ONCAlert | Upfront Therapy for mRCC

BCL2 Inhibition in CLL: Managing Toxicity and Administration

Published Online:12:32 PM, Tue July 9, 2019

Harry Erba, MD, PhD: One of the things we’re all dealing with, especially our colleagues in the community, is that we’re moving from regimens that are based in the infusion area, chemotherapies in which the patient will come in and be seen by an infusion nurse who’s well versed in toxicities. They’ll be monitored based on the expected myelosuppression and known infectious risk. Now we’re moving to these oral therapies, so why don’t we discuss a little bit about what clinicians have to be aware of with venetoclax in terms of monitoring for toxicities and management.

Matthew Davids, MD, MMSc: I think the best-known toxicity of venetoclax in CLL [chronic lymphocytic leukemia] is the risk of tumor lysis syndrome [TLS], so maybe we can start with that. That’s certainly a real risk, but fortunately it’s very effectively mitigated by the careful dose ramp-up and TLS prophylaxis and monitoring strategy. And this is not something that you need to make up. It’s very clearly outlined in the label, and so I think it’s very important when you’re starting venetoclax to follow the label. That really starts with risk stratifying the patient for TLS. Based on the size of the lymph nodes and the height of the absolute lymphocyte count, you can tell which patients are at high risk, what we call medium risk, or low risk for TLS. If they are at high risk or even if they’re at medium risk, and you’re worried that they have borderline renal function, it’s good to hospitalize those patients—at least for the initial 2 doses of venetoclax, the 20-mg and the 50-mg doses.

But low-risk patients can be safely treated in the outpatient setting, provided that laboratory monitoring can be done in real time. And this can be a challenge, but we have certain ways we can get around this, which is that we can dose very early in the morning. Sometimes I’ll ask patients to dose even before they come into the clinic. That way, when we check the labs 6 hours later, we can do that around noon and we can get the labs back before everyone leaves for the day. And if we see any signs of TLS on those 6-hour labs, we might need to draw another set of labs or bring the patient into the hospital. But most of the time, those labs look fine, we send the patient home, they come back 24 hours later, we check again, everything looks fine, and we send them on their way with some good oral hydration.

Most patients do very well with this dose ramp-up strategy. It does tend to involve a lot of fluids and hydration, so for our older patients, particularly those who may have CHF [congestive heart failure] or other issues like that, you have to monitor fluid balance. We have to make sure our patients are on allopurinol and all those usual things. That’s the experience with TLS prophylaxis and management. And then there are certainly a number of other toxicities we need to be aware of with venetoclax. So neutropenia is really the most common 1 that we see. About half of patients will develop grade 3 or 4 neutropenia when they get venetoclax with rituximab or obinutuzumab, a little bit lower with venetoclax monotherapy.

This is interesting because the neutrophil count can get quite low, but the rates of infections are pretty modest. For example, in the CLL14 study, there was only about a 5% rate of febrile neutropenia. This may relate to the mechanism of action of venetoclax. This is sort of theoretical, but certainly we think of chemotherapy as causing mucositis, and GI [gastrointestinal] irritation, and so forth. And we probably have more gut translocation of bacteria in that scenario. Whereas we don’t really see that with venetoclax. Certainly, you need to be vigilant for infections in patients on venetoclax. But the neutropenia alone is actually rarely a reason why we’d need to stop the drug. We’re fortunate in CLL world. We can give Neupogen or Neulasta growth factor support. And we can usually continue giving the venetoclax without dose interruption, unless it’s what we call grade 4 or very severe neutropenia, and then we can hold drug temporarily.

Harry Erba, MD, PhD: Recently, there have been some concerns about steroids with ibrutinib, to change the topic a little bit, where there have been fungal infections and using azole antifungals in combination. You have to worry about dose adjustments. How about any precaution about azole antifungals in CLL and the use of venetoclax?

Matthew Davids, MD, MMSc: You do have to be mindful of that as well. Particularly we recommend avoiding azoles if at all possible during the dose ramp-up because that’s where the drug exposure is the least predictable as the patients are ramping up. But once patients do get on a standard dose of venetoclax, you can adjust the dose if you need to use an azole. And that’s OK, but you do have to be aware of that.

Harry Erba, MD, PhD: How about any precaution about vaccination or pregnancy, things like that?

Matthew Davids, MD, MMSc: In general, we recommend against using live vaccinations in any CLL patients, because of the immune suppression from the disease. That’s certainly the case also in patients with CLL on venetoclax. Where this often comes up is with the shingles vaccination, so we often have patients asking about which shingles vaccine they should get. There is fortunately a newer 1, Shingrix, which is a killed inactivated vaccine, so they should be getting that and not Zostavax. Often our patients with CLL like to travel as well, and so if they’re going to a foreign country where they may need live vaccinations, that’s usually a good time to get an infectious diseases consultant on board and figure that out.

Harry Erba, MD, PhD: You’ve started the treatment. How do you monitor patients in terms of chemistries, blood counts? How often do you evaluate them?

