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Expert Discusses Value of Venetoclax After BCR Inhibition in CLL

Jason Broderick and Elizabeth Leick
Published: Friday, Feb 03, 2017

Jeffrey Jones, MD

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.

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.

OncLive: Can you discuss the design of the study?

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.

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