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Ibrutinib plus venetoclax safely induces remission in relapsed, refractory chronic lymphocytic leukemia
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The combination of ibrutinib and venetoclax appeared effective and safe among patients with relapsed or refractory chronic lymphocytic leukemia, according to results of the single-arm, phase 2 CLARITY study published in Journal of Clinical Oncology.
“Chemoimmunotherapy ... results in remission in most patients [with CLL],” Peter Hillmen, MBChB, PhD, consultant in clinical hematology at Leeds Teaching Hospitals and honorary professor of hematology at University of Leeds in the United Kingdom, and colleagues wrote. “However, chemoimmunotherapy is rarely curative, and the majority of patients experience relapse and eventually succumb to their disease. Chemoimmunotherapy is also associated with toxicity, which leads to significant immediate and late complications (including possible death) and limits its use across the whole patient population.”
Targeted therapies such as the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen) and the B-cell lymphoma 2 inhibitor venetoclax (Venclexta; AbbVie, Genentech) have improved survival and, in many cases, replaced chemoimmunotherapy for patients with CLL. However, these drugs seldom eradicate minimal residual disease (MRD) when used individually and typically are taken indefinitely or until disease progression, according to study background.
In the CLARITY study, Hillmen and colleagues administered ibrutinib in combination with venetoclax to 53 patients (median age, 64 years; range, 31-83; 69% men) with relapsed or refractory CLL (median prior therapies, 1; range, 1-6).
Eradication of MRD, in bone marrow and peripheral blood, to fewer than one CLL cell in 10,000 leukocytes after 12 months of combination therapy served as the primary endpoint. Investigator-assessed response, PFS, OS and safety served as secondary endpoints.
Results showed that 47 patients (89%) responded to treatment after 12 months, with 27 (51%) achieving complete remission.
Twenty-eight patients (53%) achieved MRD negativity in peripheral blood and 19 patients (36%) demonstrated MRD negativity in bone marrow.
One patient experienced disease progression and all patients remained alive after median follow-up of 21.1 months.
Two patients stopped the combination at 14 months after confirmation of MRD-negative remission.
Adverse events appeared manageable and consistent with the documented history of both drugs, researchers noted. One patient experienced biochemical tumor lysis syndrome. The most common grade 3 or grade 4 adverse events included neutropenia (n = 34) and infections (n = 9).
“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse events,” Hillmen and colleagues wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission. This observation is critical before taking the MRD-guided approach into larger phase 3 trials. Whether the combination leads to permanent disease eradication in a subset of these patients remains to be seen.”– by John DeRosier
Disclosures: Hillmen reports honoraria, research funding and/or travel expenses from AbbVie, Gilead Sciences, Janssen Pharmaceuticals and Roche. Please see the study for all other authors’ relevant financial disclosures.
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