormalities and renal dysfunction, the tumor lysis syndrome [TLS], which is an early event. And the second are hematologic toxicities, which can occur early or late where you can see largely neutropenia but to a certain extent, thrombocytopenia. I think a distant third in terms of the AE profile are GI [gastrointestinal] toxicities, which are relatively early events, and I think relatively limited for patients and so not as important.

Venetoclax is a drug that does require training to use. It’s not difficult, but it does require an understanding that patients have to have a prophylaxis and monitoring strategy to mitigate the risk of developing tumor lysis syndrome, which is largely based on the bulk of disease at the time venetoclax is started. And patients can be stratified into whether they have a low, intermediate, or high-risk disease based on their absolute lymphocyte count and the degree of lymphadenopathy. And, based on those findings, there are very reasonable strategies available for prophylaxis and monitoring, which when employed work very well in terms of minimizing the risk of clinical and also laboratory tumor lysis syndrome.

The difficulty is actually taking the understanding and the training and making it practical in your office or your practice because there are time constraints to when laboratory studies need to be performed, at baseline, for example, or at 8 hours, or 6 to 8 hours in a patient who’s low-risk. And in high-risk patients, you’re looking at laboratory studies that are being performed on a scale of baseline, 4, 8, 12 hours, the next day. And so logistically you need a statistics laboratory. You need to have a turnaround time that works in the context of your office for the drug to be practical. And then there are outpatient and inpatient strategies. I think if you can make that happen in the office, that toxicity is almost nonexistent.

The hematologic toxicity is an interesting one because even in the ramp-up you can start to see patients develop neutropenia, for example. The nice thing about it is if you recognize it, growth factors work well. It can almost eliminate that toxicity. And even when it occurs and maybe isn’t treated with a growth factor, there’s this tremendous discordance between the amount of neutropenia that you see at grade 3/4, which is high, and the proportion of patients who develop febrile neutropenia, which is actually quite low, under 5% if I had to summarize all the studies. I would say unless I’m forgetting another toxicity, that’s really all you need to know about toxicity management for venetoclax.

Alexey V. Danilov, MD, PhD.: I would like to add a couple of points here. It seems that in addition to risk stratifying patients, there are strategies you can use to reduce those risks. You presented CAPTIVATE data at ASCO [the American Society of Clinical Oncology annual meeting], and there were data here at ASH [the American Society of Hematology meeting] where using ibrutinib prior to venetoclax for 2 months actually partially mitigates the risk of TLS, if not completely. In fact, there were very few laboratory TLS cases in those studies. The German trials, induction with bendamustine followed by a CD20, and oral agent combinations also mitigated some of the TLS risks. Finally, there are some studies ongoing out there that on the use of obinutuzumab treatment prior to introduction of venetoclax. So there are clear ways to mitigate those risks by potentially using a lead-in with those agents.

Anthony R. Mato, MD: Can I add one other thing that I want to emphasize? There’s not yet an FDA approved strategy to mitigate risk. In the MURANO strategy, rituximab follows venetoclax escalation, venetoclax as a monotherapy, obviously. I think one of the dangers of those methods is that number 1) there’s no training really available for practitioners who may read an article and think it’s interesting to escalate every 3 days. And number 2) someone may add ibrutinib before you want to give venetoclax. And so I think the danger there, until it’s a labeled use, may put patients at risk trying to cut corners with a strategy that when you employ it, works perfectly well to mitigate the risk.

Matthew S. Davids, MD, MMSc: The other thing I would add is that you’re exactly right, that all those debulking strategies do decrease the risk of TLS if you then still follow the ramp-up schedule that’s used.  And so even though the risk is lower, the logistics are the same right now with the current ramp-up schedule. And so there are a few tricks that we can use to try to make this a little easier in the practice setting. One of the things I’ve done with some of my patients is on the day that they plan to start venetoclax, have them get up early and take the drug at 6 o’clock in the morning. They come in and see me and get the 6-hour labs [laboratory tests] at noon, and that way we can turn around the labs in the afternoon and make sure that they’re safe.

If there are issues getting labs back in a timely fashion, you can also admit patients to the hospital and do it on the inpatient setting which is a bit inconvenient, but it’s certainly the safest thing for the patient. So I certainly agree with everything that’s been said, in particular right now following the label to start venetoclax, and it is important to make sure that it’s being done safely. But I think additional creative strategies need to be explored to simplify how we do this.

Alexey V. Danilov, MD, PhD.: Yes, absolutely. Those are research strategies. I think another point regarding the hematologic toxicities is if we want to use venetoclax in combination with chemoimmunotherapy, that may actually be a limiting factor. It’s been used with R-CHOP [rituximab/cyclophosphamide/hydroxydaunomycin/Oncovin/prednisone] in patients with diffuse large B-cell lymphoma in clinical trials. The dosing schedule is not daily there, so it’s used on days 1 through 10 and then the drug is stopped because of the risks of neutropenia.

Transcript edited for clarity.

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Transcript:

William G. Wierda, MD, PhD:
We had generated a lot of MRD [minimal residual disease] data when we were doing work with FCR [fludarabine/cyclophosphamide/rituximab] and FCR-based regimens, and then we had the small molecule inhibitors become available, particularly the BTK [Bruton tyrosine kinase] inhibitors, and weren’t seeing as deep of a remission. But, with venetoclax, it really has ushered in an era again of discussion of MRD. It’s a treatment that is tolerated well by patients, including older patients. And I think we’re able to have a discussion about depth of remission, including for patients who are older and had been less able to tolerate the more intensive chemoimmunotherapy regimens.

