Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study

Abstract

Purpose: CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).

Methods: Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.

Results: One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time.

Conclusion: The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

FIG 1.

Patient flow and disposition. AEs, adverse events; MRD, minimal residual disease; PD, progressive disease; uMRD, undetectable minimal residual disease.

FIG 2.

MRD response during the prerandomization phase. (A) MRD levels serially over time in PB and best MRD response in PB and BM. (B) Forest plot of undetectable MRD in BM across patient subgroups by baseline characteristics. (C) Best MRD response of the prerandomization phase in all-treated patients and according to Confirmed uMRD status in patients eligible for random assignment. ^aBM MRD assessment was scheduled after completion of 12 cycles of combination treatment (cycle 16). ^bPer Dohner hierarchy. ^cPatients without available samples (PB, n = 1; BM, n = 8) were counted as having detectable MRD. BM, bone marrow; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy variable; MRD, minimal residual disease; PB, peripheral blood; uMRD, undetectable minimal residual disease.

FIG 3.

Impact of single-agent ibrutinib lead-in on TLS risk category. Shown are TLS risk categories at baseline and after ibrutinib lead-in in the prerandomization phase. TLS, tumor lysis syndrome.

FIG 4.

Disease-free survival. Kaplan-Meier estimates of DFS by randomized treatment arm in the Confirmed uMRD population. Tick marks indicate patients with censored data. Patients who did not experience a DFS event were censored by the last MRD sample date with a valid result or the date of last adequate disease assessment after random assignment, whichever occurred earlier. ^aThe three DFS events in the placebo arm were disease progression in two patients and MRD relapse in one patient; of the two patients with disease progression, after primary analysis one was confirmed to have partial response (not progression), for a total of two DFS events. ^bAt 12 cycles after random assignment. DFS, disease-free survival; MRD, minimal residual disease; uMRD, undetectable minimal residual disease.

FIG 5.

Rates over time of AEs of clinical interest. (A) Prevalence of AEs of clinical interest over time by randomized treatment arm for any-grade AEs and (B) grade ≥ 3 AEs. ^aAt postrandomization 7-12 months, Confirmed uMRD population: placebo (n = 42), ibrutinib (n = 42); uMRD Not Confirmed population: ibrutinib (n = 30), ibrutinib plus venetoclax (n = 29). ^bGrade 3 menorrhagia in one patient. ^cGrade 3 retroperitoneal hemorrhage in one patient. AEs, adverse events; uMRD, undetectable minimal residual disease.

FIG 6.

Best overall uMRD rates by randomized treatment arm in the uMRD Not Confirmed population. BM, bone marrow; PB, peripheral blood; uMRD, undetectable minimal residual disease.