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The Role of Venetoclax + Rituximab in CLL

Panelists: Jacqueline Barrientos, MD, Zucker School of Medicine at Hofstra/Northwell; Stephen Opat, MBBS, Monash Health; Carolyn Owen, MD, University of Calgary; Shuo Ma, MD, PhD, Feinberg School of Medicine at Northwestern Medicine; William Wierda, MD, PhD, The University of Texas MD Anderson Cancer Center
Published: Friday, Feb 14, 2020



Transcript:

William Wierda, MD, PhD: BTK [Bruton tyrosine kinase] inhibitor-based therapy fundamentally has changed our management for CLL [chronic lymphocytic leukemia]. I think another drug that is fundamentally changing our management for CLL is the BCL2 [B-cell lymphoma 2 protein] small molecular inhibitor, and venetoclax is a potent inducer of apoptosis in patients in CLL cells, and we get very deep remissions with venetoclax-based therapy in the frontline setting and in the relapsed setting.

I’d like to transition over into that strategy and in terms of frontline therapies, venetoclax-based therapy, maybe we can talk a little bit about minimal residual disease, depth of remission, and why we think that’s important. Maybe you can start with that topic.

Stephen Opat, MBBS: Thanks, Bill. The important study is the German CLL14, study which was an international study comparing the winner of the CLL11 study, which is obinutuzumab with chlorambucil versus obinutuzumab with venetoclax. That study also met its primary end point where the combination was associated with an improvement in progression-free survival [PFS] but not overall survival. What’s appealing about that trial is it’s a fixed duration trial. The patients only receive treatments for roughly 12 months. There are still issues with tumor lysis, infusion reactions. So, while the majority of the patients could be treated, it’s not straightforward. Patients often require hospitalization, particularly if they’ve got significant tumor bulk, if they’ve got a degree of renal impairment then their tumor lysis risk goes up a category.

My practice is anyone with high-risk disease or moderate-risk disease with impaired renal function, I admit to the hospital. That may be an issue in patients with a community-based practice. But again, it looks like a really good option. I think we’re very lucky, we’ve got several good options to treat patients with frontline CLL. And some patients might like a fixed duration therapy, some are happy with continuous therapy. But you have to look at, as we’ve all discussed before, individual patient factors, what the patients’ wishes are, their comorbidities, when selecting which therapies are most appropriate.

William Wierda, MD, PhD: Lots of choices, I would agree. Maybe Jacqueline you can give us your thoughts on how you select and what helps you to select and recommend a treatment. Because most of our patients come to us for a recommendation. We do have occasional patients who will come in and say, I want this, or I want this clinical trial. Which is great, but I think most of our patients look to us for direction and recommendation. So, what are things that help you in terms of making recommendations for fixed duration? The venetoclax-based first-line therapy versus the BTK inhibitor-based therapy.

Jacqueline Barrientos, MD: I think we’re in an era of truly personalized medicine when we see the patient as a whole. We need to know their comorbidities because that might affect their ability to tolerate certain drugs or the other. If you have renal insufficiency I may not be as willing to give you a drug that may cause TLS [tumor lysis syndrome] because it can be very scary to have someone get TLS once they’re on venetoclax, or even obinutuzumab.

And if you have cardiac arrhythmias, I may sway you away from that. If you have, of course, a 17p deletion patient, I would never choose a chemoimmunotherapy regimen. I would only choose, as of right now, ibrutinib because we have very good data for 17p deletion patients. And even when I saw the data presented recently for the obinutuzumab with venetoclax trial in 17p deletion patients, the PFS wasn’t as good as it what we have seen previously for ibrutinib-receiving patients in first-line for 17p deletion. So, a BTK would be my choice for a 17p deletion, at this moment.

Now, which one of the BTKs? It depends on the comorbidities. If I think that the patient may have way too many cardiac toxicities, or bleeding events, I may talk to the patient about using acalabrutinib instead of ibrutinib. And if the patient is mutated, like I said before, I would consider some chemoimmunotherapy approach as a possibility. There’s not like one-size-fits-all at this moment.

William Wierda, MD, PhD: TLS is something that we worry about. It was reported with venetoclax in the early phase I clinical trial. And that trial actually was, and others, were put on hold at the time to redesign initiation and escalation. But I think it’s done relatively safely now, initiation and escalation. We really don’t see very much TLS, clinical TLS, on the clinical trials, at least if we follow the recommendations for venetoclax initiation. I wonder if Carolyn if you could comment on what your experience has been with venetoclax initiation in either the frontline or the relapsed setting.

Carolyn Owen, MD: Yes. We participated in the CLL14 study as well, and it’s quite interesting that the TLS reports from that study actually were with obinutuzumab. And the way the study was designed with the obinutuzumab to start before the venetoclax actually leads to reduction in the white cell counts to almost to 0 in most patients before they initiate venetoclax. It reduces the TLS risk because obviously absolute site count is one of the markers for TLS risk.

We had to admit to a couple of patients at the early part of the study because the protocol mandated it, it didn’t allow you to reassign TLS risk. But in current practice I would reassess TLS risk, and if the patient didn’t have lymph nodes of more than 5 cm and the lymphocyte count drops with the obinutuzumab, I would comfortably provide the venetoclax as an outpatient. And the same with the MURANO. In that study, obviously the rituximab is added after the dose ramp-up for the venetoclax use, starting venetoclax in a patient as they are with their TLS risk, you don’t get to modify the risk first.

I’m very comfortable giving IV [intravenous] hydration in the outpatient setting and having the patient take their drugs first thing in the morning and reassess the laboratory tests at the end of the day within the treatment area and only admit if there’s sign of a problem with the labs. And I really don’t see it often at all. Usually at most you see 1 minor change, but certainly not TLS. I think that with experience even smaller centers can become competent at providing the agents. You just have to obviously start with a bit more caution.

