Outcomes in Patients with High-Risk Features after Fixed-Duration Ibrutinib plus Venetoclax: Phase II CAPTIVATE Study in First-Line Chronic Lymphocytic Leukemia

Abstract

Purpose: The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] in CAPTIVATE.

Patients and methods: Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment.

Results: Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were >95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six-month overall survival (OS) rates were >95% regardless of high-risk features.

Conclusions: Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features. See related commentary by Rogers, p. 2561.

Figure 1.

Best overall response in patients with versus without high-risk features (A) and in the subsets of patients with or without del(17p)/TP53 mutation and with unmutated IGHV or mutated IGHV (B). Best uMRD response^a in patients with versus without high-risk features (C) and in the subsets of patients with or without del(17p)/TP53 mutation and with unmutated IGHV or mutated IGHV (D). Error bars represent 95% CIs. ^aPatients with missing MRD status were considered to have detectable MRD. Abbreviations: BOR, best overall response; mIGHV, mutated IGHV; mut, mutation; nPR, nodular partial response; uIGHV, unmutated IGHV.

Figure 2.

Kaplan–Meier curves of PFS in patients with versus without high-risk features (A) and in the subsets of patients with or without del(17p)/TP53 mutation and with unmutated IGHV or mutated IGHV (B). Kaplan–Meier curves of OS in patients with versus without high-risk features (C) and in the subsets of patients with or without del(17p)/TP53 mutation and with unmutated IGHV or mutated IGHV (D). Tick marks indicate censored patients. ^aDue to many patients being censored between months 36 and 42 in the del(17p)/TP53 mutation subset, PFS events among a small number of patients “at risk” beyond month 36 can lead to perceived large drops in PFS. Abbreviations: mIGHV, mutated IGHV; mut, mutation; uIGHV, unmutated IGHV.