Frontline CLL Treatment: Addressing Unmet Needs

Danielle M. Brander, MD: In terms of what the remaining unmet needs are for patients with CLL [chronic lymphocytic leukemia] or SLL [small lymphocytic leukemia], now that there are several novel agents that have been approved and others are far along in development, there a couple of areas to discuss and also ongoing clinical trials to address some of these areas of unmet need.

One of the areas, in terms of unmet need for patients with CLL or SLL, is for patients to be able to receive a therapy that’s going to eliminate as much disease as possible up front with a novel therapy-based approach such that you can accomplish 2 things. If you can eliminate more disease up front, especially for young patients or patients with high-risk disease markers, it may prevent subsequent development of resistance or progression down the road. The other reason for trying to achieve a greater degree of depth of response in the frontline setting is that it potentially enables time-limited therapy, meaning patients don’t have to be on the novel agents for years where they could be at risk for development of intolerance or of resistance.

How we measure depth of response is certainly beyond going into full detail here, but often you’ll hear the terms undetectable minimal residual disease [MRD], or measurable residual disease, and how can that be used as a target in CLL or how we use the results of MRD to inform our therapy choices. There are a few clinical trials looking at combination, novel-novel inhibitor combination, to achieve undetectable MRD, or to look at the role of undetectable MRD in the treatment of patients with CLL. One of these is the CAPTIVATE clinical trial, which is a combination trial of ibrutinib plus venetoclax. Patients receive the ibrutinib for the first 3 cycles, and venetoclax is added in subsequently in combination. This study was designed so that patients, depending on their MRD status, at the end of that 1 year of combination, they’d then be randomized among their cohort. The cohort that met the undetectable MRD were randomized then to continue on ibrutinib or to receive a placebo. The patients still with detectable minimal residual disease would be randomized between ibrutinib or the combination to continue with ibrutinib and venetoclax.

The data that we have available published online with the ASH [American Society of Hematology annual meeting] abstracts will be reporting on the MRD cohort, that is the patients who were part of the cohort to randomize based on whether they met the undetectable MRD. As part of this trial, there is a cohort that wasn’t reported on yet that were time-limited therapies. Of the patients in the MRD cohort who reached undetectable MRD, at the initial date of reporting, there doesn’t seem to be a difference in the duration of response a year after for patients who had been randomized to get the placebo, so functionally stopped therapy versus continue on the ibrutinib.

This is interesting because, so far, it looks like that combination of ibrutinib then adding in and receiving ibrutinib plus venetoclax, has high undetectable MRD levels at the end of that 1 year. But also if patients do achieve that, they seem, at the follow-up we have available, to be able to continue functionally off therapy versus continuing on the ibrutinib. This will be an interesting study for just the MRD cohort and later to be able to look at the time-limited therapy cohort, all of the correlatives, and how MRD will be incorporated.

The trial, though it addresses the unmet need of trying to achieve deeper response and the role of that, the MRD testing outside of clinical trials is still not a standard of care for all patients with CLL. For some patients, it may not ultimately be the goal. Some patients can do well on BTK [Bruton tyrosine kinase] inhibitor monotherapy for many years. It’s an important reason to do clinical trials, but not that it’s standard of care that all patients with CLL should be getting the MRD testing, at least not by the data we have available so far.

Another thing in novel-novel therapy combinations to meet these unmet needs, is asking in the frontline setting: which is superior, for patients to do continuous therapy versus a novel-novel therapy combination and potentially achieve undetectable MRD and be able to stop therapy?

There are 2 randomized studies, they’re somewhat complementary. They are ibrutinib plus obinutuzumab with or without the addition of venetoclax, and there are 2 cooperative group studies. The study for patients younger than age 70 is time-limited in the combination cohort. Patients are either randomized to ibrutinib/obinutuzumab or ibrutinib/obinutuzumab plus venetoclax. If they’re in that plus venetoclax arm, that is a time-limited therapy. Information is collected on patients being able to achieve undetectable measurable residual disease at the end of that combination, but decisions of continuing on therapy after that, it is a time-limited therapy.

The complementary study is the Alliance study for patients older than age 70, and it’s the same drugs and randomization, either ibrutinib plus obinutuzumab versus ibrutinib, obinutuzumab, plus venetoclax. In this setting, after the combination in that novel-novel combination arm, the achievement of undetectable MRD then determines patients’ subsequent therapy.

The unmet need here is, for different groups of patients, which is better, the continuous therapy versus novel-novel combinations? Though undetectable MRD might be higher with novel-novel, these studies will help to look at other complex things like, does it increase toxicity, does it increase toxicity in a certain group of patients? This will help address multiple questions that are ongoing. In terms of novel-novel, those first studies incorporated ibrutinib, as ibrutinib was the first BTK inhibitor approved in the front line. But there are also novel-novel combinations with or without anti-CD20 antibody with other BTK inhibitors, such as acalabrutinib as well as zanubrutinib. These are important to point out because all covalent BTK inhibitors are not the same. Without these trials, we won’t learn other important factors like intolerance or adverse effects when used in these combinations. We’ll look to these studies as well to see potentially the difference of the BTK inhibitors.

Transcript Edited for Clarity