Abstract 3024: Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia

Abstract

Abstract Minimal residual disease (MRD) is an important clinical endpoint in chronic lymphocytic leukemia (CLL) because it correlates with progression free survival and overall survival. The objective of this work is to investigate the impact of venetoclax (VEN) exposures on undetectable MRD rates in blood and bone marrow (BM) in relapsed/refractory (R/R) CLL patients receiving VEN monotherapy or combination therapy with rituximab (RTX). Data from a total of 708 patients from four VEN monotherapy studies and one combination Phase 1b study (VEN + 6-9 cycles of RTX) in R/R CLL patients were utilized to perform this analysis. The median number of prior therapies in these studies was 3, 42% of the patients had 17p chromosomal deletion and 28% had prior B-Cell Receptor inhibitor (BCRi) therapy. Blood and BM MRD assessments were available for 70% and 38%, respectively, of patients included in the analysis. Absence of an MRD measurement was assumed as detectable MRD for the purposes of this analysis. The average concentration (Cavg) of VEN was computed for each patient by fitting a population pharmacokinetic model to the observed VEN concentration data. The model was used to calculate area under the curve and compute Cavg accounting for VEN dose ramp-ups, reductions and interruptions. The relationships between venetoclax Cavg and undetectable MRD rates were assessed by using quartile plots. Logistic regression analyses were also conducted to quantify the exposure-response relationship. With VEN monotherapy, the undetectable MRD rates in blood and BM increased with the increase in VEN exposures. With VEN + RTX combination treatment, the undetectable MRD rates in blood and BM showed an increase with increasing VEN average concentration, but the benefit saturated with limited increase at exposures beyond 400mg. Logistic regression analyses indicated statistically significant (p<0.01) relationships between VEN average concentrations and undetectable MRD rates in both blood and BM. These results demonstrate that higher venetoclax concentrations are associated with higher undetectable MRD rates in both blood and BM. When VEN is combined with RTX, an increase in VEN dose beyond 400mg is unlikely to result in higher undetectable MRD rates. Citation Format: Sathej Gopalakrishnan, Rajeev Menon, Brenda Chyla, Divya Samineni, Amanda Jacobson, Su Young Kim, Sven Mensing, Ahmed Hamed Salem. Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3024.