Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440)

Abstract

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

Figure 1.

Treatment and dosing schedules. Schedule A: venetoclax followed by BR/BG. Schedule B: BR/BG followed by venetoclax. Schedule A with Ven-BR was explored in R/R patients before schedule B in the R/R and 1L populations. Data from schedule A provided safety guidance for subsequent dose-finding for patients in schedule B after a data review by the IMC and SOC. Venetoclax ramp-up: 3 weeks for the 100-mg cohort, 4 weeks for the 200-mg cohort, and 5 weeks for the 400-mg cohort; the treatment plan consisted of venetoclax plus BR or BG (6 x 28-day cycles) in combination with venetoclax, then single-agent venetoclax; each cohort continued treatment until PD, death, or unacceptable toxicity in R/R patients, or for a total of 1-year treatment duration in 1L patients (with potential for extension if BM was positive for MRD or patient had PR). Venetoclax ramp-up and maximum cohort dose are indicated by the blue arrows. BR/BG dosing schedule: bendamustine: 90 mg/m2 (1L) or 70 mg/m2 (R/R) D1–2 per cycle for six cycles; R: 375 mg/m2 (C1) then 500 mg/m2 (C2–6) D1 per cycle; G: 100 mg D1, 900 mg D2, 1,000 mg D8 and D15 C1 then 1,000 mg D1 (C2–6). Ven: venetoclax; B: bendamustine: R: rituximab; D: day; C: cycle; G: obinutuzumab; W: week; R/R: relapsed/refractory; 1L: first-line; IMC: internal monitoring committee; SOC: scientific overview committee; PD: disease progression; BM: bone marrow; MRD: minimal residual disease: PR: partial response.

Figure 2.

Minimal residual disease status by flow in peripheral blood and bone marrow in the (a) relapsed/refractory population and (b) untreated population. Discontinued includes patients who discontinued study due to PD, death, or AE (if applicable) before achieving the specified landmark time point; missing includes patients who reached the time-point but had no sample available for MRD analysis; undetermined includes patients with MRD level <10-4, but <200,000 leukocytes analyzed. uMRD: <1 CLL cell per 104 mononuclear cells; low-level MRD: ≥1 CLL cell per 104 mononuclear cells to <1 CLL cell per 104 mononuclear cells; high-level MRD: ≥1 CLL cell per 102 mononuclear cells. MRD: minimal residual disease; PB: peripheral blood; BM: bone marrow; R/R: relapsed/refractory; 1L first-line; R: rituximab; B: bendamustine; Ven: venetoclax; G: obinutuzumab; PD: disease progression; AE: adverse event; uMRD: undetectable MRD; CLL: chronic lymphocytic leukemia.

Figure 3.

Minimal residual disease kinetics in individual patients in the (a) relapsed/refractory population and (b) first-line population. Undetectable minimal residual disease (uMRD) was defined as <1 chronic lymphocytic leukemia (CLL) cell per 104 mononuclear cells in samples with a minimum of 200,000 leukocytes (<10-4). Low-level MRD was defined as between 1 CLL cell per 104 and 1 cell per 102 mononuclear cells (≥10-4–<10-2). High-level MRD was defined as ≥1 CLL cell per 102 mononuclear cells (≥10-2). MRD: minimal residual disease; R/R: relapsed/refractory; 1L: first-line; Ven: venetoclax; B: bendamustine; R: rituximab; PB: peripheral blood; BM: bone marrow; IGHV: immunoglobulin heavy-chain variable region; Tx: treatment; PD: disease progression; G: obinutuzumab; uMRD: undetectable MRD; CLL: chronic lymphocytic leukemia.

Figure 4.

Progression-free survival. 1L: first-line; Ven: venetoclax; B: bendamustine; R: rituximab; G: obinutuzumab; R/R: relapsed/refractory.