Evolving Therapies in Chronic Lymphocytic Leukemia - Episode 18

Venetoclax Combinations, Safety and Efficacy

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William Wierda, MD, PhD: I’m going to ask Dr Allan in a second about the new and novel combinations of targeted therapies, but maybe Dr Burke can give us an idea of his experience with venetoclax tolerability and safety. What are the things you’re thinking about when you’re planning patients on venetoclax? What’s been your experience with tolerability and safety?

John Burke, MD: I would add a few comments. As an oncologist, I think it’s amazing when patients come in and tell me they have no adverse effects and I hear that a lot with venetoclax. I use it quite a bit. I don’t mean to say that it has no adverse effects, but patients come in after 6, 9, 12 months of therapy and they say they feel fine. That’s not everyone, but it’s a lot of patients. I find venetoclax to be a well-tolerated drug. One issue I’ve had with patients’ tolerance of venetoclax is neutropenia. In order to try to maintain them on a full dose, I give a fair amount of growth factor, particularly during the first 6 months when they’re on obinutuzumab.

I’ve had 1 patient for whom I had to stop therapy because of thrombocytopenia. He went into the teens and didn’t come out of it, but I think his underlying liver disease was the cause. Rarely have I had to stop therapy, and so in general I think venetoclax is a well-tolerated drug. I found that giving GCSF helps me maintain dose intensity without having too many pauses. I’ve had to admit 1 patient with a neutropenic fever, but that is rare.

In the frontline setting, as we heard from Dr Shadman, you can debulk patients with obinutuzumab and reduce their tumor burden. I have never had to admit a patient for tumor lysis syndrome [TLS] prevention in the frontline setting because I’m in no rush to start venetoclax. I don’t feel the need to follow the label to start venetoclax on day 22 of cycle 1 all the time. You can give patients a couple of extra doses of obinutuzumab if you need and debulk them further before starting venetoclax to make sure it’s safe.

I’ll repeat a CT scan. With this method, I’ve been able to keep every patient as an outpatient. By doing that, following the label, and checking the TLS labs on schedule on day 2 and on day 3, it’s been very safe. I had really no problems with venetoclax.

William Wierda, MD, PhD: Dr Allan, tell us about the combinations BTK [Bruton tyrosine kinase] inhibitor plus BCL2 inhibitor, the interest in the combinations, and the results.

John Allan, MD: I should give credit to The University of Texas MD Anderson Cancer Center for publishing data that show for the first time the preclinical synergy between BTK inhibitors and BCL2 inhibitors. We are seeing this now translate to clinical efficacy as well, not just additive properties between these drugs. We can utilize the modulation of different pathways and then hit them hard with both of these drugs. A lot of work has been done.

There have now been a few clinical trials. Nitin Jain from MD Anderson has published some of the first frontline data with combination BCL2 inhibitors, venetoclax, and ibrutinib and showed MRD [minimal residual disease] rates that rival or were better than what we used to see with chemoimmunotherapy, especially in high-risk patients. We are seeing that clinically. There has now been transition where the industry has started to turn out larger-phase studies with more patients.

We’re starting to introduce MRD-based thoughts and response adaptive therapies vs fixed duration. One of the major studies we will watch for updates is the CAPTIVATE study, which is a study by Pharmacyclics looking at a combination of ibrutinib-venetoclax in treatment-naïve frontline patient all comers. This study is special in that it has 2 cohorts.

The first cohort is an MRD-response adapted cohort, where the patients are debulked with ibrutinib for 3 months and then treated with an additional 12 months of venetoclax plus ibrutinib, so 12 months of combination but 15 months of total treatment. At the end of that time in the first cohort, MRD assessments are made in the bone marrow. At previous congresses, the groups have published MRD rates in the bone marrow showing up to 72% of patients are MRD negative in the bone marrow with the combination of ibrutinib and venetoclax.

Let me remind you, there are no anti-CD20 monoclonal antibodies in this treatment regimen. This is all completely oral, which makes the study unique and special, and we’re seeing impressive results. The CAPTIVATE study is randomizing the MRD-negative patients. Remember, 72% of over 160, 170 patients were MRD negative. They were randomized in a placebo double-blind fashion to placebo or continual maintenance ibrutinib. For the first time, we’re going to see if we need maintenance.