Matthew Davids, MD, MMSc: That first 5-week period during the ramp-up is obviously quite intensive. You’re monitoring multiple times during that first day and then 24 hours later. But if patients do well during that initial ramp-up, I’ll start to space the visits out. If patients are not having particular adverse events, usually monthly visits within the first few months and then every 2 months. Eventually in patients who have been on a drug for, say, 9 months or so, I’ll start to space out to visits every 3 months.

Harry Erba, MD, PhD: Do you educate patients about what to expect at home? Do you tell them how to take the drug, what to avoid? Do you take it with food, things like that?

Matthew Davids, MD, MMSc: The way the drug was developed in the trials, we would always give it 30 minutes after breakfast, and that actually did seem to improve the drug exposure a bit. Although, in practice, it doesn’t really make a big difference, so there’s actually no specific restrictions that they need to follow around food. I just recommend they take it at the same time every day. There are some interactions with the typical CYP3A-related foods: grapefruit juice, Seville oranges, and these sorts of things. They do need to be mindful of that. But it’s pretty straightforward to take it once they’re on it.

Harry Erba, MD, PhD: You mentioned with the obinutuzumab study that they started the obinutuzumab and then added in the venetoclax. Is that the same with rituximab, you would start that first?

Matthew Davids, MD, MMSc: It’s actually the opposite in the MURANO study. This is probably a source of confusion, and understandably so. And it relates to the pathway of development. The rituximab-venetoclax combination was very early in the process of venetoclax. It really grew out of a time when we were quite worried about TLS as being a very common problem. And so the concern with the rituximab-based regimen was that having rituximab on first might increase the risk of tumor lysis syndrome. And so it was switched around to do the venetoclax ramp-up first to try to cytoreduce and then add in the Rituxan.

By the time the venetoclax-obinutuzumab design came along, we were more comfortable that TLS was occurring at lower rates, and we had experience with CD20 plus venetoclax. They decided to switch it around, which I think actually was a good idea because, as I mentioned before, the obinutuzumab has very effectively debulked patients during that first month, in particular, and it’s very easy to see the lymphocyte coming down. In the CLL14 study, they didn’t repeat CT [computed tomography] scans, so we don’t know exactly how much the lymph nodes were decreased after those first 22 days. But certainly, from what the investigators have said, the palpable lymph node disease had begun to shrink at that point. And so I think that’s been an effective strategy to mitigate TLS.

Harry Erba, MD, PhD: What was the incidence of TLS in the study of venetoclax and obinutuzumab?

Matthew Davids, MD, MMSc: Interestingly it was quite low. But the handful of patients who got TLS actually had it during that first 3-week period on the obinutuzumab, before they even started venetoclax. There were no incidents of even laboratory TLS in patients who had started on the venetoclax portion.

Transcript edited for clarity.

Harry Erba, MD, PhD: One of the things we’re all dealing with, especially our colleagues in the community, is that we’re moving from regimens that are based in the infusion area, chemotherapies in which the patient will come in and be seen by an infusion nurse who’s well versed in toxicities. They’ll be monitored based on the expected myelosuppression and known infectious risk. Now we’re moving to these oral therapies, so why don’t we discuss a little bit about what clinicians have to be aware of with venetoclax in terms of monitoring for toxicities and management.

Matthew Davids, MD, MMSc: I think the best-known toxicity of venetoclax in CLL [chronic lymphocytic leukemia] is the risk of tumor lysis syndrome [TLS], so maybe we can start with that. That’s certainly a real risk, but fortunately it’s very effectively mitigated by the careful dose ramp-up and TLS prophylaxis and monitoring strategy. And this is not something that you need to make up. It’s very clearly outlined in the label, and so I think it’s very important when you’re starting venetoclax to follow the label. That really starts with risk stratifying the patient for TLS. Based on the size of the lymph nodes and the height of the absolute lymphocyte count, you can tell which patients are at high risk, what we call medium risk, or low risk for TLS. If they are at high risk or even if they’re at medium risk, and you’re worried that they have borderline renal function, it’s good to hospitalize those patients—at least for the initial 2 doses of venetoclax, the 20-mg and the 50-mg doses.

But low-risk patients can be safely treated in the outpatient setting, provided that laboratory monitoring can be done in real time. And this can be a challenge, but we have certain ways we can get around this, which is that we can dose very early in the morning. Sometimes I’ll ask patients to dose even before they come into the clinic. That way, when we check the labs 6 hours later, we can do that around noon and we can get the labs back before everyone leaves for the day. And if we see any signs of TLS on those 6-hour labs, we might need to draw another set of labs or bring the patient into the hospital. But most of the time, those labs look fine, we send the patient home, they come back 24 hours later, we check again, everything looks fine, and we send them on their way with some good oral hydration.

Most patients do very well with this dose ramp-up strategy. It does tend to involve a lot of fluids and hydration, so for our older patients, particularly those who may have CHF [congestive heart failure] or other issues like that, you have to monitor fluid balance. We have to make sure our patients are on allopurinol and all those usual things. That’s the experience with TLS prophylaxis and management. And then there are certainly a number of other toxicities we need to be aware of with venetoclax. So neutropenia is really the most common 1 that we see. About half of patients will develop grade 3 or 4 neutropenia when they get venetoclax with rituximab or obinutuzumab, a little bit lower with venetoclax monotherapy.

