Expert Discusses Value of Venetoclax After BCR Inhibition in CLL

Jeffrey Jones, MD

The B-cell receptor (BCR) inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) have revolutionized the treatment of chronic lymphocytic leukemia (CLL); however, “There are still a significant number of patients who will relapse after those therapies or discontinue because they’re intolerant,” said Jeffrey Jones, MD.

At the 2016 ASH Annual Meeting, Jones presented findings from a phase II study demonstrating high response rates with the BCL-2 inhibitor venetoclax (Venclexta) among patients with CLL who had progressed, relapsed, or were refractory to ibrutinib (n = 43), idelalisib (n = 21), or both agents (n = 4). The overall response rate with venetoclax was 67%, including 70% of patients previously treated with ibrutinib and 62% treated with idelalisib.

OncLive: Can you discuss the design of the study?

In an interview with OncLive at ASH, Jones, an assistant professor of Internal Medicine in the Division of Hematology at The Ohio State University, discussed the promising early data for venetoclax in CLL after progression on BCR-pathway inhibitors, as well as the next steps with the research.Jones: One of the things that happens in clinical medicine is new advances, no matter how great they are, often create new clinical situations and new unmet medical needs. That's happened in CLL medicine with the addition of kinase inhibitor therapy—although it is remarkably effective for the majority of patients, there are still a significant number of patients who will relapse after those therapies or discontinue because they're intolerant.

The new drug venetoclax, an oral inhibitor BCL-2, was recently approved here in the United States for treatment of CLL with deletion 17p relapsing after at least one prior therapy. That drug has a unique mechanism distinct from ibrutinib or idelalisib that makes it interesting to assess in the context of treatment failure after those drugs.

This trial was a phase II study of single-agent venetoclax in 2 parallel cohorts of patients. One was a group of patients progressing after or during treatment with ibrutinib. The second cohort of patients was progressing after or during treatment with idelalisib. In fact, the majority of patients, about 43 patients, treated in the ibrutinib arm progressed during ibrutinib treatment. On the other hand, the majority of patients treated in the idelalisib arm were treated after discontinuing ibrutinib for reasons of toxicity or tolerance. Slightly different groups of patients.

Overall, venetoclax was highly effective in both groups of patients. In the ibrutinib arm where patients had been in treatment longer, the overall response rate was 70%; it was 62% in the arm after prior treatment with idelalisib. That compares favorably with prior studies of single-agent venetoclax in relapsed/refractory CLL, many of whom had never been exposed to a kinase inhibitor.

One concern that's arisen as venetoclax is moved into the clinic is the need to better understand its toxicity profile. In some earlier studies of venetoclax, there were cases of hyperacute tumor lysis syndrome that required urgent intervention in order to manage. Modifications were made in prophylactic measures and a careful dose ramp-up schedule that was employed in the trial we're speaking about.

Is there a reason you wanted to look at venetoclax specifically?

What will the findings of this study mean for patients?

What are the next steps for this research?

With that, there were only 2 cases of biochemical tumor lysis reported in this trial between both groups of patients. Neither of those cases required urgent medical intervention like hemodialysis. The remainder of the toxicity was consistent with what had been reported in the past—chiefly hematologic, mostly neutropenia and thrombocytopenia, but not associated with a higher incidence of infection beyond what might expected in a group of relapsed and refractory CLL patients.Retrospective data that has been presented previously and is being updated at this meeting suggests that older drugs like chemotherapy and single-agent monoclonal antibodies achieve suboptimal responses in this setting, with overall response rates no higher than 30% in patients progressing after 1 or both kinase inhibitors. Looking for drugs that have a novel mechanism of action and have a favorable safety profile is what really generates interest in general. Venetoclax is a drug like that with a distinct mechanism of action, favorable safety profile, and excellent single-agent activity, making it chief among the available drugs that are in advanced stages of clinical development. Plus, since it's an oral agent, it doesn't require hospitalization in most patients for care. There's no clinic visits for infusions. It improves patient acceptability.As kinase inhibitors move beyond academic practice and become more widely adapted in the community, there's going to be a growing group of patients exposed to those drugs and unfortunately a larger group of patients whose disease will progress after treatment with those drugs. This is really the first prospective study in this emerging group of patients that demonstrates there is an effective option with a favorable risk benefit ration. I think this immediately suggests that the first best choice for patients, and particularly those progressing after ibrutinib who don't have access to investigational therapies, is this treatment with venetoclax.We're presenting data on the first group of patients that was accrued to the trial. There are just over 60 patients. A larger group of patients has been treated in an expansion cohort after treatment with one or both of the kinase inhibitors. What we're really interested to understand is how durable these first responses will be. Are there some patients who are prone to early relapse? If so, can we identify who those patients are to think about other strategies for them, maybe combination strategies or early referral to transplant or CAR T-cell therapy? Among the patients who achieved durable responses, is there some indicator where the responses are sufficiently deep so they might be able to discontinue therapy in the future?

Overall, many people are interested in thinking about these drugs given concurrently rather than sequentially, as was done in this trial. Is there a way of giving ibrutinib with venetoclax as a way of preventing the clinical situation we're describing, which is a high-risk patient with disease progressing because of acquired resistance [to one of those drugs]? Many of our great successes in oncology have come with combination therapies using drugs with nonoverlapping mechanisms of action and nonoverlapping toxicity profiles. That's the next step as we move forward with the novel targeted agents.

Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 637.