William Wierda, MD, PhD: And be familiar with it.

Carolyn Owen, MD: Exactly.

Transcript Edited for Clarity

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Transcript:

William Wierda, MD, PhD: BTK [Bruton tyrosine kinase] inhibitor-based therapy fundamentally has changed our management for CLL [chronic lymphocytic leukemia]. I think another drug that is fundamentally changing our management for CLL is the BCL2 [B-cell lymphoma 2 protein] small molecular inhibitor, and venetoclax is a potent inducer of apoptosis in patients in CLL cells, and we get very deep remissions with venetoclax-based therapy in the frontline setting and in the relapsed setting.

I’d like to transition over into that strategy and in terms of frontline therapies, venetoclax-based therapy, maybe we can talk a little bit about minimal residual disease, depth of remission, and why we think that’s important. Maybe you can start with that topic.

Stephen Opat, MBBS: Thanks, Bill. The important study is the German CLL14, study which was an international study comparing the winner of the CLL11 study, which is obinutuzumab with chlorambucil versus obinutuzumab with venetoclax. That study also met its primary end point where the combination was associated with an improvement in progression-free survival [PFS] but not overall survival. What’s appealing about that trial is it’s a fixed duration trial. The patients only receive treatments for roughly 12 months. There are still issues with tumor lysis, infusion reactions. So, while the majority of the patients could be treated, it’s not straightforward. Patients often require hospitalization, particularly if they’ve got significant tumor bulk, if they’ve got a degree of renal impairment then their tumor lysis risk goes up a category.

My practice is anyone with high-risk disease or moderate-risk disease with impaired renal function, I admit to the hospital. That may be an issue in patients with a community-based practice. But again, it looks like a really good option. I think we’re very lucky, we’ve got several good options to treat patients with frontline CLL. And some patients might like a fixed duration therapy, some are happy with continuous therapy. But you have to look at, as we’ve all discussed before, individual patient factors, what the patients’ wishes are, their comorbidities, when selecting which therapies are most appropriate.

William Wierda, MD, PhD: Lots of choices, I would agree. Maybe Jacqueline you can give us your thoughts on how you select and what helps you to select and recommend a treatment. Because most of our patients come to us for a recommendation. We do have occasional patients who will come in and say, I want this, or I want this clinical trial. Which is great, but I think most of our patients look to us for direction and recommendation. So, what are things that help you in terms of making recommendations for fixed duration? The venetoclax-based first-line therapy versus the BTK inhibitor-based therapy.

Jacqueline Barrientos, MD: I think we’re in an era of truly personalized medicine when we see the patient as a whole. We need to know their comorbidities because that might affect their ability to tolerate certain drugs or the other. If you have renal insufficiency I may not be as willing to give you a drug that may cause TLS [tumor lysis syndrome] because it can be very scary to have someone get TLS once they’re on venetoclax, or even obinutuzumab.

And if you have cardiac arrhythmias, I may sway you away from that. If you have, of course, a 17p deletion patient, I would never choose a chemoimmunotherapy regimen. I would only choose, as of right now, ibrutinib because we have very good data for 17p deletion patients. And even when I saw the data presented recently for the obinutuzumab with venetoclax trial in 17p deletion patients, the PFS wasn’t as good as it what we have seen previously for ibrutinib-receiving patients in first-line for 17p deletion. So, a BTK would be my choice for a 17p deletion, at this moment.

Now, which one of the BTKs? It depends on the comorbidities. If I think that the patient may have way too many cardiac toxicities, or bleeding events, I may talk to the patient about using acalabrutinib instead of ibrutinib. And if the patient is mutated, like I said before, I would consider some chemoimmunotherapy approach as a possibility. There’s not like one-size-fits-all at this moment.

William Wierda, MD, PhD: TLS is something that we worry about. It was reported with venetoclax in the early phase I clinical trial. And that trial actually was, and others, were put on hold at the time to redesign initiation and escalation. But I think it’s done relatively safely now, initiation and escalation. We really don’t see very much TLS, clinical TLS, on the clinical trials, at least if we follow the recommendations for venetoclax initiation. I wonder if Carolyn if you could comment on what your experience has been with venetoclax initiation in either the frontline or the relapsed setting.

Carolyn Owen, MD: Yes. We participated in the CLL14 study as well, and it’s quite interesting that the TLS reports from that study actually were with obinutuzumab. And the way the study was designed with the obinutuzumab to start before the venetoclax actually leads to reduction in the white cell counts to almost to 0 in most patients before they initiate venetoclax. It reduces the TLS risk because obviously absolute site count is one of the markers for TLS risk.

We had to admit to a couple of patients at the early part of the study because the protocol mandated it, it didn’t allow you to reassign TLS risk. But in current practice I would reassess TLS risk, and if the patient didn’t have lymph nodes of more than 5 cm and the lymphocyte count drops with the obinutuzumab, I would comfortably provide the venetoclax as an outpatient. And the same with the MURANO. In that study, obviously the rituximab is added after the dose ramp-up for the venetoclax use, starting venetoclax in a patient as they are with their TLS risk, you don’t get to modify the risk first.

I’m very comfortable giving IV [intravenous] hydration in the outpatient setting and having the patient take their drugs first thing in the morning and reassess the laboratory tests at the end of the day within the treatment area and only admit if there’s sign of a problem with the labs. And I really don’t see it often at all. Usually at most you see 1 minor change, but certainly not TLS. I think that with experience even smaller centers can become competent at providing the agents. You just have to obviously start with a bit more caution.

William Wierda, MD, PhD: And be familiar with it.

Carolyn Owen, MD: Exactly.

Transcript Edited for Clarity
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