This is interesting because the neutrophil count can get quite low, but the rates of infections are pretty modest. For example, in the CLL14 study, there was only about a 5% rate of febrile neutropenia. This may relate to the mechanism of action of venetoclax. This is sort of theoretical, but certainly we think of chemotherapy as causing mucositis, and GI [gastrointestinal] irritation, and so forth. And we probably have more gut translocation of bacteria in that scenario. Whereas we don’t really see that with venetoclax. Certainly, you need to be vigilant for infections in patients on venetoclax. But the neutropenia alone is actually rarely a reason why we’d need to stop the drug. We’re fortunate in CLL world. We can give Neupogen or Neulasta growth factor support. And we can usually continue giving the venetoclax without dose interruption, unless it’s what we call grade 4 or very severe neutropenia, and then we can hold drug temporarily.

Harry Erba, MD, PhD: Recently, there have been some concerns about steroids with ibrutinib, to change the topic a little bit, where there have been fungal infections and using azole antifungals in combination. You have to worry about dose adjustments. How about any precaution about azole antifungals in CLL and the use of venetoclax?

Matthew Davids, MD, MMSc: You do have to be mindful of that as well. Particularly we recommend avoiding azoles if at all possible during the dose ramp-up because that’s where the drug exposure is the least predictable as the patients are ramping up. But once patients do get on a standard dose of venetoclax, you can adjust the dose if you need to use an azole. And that’s OK, but you do have to be aware of that.

Harry Erba, MD, PhD: How about any precaution about vaccination or pregnancy, things like that?

Matthew Davids, MD, MMSc: In general, we recommend against using live vaccinations in any CLL patients, because of the immune suppression from the disease. That’s certainly the case also in patients with CLL on venetoclax. Where this often comes up is with the shingles vaccination, so we often have patients asking about which shingles vaccine they should get. There is fortunately a newer 1, Shingrix, which is a killed inactivated vaccine, so they should be getting that and not Zostavax. Often our patients with CLL like to travel as well, and so if they’re going to a foreign country where they may need live vaccinations, that’s usually a good time to get an infectious diseases consultant on board and figure that out.

Harry Erba, MD, PhD: You’ve started the treatment. How do you monitor patients in terms of chemistries, blood counts? How often do you evaluate them?

Matthew Davids, MD, MMSc: That first 5-week period during the ramp-up is obviously quite intensive. You’re monitoring multiple times during that first day and then 24 hours later. But if patients do well during that initial ramp-up, I’ll start to space the visits out. If patients are not having particular adverse events, usually monthly visits within the first few months and then every 2 months. Eventually in patients who have been on a drug for, say, 9 months or so, I’ll start to space out to visits every 3 months.

Harry Erba, MD, PhD: Do you educate patients about what to expect at home? Do you tell them how to take the drug, what to avoid? Do you take it with food, things like that?

Matthew Davids, MD, MMSc: The way the drug was developed in the trials, we would always give it 30 minutes after breakfast, and that actually did seem to improve the drug exposure a bit. Although, in practice, it doesn’t really make a big difference, so there’s actually no specific restrictions that they need to follow around food. I just recommend they take it at the same time every day. There are some interactions with the typical CYP3A-related foods: grapefruit juice, Seville oranges, and these sorts of things. They do need to be mindful of that. But it’s pretty straightforward to take it once they’re on it.

Harry Erba, MD, PhD: You mentioned with the obinutuzumab study that they started the obinutuzumab and then added in the venetoclax. Is that the same with rituximab, you would start that first?

Matthew Davids, MD, MMSc: It’s actually the opposite in the MURANO study. This is probably a source of confusion, and understandably so. And it relates to the pathway of development. The rituximab-venetoclax combination was very early in the process of venetoclax. It really grew out of a time when we were quite worried about TLS as being a very common problem. And so the concern with the rituximab-based regimen was that having rituximab on first might increase the risk of tumor lysis syndrome. And so it was switched around to do the venetoclax ramp-up first to try to cytoreduce and then add in the Rituxan.

By the time the venetoclax-obinutuzumab design came along, we were more comfortable that TLS was occurring at lower rates, and we had experience with CD20 plus venetoclax. They decided to switch it around, which I think actually was a good idea because, as I mentioned before, the obinutuzumab has very effectively debulked patients during that first month, in particular, and it’s very easy to see the lymphocyte coming down. In the CLL14 study, they didn’t repeat CT [computed tomography] scans, so we don’t know exactly how much the lymph nodes were decreased after those first 22 days. But certainly, from what the investigators have said, the palpable lymph node disease had begun to shrink at that point. And so I think that’s been an effective strategy to mitigate TLS.

Harry Erba, MD, PhD: What was the incidence of TLS in the study of venetoclax and obinutuzumab?

Matthew Davids, MD, MMSc: Interestingly it was quite low. But the handful of patients who got TLS actually had it during that first 3-week period on the obinutuzumab, before they even started venetoclax. There were no incidents of even laboratory TLS in patients who had started on the venetoclax portion.

Transcript edited for clarity.
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