Ibrutinib and Venetoclax for First-Line Treatment of CLL

Abstract

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.

Methods: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10^-4).

Results: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.

Conclusions: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Figure 1.. Study Schema and Response to Treatment.

Panel A shows the study schema. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles (each cycle was 28 days), and then venetoclax was added. The dose of venetoclax was escalated weekly to a target dose of 400 mg once daily. Combined ibrutinib and venetoclax were administered for a total of 24 cycles. Patients who remained positive for minimal residual disease (MRD) in bone marrow at the end of combined treatment could continue ibrutinib alone until disease progression or unacceptable toxic effects. Clinical responses and MRD were measured after 3 cycles of ibrutinib monotherapy and then after every 3 cycles for the first 12 cycles of the combination and every 6 cycles for cycles 13 to 24 of the combination. Panel B shows response to treatment over time. Responses (complete remission, with or without normal blood count recovery; partial remission; and undetectable MRD in bone marrow) are shown for patients after 3 cycles of ibrutinib monotherapy and at different time points for the combination therapy.