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

Andrew W. Roberts, Shuo Ma, Thomas J. Kipps, Steven E. Coutre, Matthew S. Davids, Barbara Eichhorst, Michael Hallek, John C. Byrd, Kathryn Humphrey, Lang Zhou, Brenda Chyla, Jacqueline Nielsen, Jalaja Potluri, Su Young Kim, Maria Verdugo, Stephan Stilgenbauer, William G. Wierda and John F. Seymour

Key Points

  • Patients with relapsed CLL achieving complete remission or undetectable MRD on venetoclax treatment have the most durable responses

  • Less durable responses are associated with bulky adenopathy, TP53 aberrations, NOTCH1 mutations and prior refractoriness to BCR inhibitors

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 four 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% 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 ({greater than or equal to}5cm), 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.

  • Submitted October 24, 2018.
  • Revision received March 31, 2019.
  • Accepted March 31, 2019.