The treatment landscape for chronic lymphocytic leukemia (CLL) changed significantly with the introduction of novel oral agents that target B-cell receptor signaling and the anti-apoptotic protein BCL2. Among these agents are the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the Bcl-2 inhibitor venetoclax, which are approved therapies for CLL/small lymphocytic lymphoma (SLL) as a single agent or combined with the anti-CD20 antibodies rituximab or obinutuzumab. Both ibrutinib and venetoclax are generally well tolerated as monotherapy and have non-overlapping toxicity profiles. In addition, preclinical studies have indicated potential synergistic activity, which has led to an exploration of the combination in patients with CLL/SLL.

The multicenter, phase 2 CAPTIVATE study investigated ibrutinib plus venetoclax as first-line treatment of CLL/SLL in two separate cohorts: minimal residual disease- guided randomized treatment discontinuation (MRD) and fixed duration (FD). In both cohorts, patients ≤70 years received three cycles of ibrutinib lead-in (420 mg daily) followed by 12 cycles of the combination of ibrutinib (420 mg daily) plus venetoclax (400 mg daily after the standard 5-week ramp-up). Patients in the MRD cohort with confirmed undetectable MRD (uMRD) were randomized to receive treatment with ibrutinib or placebo; and those who did not achieve confirmed uMRD to ibrutinib or continued ibrutinib plus venetoclax. Results from this cohort were reported previously, with uMRD achieved in 75% of patients in peripheral blood (PB) and 68% in bone marrow (BM), and 30-month progression-free survival (PFS) rates consistently ≥95% across subsequent MRD-guided randomized treatments.

Findings from the FD cohort were published recently. Overall, 159 patients were enrolled in this cohort, including 136 patients without del(17p). A high proportion of patients had one or more risk features, including del(17p)/mutated TP53, del(11q), and unmutated IGHV gene. The primary endpoint was complete response (CR) rate by investigator assessment in patients without del(17p), and this was met with a CR rate of 56% (P < 0.0001). A similar CR rate was observed in the all-treated population and across most of the high-risk subgroups. Of note, 99% of patients with sufficient follow-up maintained their CR for ≥12 cycles. In addition to high CR rates, treatment with ibrutinib plus venetoclax yielded high rates of uMRD in both PB and BM that are consistent with results from the MRD cohort. In the all-treated population, the best uMRD rates were 77% in PB and 60% in BM. uMRD rates were high across patient subgroups, including those with high-risk features. At a median follow-up of 27.9 months, the 24-month PFS and overall survival rates were 95% and 98%, respectively. The ibrutinib plus venetoclax regimen was well tolerated, and 92% of patients completed the full fixed-duration regimen. The safety profile in the FD cohort was similar to that reported for the MRD cohort, and no new safety signals were observed. Only a small percentage of patients required dose reduction or discontinuation of one or both treatment agents. Importantly, tumor debulking with three cycles of ibrutinib lead-in reduced the proportion of patients with high tumor burden who are at high risk for tumor lysis syndrome (TLS). Consequently, the hospitalization for TLS monitoring and prophylaxis decreased from 40% at baseline to 18% after ibrutinib lead-in.

Based on these results, the authors describe the ibrutinib plus venetoclax combination as “an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that drives deep, durable responses and can be delivered in the outpatient setting for most young, fit patients with CLL/SLL.” They note that since the overall population of patients with CLL tends to be older and have more comorbidities, the CAPTIVATE results may be less applicable for these patients. In patients who relapsed after the FD regimen, the authors observed promising responses from ibrutinib monotherapy retreatment and a lack of resistance-associated mutations in BTK, PLCg2, or BCL-2.

Reference:
Tam C et al. Blood. 2022 Feb 23. [Online ahead of print].