Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables

Abstract

To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

Trial registration: ClinicalTrials.gov NCT01328626 NCT01889186 NCT01682616 NCT02141282.

Conflict of interest statement

Conflict-of-interest disclosure: A.W.R. received research funding from AbbVie and Janssen; is an employee of the Walter and Eliza Hall Institute of Medical Research, which receives milestone and royalty payments related to venetoclax (employees of Walter and Eliza Hall Institute also may be eligible for financial benefits related to these payments); and receives a financial benefit as a result of previous research related to venetoclax. S.M. received research funding from AbbVie, Pharmacyclics, Novartis, Gilead, Acerta, and Incyte; is an advisory board member for AbbVie, AstraZeneca, Genentech, Gilead, Janssen, Pharmacyclics; and provides lecturing for Genentech, Pharmacyclics, and Janssen. T.J.K. is a consultant and received research funding from AbbVie. S.E.C. received research funding from AbbVie, Gilead, and Pharmacyclics. M.S.D. is a consultant and/or advisory board member for AbbVie, Genentech, Roche, Pharmacyclics, Janssen, Gilead, Verastem, TG Therapeutics, Acerta, Astra-Zeneca, Sunesis, and MEI Pharma and received institutional research funding from Genentech, Pharmacyclics, TG Therapeutics, Surface Oncology, and Bristol-Myers Squibb. B.E. received research funding, honoraria (consultant or advisory board member), and travel support from AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, and Roche. M.H. received research funding from GlaxoSmithKline, Mundipharma, Janssen, Celgene, Gilead, AbbVie, and Roche, and is a consultant and advisory board member for AbbVie, Roche, and Genentech. J.C.B. received clinical trial support from Pharmacyclics and Acerta and is an unpaid consultant for Genentech, AbbVie, Acerta, Pharmacyclics, and the Leukemia and Lymphoma Society LLC. K.H. is an employee of Roche and may own Roche stock or options. L.Z., B.C., J.N., J.P., S.Y.K., and M.V. are employees of AbbVie and may hold stock or stock options. S.S. received research funding, honoraria (consultant or advisory board member), and travel support from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi. W.G.W. received research funding from AbbVie and Genentech. J.F.S. received research funding from AbbVie and Genentech and is a consultant and advisory board member to Roche and Genentech.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Time to response and MRD clearance in all patients receiving venetoclax. (A) Inverted Kaplan-Meier plot showing the cumulative percentage of patients with objective response and CR/CRi as a function of time. (B) Plot showing the cumulative percentage of patients who have documented clearance of minimal residual disease negativity (U-MRD) in peripheral blood (PB) and bone marrow (BM) over time. Analyses in A and B are intent to treat.

Figure 2.

Survival and durability of benefit on venetoclax. (A) Kaplan-Meier plot showing the OS and PFS rates of all patients over time; number of patients at risk at each point is shown below the graph. (B) OS and PFS rates of patients who received 400 mg/day of venetoclax monotherapy over time; patients at risk at each point are shown below the graph. (C-D) Duration of response for all patients and for those patients who received 400 mg/day of monotherapy, respectively.

Figure 3.

Progression and durability of response rates over time, according to response depth. (A) Kaplan-Meier plot showing the PFS rates of all patients over time, stratified by best objective response. (B) DoR for all patients, starting from the day of best response, stratified by best overall response. (C) Duration of response for all patients, stratified by response at the 9-month landmark. (D) Duration of response for all patients with available data, stratified by MRD status (in peripheral blood) at the 24-month landmark. Patients at risk at each point are shown beneath each graph. MRD positive, detectable MRD; nPR, nodular PR.

Figure 4.

Summary of univariate analyses of pretreatment factors for association with response outcomes. This figure shows the overall response rates, CR/CRi rates, and relapse rates segregated according to different pretreatment variables, along with the associated ORs and HRs for those values in univariate analyses. (Left) Overall response rate (includes patients with CR, CRi, PR, or nPR); the corresponding OR represents the likelihood for failure to respond compared with the first listed category for each variable. (Middle) Complete response rate; the OR represents the likelihood for failure to achieve CR/CRi. (Right) The relative relapse rate; the HR for loss of response, which is also represented numerically to the right of the graph. The N column represents the number of patients with data for each category. Dotted vertical lines for response rate and CR/CRi rate represent the overall rates observed for all patients. For the relative relapse rate, the vertical dotted line represents a HR of 1.0 (no hazard) associated with the first listed category for each variable). ORs and HRs are shown with 95% CIs for each column. Variables tested but found to be nonsignificant on univariate analyses and not shown in the figure were age (≥70, <70 years) and sex. For these analyses, where data on a cytogenetic abnormality or mutation in TP53, NOTCH1, SF3B1, or IGHV was missing, the patient was included in the no category. del, deletion; mut, mutated.