Recent Advances in the Treatment of Chronic Lymphocytic Leukemia - Episode 10
Recommendations for combining an anti-CD20 antibody with a Bruton tyrosine kinase inhibitor or venetoclax in doublet or triplet regimens for the treatment for chronic lymphocytic leukemia (CLL).
William Wierda, MD, PhD: We touched a lot on ibrutinib plus venetoclax. There’s also data with zanubrutinib plus venetoclax. We touched on that and acalabrutinib (ACALA) plus venetoclax (VEN). Debbie, maybe you can highlight there was an abstract that was reported with a randomized trial design of ACALA-VEN. And then there’s also been single-arm phase 2 data reported for ACALA-VEN-OBIN (obinutuzumab) and zanubrutinib (ZANU)-VEN-OBIN. Can give your thoughts on those trials, and what your thoughts are on if there’s clinical benefit that we might see with a triplet compared with a doublet?
Deborah M. Stephens, DO: Yes, this is based on a couple of things. If acalabrutinib and zanubrutinib are less toxic than ibrutinib, why not combine them with venetoclax instead of ibrutinib? It’s also based on the fact if 1 drug is good, 2 drugs are better, or 3 drugs even better. And we’re trying to figure out where the balancing point is with all of that because certainly it does appear that toxicity is added the more drugs you add. And we must catch that balancing point of keeping the efficacy without causing significant toxicity. We haven’t even touched upon financial toxicity in this yet, because, of course, all these agents are expensive drugs. And that also factors in. If you have 3 of them, is it 3 times the cost of what it would cost to just take 1 of these therapies? But all in all, all these trials are showing great response, good rates of MRD [minimal residual disease] undetectability of approximately 70%. Usually, those time points are at 12 to 15 months after starting therapy.
One of the studies Dr Mato has been involved in developing is this upcoming MAGIC study. And it also looks at a different spin on this, looking at acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab, which is the standard-of-care arm. This study, of course, will look at progression-free survival (PFS), and it’s going to be a big study with plans to enroll about 600 patients. One of the things I like about the design is it allows for a way to make these regimens MRD guided. And most of you saw the data that was presented last year at ASH [American Society of Hematology meeting 2021] and now published on the CLL14 study that showed that after that year of venetoclax and obinutuzumab, all MRD-detectable remissions are not equal. They looked at clonal dynamics, and some of [the cases in which] those patients with CLL chronic lymphocytic leukemia) were positive had been continuously increasing before that set time point. It’s possible those patients might never achieve MRD undetectability because their MRD was already escalating on the combination. Then there were also patients for whom MRD was still positive, but you could see a decline before that set time point that they checked it. And that was showing that maybe further therapy would help these patients.
In this upcoming study, on both of the arms you get 1 year of the combination therapy and then MRD is assessed. If it’s undetectable, then the patient can stop all therapy. If it’s still detectable, the patient can continue therapy until a time at which the MRD becomes undetectable. This is a good study combining all the strategies that we’ve seen before. As of right now, clinically, MRD is not quite as useful but once we see the results of studies like this that use that data from MRD to drive what your next step is, it will give us a real reason to start checking MRD status.
William Wierda, MD, PhD: We talked about CD20. Callie, we can come to you in terms of what your recommendations are for CD20 antibody use in the setting of BTK [Bruton tyrosine kinase] inhibitors? And then maybe you could touch on the setting of BCL-2 inhibitor and whether you prefer 1 of the CD20 antibodies over another in either setting.
Catherine Callaghan Coombs, MD: In the context of BTK inhibitors, I’ll first tackle ibrutinib. We have 2 randomized trials showing no meaningful added benefit from the addition of rituximab (RITUX) to ibrutinib. And when I use ibrutinib, I use it as a monotherapy, given that the addition of RITUX adds cost, adds infusion chair time without improving PFS or OS [overall survival]. ACALA is a different story. We have the ELEVATE CLL TN trial, which was a nicely done trial, a 3-arm trial of patients with newly-treated CLL who got either ACALA monotherapy, ACALA with obinutuzumab, or the comparator arm of chlorambucil and obinutuzumab. With some longer-term follow-up, it does seem that the curves for PFS are separating in favor of the obinutuzumab arm.