It’s probably important to have a little discussion about venetoclax and some of the features that are clinically relevant and important. With MURANO we started to see more usage. MURANO allowed, or enabled, or was the reason for approval of venetoclax, not only in relapsed CLL [chronic lymphocytic leukemia] with 17p, which was the initial indication for monotherapy, but now broadly for relapsed disease. But, Anthony, we can start with initiating treatment, and what’s the feature that concerns us most in terms of initiation of venetoclax, and as patients are on a stable dose, what are the other features that we need to look for?

Anthony R. Mato, MD: I feel like from an AE [adverse event] perspective, venetoclax is a relatively easy drug to understand. It has 2 major AEs that we think about. One is electrolyte abnormalities and renal dysfunction, the tumor lysis syndrome [TLS], which is an early event. And the second are hematologic toxicities, which can occur early or late where you can see largely neutropenia but to a certain extent, thrombocytopenia. I think a distant third in terms of the AE profile are GI [gastrointestinal] toxicities, which are relatively early events, and I think relatively limited for patients and so not as important.

Venetoclax is a drug that does require training to use. It’s not difficult, but it does require an understanding that patients have to have a prophylaxis and monitoring strategy to mitigate the risk of developing tumor lysis syndrome, which is largely based on the bulk of disease at the time venetoclax is started. And patients can be stratified into whether they have a low, intermediate, or high-risk disease based on their absolute lymphocyte count and the degree of lymphadenopathy. And, based on those findings, there are very reasonable strategies available for prophylaxis and monitoring, which when employed work very well in terms of minimizing the risk of clinical and also laboratory tumor lysis syndrome.

The difficulty is actually taking the understanding and the training and making it practical in your office or your practice because there are time constraints to when laboratory studies need to be performed, at baseline, for example, or at 8 hours, or 6 to 8 hours in a patient who’s low-risk. And in high-risk patients, you’re looking at laboratory studies that are being performed on a scale of baseline, 4, 8, 12 hours, the next day. And so logistically you need a statistics laboratory. You need to have a turnaround time that works in the context of your office for the drug to be practical. And then there are outpatient and inpatient strategies. I think if you can make that happen in the office, that toxicity is almost nonexistent.

The hematologic toxicity is an interesting one because even in the ramp-up you can start to see patients develop neutropenia, for example. The nice thing about it is if you recognize it, growth factors work well. It can almost eliminate that toxicity. And even when it occurs and maybe isn’t treated with a growth factor, there’s this tremendous discordance between the amount of neutropenia that you see at grade 3/4, which is high, and the proportion of patients who develop febrile neutropenia, which is actually quite low, under 5% if I had to summarize all the studies. I would say unless I’m forgetting another toxicity, that’s really all you need to know about toxicity management for venetoclax.

Alexey V. Danilov, MD, PhD.: I would like to add a couple of points here. It seems that in addition to risk stratifying patients, there are strategies you can use to reduce those risks. You presented CAPTIVATE data at ASCO [the American Society of Clinical Oncology annual meeting], and there were data here at ASH [the American Society of Hematology meeting] where using ibrutinib prior to venetoclax for 2 months actually partially mitigates the risk of TLS, if not completely. In fact, there were very few laboratory TLS cases in those studies. The German trials, induction with bendamustine followed by a CD20, and oral agent combinations also mitigated some of the TLS risks. Finally, there are some studies ongoing out there that on the use of obinutuzumab treatment prior to introduction of venetoclax. So there are clear ways to mitigate those risks by potentially using a lead-in with those agents.

Anthony R. Mato, MD: Can I add one other thing that I want to emphasize? There’s not yet an FDA approved strategy to mitigate risk. In the MURANO strategy, rituximab follows venetoclax escalation, venetoclax as a monotherapy, obviously. I think one of the dangers of those methods is that number 1) there’s no training really available for practitioners who may read an article and think it’s interesting to escalate every 3 days. And number 2) someone may add ibrutinib before you want to give venetoclax. And so I think the danger there, until it’s a labeled use, may put patients at risk trying to cut corners with a strategy that when you employ it, works perfectly well to mitigate the risk.

Matthew S. Davids, MD, MMSc: The other thing I would add is that you’re exactly right, that all those debulking strategies do decrease the risk of TLS if you then still follow the ramp-up schedule that’s used.  And so even though the risk is lower, the logistics are the same right now with the current ramp-up schedule. And so there are a few tricks that we can use to try to make this a little easier in the practice setting. One of the things I’ve done with some of my patients is on the day that they plan to start venetoclax, have them get up early and take the drug at 6 o’clock in the morning. They come in and see me and get the 6-hour labs [laboratory tests] at noon, and that way we can turn around the labs in the afternoon and make sure that they’re safe.

If there are issues getting labs back in a timely fashion, you can also admit patients to the hospital and do it on the inpatient setting which is a bit inconvenient, but it’s certainly the safest thing for the patient. So I certainly agree with everything that’s been said, in particular right now following the label to start venetoclax, and it is important to make sure that it’s being done safely. But I think additional creative strategies need to be explored to simplify how we do this.

Alexey V. Danilov, MD, PhD.: Yes, absolutely. Those are research strategies. I think another point regarding the hematologic toxicities is if we want to use venetoclax in combination with chemoimmunotherapy, that may actually be a limiting factor. It’s been used with R-CHOP [rituximab/cyclophosphamide/hydroxydaunomycin/Oncovin/prednisone] in patients with diffuse large B-cell lymphoma in clinical trials. The dosing schedule is not daily there, so it’s used on days 1 through 10 and then the drug is stopped because of the risks of neutropenia.

Transcript edited for clarity.
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