Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

Abstract

Background: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.

Methods: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.

Findings: Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.

Interpretation: A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.

Funding: AbbVie Inc and Genentech Inc.

Conflict of interest statement

Declaration of interests

JFS reports research grant funding from AbbVie and being a consultant and advisory board member for AbbVie, Roche, and Genentech. SM reports research grant funding from Genentech, AbbVie, Pharmacyclics, Novartis, Gilead, Acerta, and Xeme, and advisory board consulting and lecturing for Genentech, Pharmacyclics, and Gilead. DMB reports being a consultant for Gilead. MYC reports research grant funding from AbbVie, being an advisory board member and consultant for AbbVie, Novartis, Pharmacyclics, and Gilead, and being a member of the speakers’ bureau for Gilead. JB reports research grant funding from Gilead, Pharmacyclics, and AbbVie, and advisory board consulting for AbbVie, Gilead, Janssen, and Pharmacyclics. MSD is a consultant for AbbVie, Genentech, Infinity, Gilead, Janssen, TG Therapeutics, Celgene, and Pharmacyclics, and reports research grant funding from Infinity, TG Therapeutics, Genentech, and Pharmacyclics. MAA reports research grant funding from AbbVie, and is an employee of Walter and Eliza Hall Institute of Medical Research, which receives milestone payments related to venetoclax. CST is a consultant for AbbVie and Roche, and receives speaking fees from Roche. BP, SKA, WM, MZ, LLL, MD, EC, MV, SYK, RAH, and GBG are employees of AbbVie and could own stock. AWR reports research grant funding from AbbVie, Beigene, Janssen, Servier, Amgen, and Genentech, and is an employee of Walter and Eliza Hall Institute of Medical Research, which receives milestone payments related to venetoclax. AWB, STR, and TJK declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Overall response, complete response, and bone marrow negative minimal residual disease response

Patients treated with venetoclax and rituximab achieved deep responses in the overall population (n=49) and in exploratory analyses of adverse prognosis subgroups. Left, overall responses; middle, complete response or complete response with incomplete marrow recovery; right, 7-month bone marrow minimal residual disease-negative. Medians (95% CIs) are shown; dashed lines indicate the 95% CIs for the overall population. *Four patients did not receive prior rituximab; see table 1. †Data not available for all patients in the FISH subgroups; see table 1.

Figure 2. Durability of response

(A) Time to progression for all 49 enrolled patients (13 patients had events). (B) Duration of response for all 42 responders (nine patients had events). (C) Duration of response by overall response category: complete response or complete response with incomplete marrow recovery (CR/CRi; n=25, two patients had events) versus partial response (PR; n=17, seven patients had events). (D) Duration of response in patients negative for minimal residual disease (MRD) at 7 months (n=22, one patient had an event) versus patients who had minimal residual disease at 7 months (n=15, five patients had events) status. Tick marks on the curves indicate patients censored for each outcome measure.

Figure 3. Drug withdrawal and retreatment

Time on and off venetoclax for 13 patients with deep response who ceased venetoclax therapy: two with marrow minimal residual disease-positive complete response or complete response with incomplete marrow recovery, ten with marrow minimal residual disease-negative complete response or complete response with incomplete marrow recovery, one with marrow minimal residual disease-negative partial response (PR). Ten patients remain in follow-up. Two (asterisks) discontinued the trial and one (dagger) was lost to follow-up without progressing. Plot shows time on venetoclax therapy (green) and time off venetoclax therapy (purple). The time of best deep response is annotated with a circle and includes International Workshop for Chronic Lymphocytic Leukaemia response and minimal residual disease status. Two patients stopped therapy for adverse events and at their next scheduled assessment achieved their best response so remained off therapy. The vertical dashed line at month 7 represents the first protocol-specified marrow assessment of minimal residual disease in the marrow. For the two patients with disease who progressed while off therapy, the timepoint of progression is indicated with hash marks and reinitiation of venetoclax is shown in green. Both have re-achieved an overall response. MRD=minimal residual disease. CR/CRi=complete response or complete response with incomplete marrow recovery. iwCLL=International Workshop for Chronic Lymphocytic Leukaemia response.