At this point, I am still not widely adding it, mainly because when I’m discussing up-front therapy with a patient, it’s either do you want kind of an intensive, time-limited therapy option with the addition of obinutuzumab? But then, I would add it with venetoclax to do the CLL14 regimen. And then the patients that are opting for a less intense, indefinite therapy option are generally the ones who don’t want to add an IV [intravenous] therapy. I don’t think it’s the wrong thing to do, and I do think there is a modest PFS benefit, but it comes with these other nuances, which is having to come in for an infusion; and then there are the infusion reactions with obinutuzumab which, admittedly, are quite a bit less when they’re on a concurrent BTK inhibitor as compared with getting it by itself kind of as part of the lead-in for combining it with venetoclax.
The last thing I’ll mention with combinations of BTK inhibitors is that obinutuzumab has also been combined with ibrutinib in the iLLUMINATE study. Unfortunately, we don’t have randomized data between ibrutinib with obinutuzumab and ibrutinib by itself, but I generally do not add obinutuzumab when I’m doing ibrutinib. Who knows, we don’t have that comparator. The ACALA data is provocative, but I’m not at this point sure that the added inconvenience of doing the IV therapy is worth that modest benefit in PFS.
The next thing you asked was the addition of a CD20 with venetoclax. For me, it’s beneficial. We have, of course, several studies looking at that. In the frontline, we’ve spoken about the CLL14 data that shows excellent rates of MRD. I was, of course, impressed with the CLL13 trial, where we see how much better OBIN is compared with rituximab in the frontline setting with the 1 year of venetoclax. And then, of course, we have these favorable results from the long-term follow-up of the MURANO trial, which are different than CLL13. And this starts with venetoclax and then the RITUX is added in, and it’s 2 years of venetoclax, but a really impressive median PFS for a relapsed trial of just under 54 months.
What we don’t have is head-to-head data of VEN vs VEN plus an anti-CD20. The VEN monotherapy data doesn’t look quite as good, and VEN monotherapy in general is a treat-to-progression. Could we get MRD negative with VEN alone? I mean maybe, but the studies of VEN monotherapy are in such highly refractory patients. The rates were low. Would that be different now in a modern population where patients aren’t so quite refractory? Maybe, maybe not. But I, in general, do add it to VEN, a CD20, and I typically do obinutuzumab in the front line. And I have been doing RITUX in the relapsed setting, again just reflecting upon the favorable results from MURANO. Of course, some people—I wonder if they’ll extrapolate from CLL13 and just everyone switch to OBIN in the relapsed setting. I’m not quite ready to do that, but I certainly would wonder what other people think.
Nicole Lamanna, MD: I’m going to agree, absolutely. Regardless, if you’re using a BTK inhibitor or VEN, VEN is different because it’s time limited and you’re combining the monoclonal antibodies and the benefit that we’ve seen with the data already presented. It’s time limited. We’ll, of course, combine it with a CD20 monoclonal. If I’m going to give it as monotherapy, they’re staying on it anyway. But for the BTK inhibitors, agreed, unless there’s a certain circumstance, maybe an autoimmune issue, we need to quickly get in those counts because they have an autoimmune problem, and it won’t improve that quickly with a BTK inhibitor. Then maybe I’ll front-load them with the antibody and then do the BTK inhibitor. But those are rare circumstances. If they’re going to be on a BTK inhibitor as monotherapy, I often don’t include the CD20. But certainly, the acalabrutinib-obinutuzumab data is intriguing, and I’m looking forward to a longer follow-up to see how that PFS curve goes over time but typically not giving it routinely.
William Wierda, MD, PhD: My preference is to give obinutuzumab whether it’s in the front line or the relapsed setting. Obinutuzumab is approved in the frontline setting. It’s not approved technically in the relapsed setting, but that doesn’t prevent me from using it, and it is in the NCCN (National Comprehensive Cancer Network) guidelines, [so] we usually can get it covered. It does have to have more toxicity associated with it; cytopenias. I’ve had transaminitis, but it for sure it is a more potent antibody in terms of disease, treating disease, and eliminating leukemia cells in CLL, in my own experience.
Transcript edited for clarity.