In the United States, both ibrutinib, a Bruton’s tyrosine kinase inhibitor, and venetoclax, a B-cell lymphoma 2 inhibitor, are approved for the treatment of chronic lymphocytic leukemia (CLL) in the frontline and relapsed/refractory settings. Preclinical evidence of synergistic antitumor activity with ibrutinib + venetoclax combination therapy demonstrated high rates of remission with undetectable minimal residual disease (uMRD) in patients with CLL or mantle-cell lymphoma. The multicenter phase 2 CAPTIVATE study (PCYC-1142; NCT02910583) is evaluating ibrutinib + venetoclax combination therapy in the first-line treatment of CLL/small lymphocytic lymphoma.
In the CAPTIVATE study, eligible patients were aged <70 years and were previously untreated for CLL requiring therapy. Patients received ibrutinib 420 mg daily for 3 cycles, followed by ibrutinib + venetoclax (5-week ramp-up to 400 mg daily orally) for 12 cycles. MRD-guided randomization occurred at 24 cycles, where patients were assessed for bone marrow (BM) uMRD; only MRD-positive patients were permitted to continue ibrutinib. The key end points prior to MRD-guided randomization included uMRD (<10-4 by 8-color flow cytometry), venetoclax-related tumor lysis syndrome (TLS) risk, pharmacokinetics, and adverse events (AEs). MRD status was evaluated in peripheral blood (PB) after 6, 9, and 12 cycles of ibrutinib + venetoclax, and in BM after 12 cycles of ibrutinib + venetoclax. A total of 164 patients were enrolled in the study, and 151 patients (90%) completed all 12 cycles of ibrutinib + venetoclax. The median age in the study population was 58 years; 20% had del(17p) or TP53 mutation, 17% had del(11q) alteration without del(17p), 19% had complex karyotype, 59% had unmutated IGHV, and 32% had lymph nodes ≥5 cm. The median duration of treatment was 14.7 months with ibrutinib and 12.0 months with venetoclax.
At any time after baseline, uMRD was achieved in 75% of patients (122/163) in PB and in 72% of patients (111/155) in BM; 93% of patients with uMRD in PB with matched BM samples achieved uMRD in both PB and BM. The proportion of patients who achieved PB uMRD following combined ibrutinib + venetoclax increased over time (after 6 cycles, 57%; after 9 cycles, 68%; after 12 cycles, 73%). The uMRD achieved in BM extended to all high-risk subgroups, including the del(17p) or TP53 mutation, del(11q), trisomy 12, and unmutated-IGHV status groups. Rates of uMRD in PB were also consistent with BM results.
At a median follow-up of 14.7 months (range, 0.5-19.9), response by International Workshop on Chronic Lymphocytic Leukemia criteria was achieved in 97% of patients, 3 patients (2%) had disease progression (1 Richter transformation during single-agent ibrutinib lead-in, 1 after discontinuation of ibrutinib lead-in due to AE, and 1 during treatment with ibrutinib + venetoclax).
After 3 cycles of ibrutinib lead-in, hospitalization was avoided in 76% of at-risk patients, and TLS risk was downgraded from high baseline risk to medium or low risk.
The most common AEs (any grade, in ≥15% of patients) during both single-agent ibrutinib and ibrutinib + venetoclax treatment were diarrhea, arthralgia, fatigue, headache, nausea, upper respiratory tract infection , neutropenia, vomiting, hypertension, and thrombocytopenia. AEs leading to treatment discontinuation occurred in 5% of patients treated with ibrutinib + venetoclax). Overall, the most common grade 3/4 AEs included neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhea (5%).
Based on these results, it was concluded that first-line ibrutinib + venetoclax treatment resulted in high rates of uMRD in both PB and BM in patients with CLL, with a safety profile consistent with AEs known for both agents.
Tam CS, et al. ASH Abstract 35. Session 642.