We will find out if a patient population seems to benefit from maintenance. We are putting MRD into a response-adapted thought where we’re not measuring MRD, not knowing what to do with it. We’re going to start to learn what to do with it. The 25% of patients who don’t achieve MRD are randomized to monotherapy ibrutinib vs continuing the doublet venetoclax-ibrutinib and then a period of continual ibrutinib after that. That will be an interesting group to see who is not reaching MRD and then how well they do.

In that group, we’ll be also able to see if their MRD is deepening over time, because that is the big question. Right now, a lot of the data show that patients either reach MRD negativity or don’t within the first year or 2. After the second year, MRD doesn’t seem to deepen. There is something about the biology of CLL [chronic lymphocytic leukemia] that keeps MRD from deepening. The study also has a fixed-duration cohort where they enrolled another several hundred—150, 160, 170—patients who are receiving the same regimen and stopping regardless of their MRD status.

Because of the power of these 2 cohorts, they will be able to do a cross-study comparison to understand the value of stopping and the value of continual maintenance therapy in the patients who do achieve MRD. There’s a lot of power in the study. Now there are many other studies that are looking at combinations of triplet and stopping therapies, and we can go through a whole list of them. A few studies were conducted by cooperative groups.

Alliance has a study, A041702, in older patients with a triplet obinutuzumab-ibrutinib-venetoclax vs ibrutinib-obinutuzumab, where those patients are going to have a response-adapted therapy and at the end of that a combination therapy. There is an ECOG study as well, EA9161, which is for patients younger than 70 years old, where patients have a fixed-duration for the triplet regimen vs continual therapy of ibrutinib-obinutuzumab. A limitation of the study is that there isn’t a monotherapy ibrutinib arm or a fourth arm without anti-CD20 monoclonal antibodies plus the combination therapy.

We are limited in terms of understanding the benefit of that anti-CD20, whether it is going to help or not. We’ll start to see MRD rates, and these are all very similar patient populations, so we will be able to make comparisons across studies to see if these MRD rates are any different or can have an additive effect. Can we push people into the 80% bone marrow disease negative state with anti-CD20 plus the doublet?

These are exciting times, and over the next 2 or 3 years we’re going to start to see answers to those questions as the data continue to mature. These studies have an ability to impact how we might treat patients in the future. Right now, we use monotherapy sequencing treatments.

In the future, we will likely—as we did with fludarabine in adding cyclophosphamide and then rituximab—start to add all our treatments, putting our best foot forward, getting the vast majority of people to MRD-negative states. We’ll pick and choose the high-risk patient who we’ll be able to leave on a continual maintenance therapy vs the low-risk patient who might be able to receive 15-month stop and then maybe go 6, 7, 8 years and then receive the regimen again as a second treatment for a fixed-duration. Over the course of 15 years, they may have 2 or 3 years of total treatment.

That’s where it’s moving. A lot of these questions that are up in the air may be moot and obsolete in a few years as we transition to combination therapy. I’m not saying combination therapy is going to be right for every patient. There might be a patient who is older and frail and may not be right for combination therapy. We have found from these studies that there do seem to be increased toxicities. Nothing new, but things like diarrhea might be a little more severe with a combination therapy.

There are also some cytopenia issues that we start to see with combination therapy. Therefore, some of our frailer patients who are older and have low-risk disease, they’re in their late 70s or early 80s and might do beautifully with a BTK inhibitor and never need another treatment in their lifetime. Treatment is not going to be 1 size fits all. For our younger patients who are more fit or older patients, combination therapy is an exciting opportunity for them to achieve the MRD-negative state, which we do believe is important, especially if we’re going to try to stop therapy.

That’s where some of the combination data are initially starting to come out. Some studies are being done with acalabrutinib. They’re being done with PI3K inhibitors in combination with venetoclax. As long as it’s a B-cell receptor antagonist PI3K or BTK, this synergy that you get with the BCL2 in modulation of that BCL2-protein population, you definitely see this synergy along with B-cell receptor antagonists.

We’re going to have a lot of options for patients. We are going to be able to tailor treatment, and we should keep an eye out for how these studies mature and when they start to report out, definitely with PFS [progression-free survival] rate as we start to get 3, 4 years out on some of these studies.

Transcript Edited for Clarity