Presenting Authors: Uvette Lou, PharmD, BCOP, and Matthew Lei, PharmD, BCOP, Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA, and Department of Pharmacy, Massachusetts General Hospital, Boston, MA
Co-Authors: Mark Sorial, PharmD, BCOP, Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA, and Department of Pharmacy, Massachusetts General Hospital, Boston, MA; Michelle Yu and Andrea Medrano, BS, PharmD Candidate, Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA, and Northeastern University School of Pharmacy and Pharmaceutical Sciences, Boston, MA; Jeremy S. Abramson, MD, MS, and Jacob D. Soumerai, MD, Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, MA
BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), venetoclax and obinutuzumab resulted in higher complete response rates compared with chemoimmunotherapy1,2 and is FDA approved as first-line therapy but not in relapsed/refractory (R/R) CLL/SLL, where venetoclax plus rituximab is approved despite studies indicating that obinutuzumab is the more effective monoclonal antibody in CLL.1,2 Venetoclax and obinutuzumab incorporates an obinutuzumab lead-in phase, which allows for cytoreduction and reduces venetoclax-related tumor lysis syndrome (TLS) risk, whereas in venetoclax plus rituximab, venetoclax starts first, not allowing for cytoreduction. We report 3-year follow-up of our experience with safety and efficacy of venetoclax and obinutuzumab in R/R CLL/SLL.
METHODS: This retrospective study included patients aged ≥18 years with R/R CLL who received venetoclax and obinutuzumab at Massachusetts General Hospital locations between July 2019 and June 2022. Updated progression and survival data were collected through October 9, 2024. Safety end points included laboratory or clinical TLS per Howard criteria, infusion-related reactions (IRRs), and hematologic adverse events defined per Common Terminology Criteria for Adverse Events v5.0. Efficacy end points included progression-free survival (PFS) and overall survival (OS), which were estimated using Kaplan-Meier method.
RESULTS: We identified 40 consecutive R/R CLL patients treated with venetoclax and obinutuzumab. Median follow-up was 41 months (range, 2-64). Median age was 72 (range, 51-94) years, with 31 (78%) patients aged ≥65 years, 28% (n=11/39) with del(17p)/TP53 alterations, and 66% (n=21/32) with unmutated IGHV. Median previous treatments was 1 (range, 1-6), with 55% (n=22) previously treated with Bruton tyrosine kinase inhibitor. Median creatinine clearance (CrCl) was 57 mL/min (range, 22-134), with CrCl <60 mL/min in 53% (n=21) of patients. Laboratory TLS occurred in 3% (n=1) of patients, arising during obinutuzumab initiation; no patients had clinical TLS. IRRs occurred in 30% (n=12), with 27% (n=11) having grades 1 or 2 and 3% (n=1) grade 3. Four of 11 (36%) patients who had grade 1 or 2 IRRs were treated as inpatients. Grade 3/4 hematologic adverse events occurred in 60% (n=24; neutropenia, 50%; anemia, 25%; thrombocytopenia, 45%). The 3-year PFS and OS rates were 65% (95% confidence interval [CI], 0.51-0.82) and 84% (95% CI, 0.73-0.97), respectively.
CONCLUSION: In 3-year follow-up, venetoclax and obinutuzumab continued to be safe and effective treatment for R/R CLL. Laboratory TLS occurred more frequently during obinutuzumab initiation (3%) than with venetoclax (0%), which may reflect obinutuzumab use over rituximab, or venetoclax and obinutuzumab use in real-world patients with comorbidities that may have excluded them from prospective trials. More intensive TLS mitigation and monitoring should be considered when starting the obinutuzumab phase of venetoclax and obinutuzumab in R/R CLL, including inpatient administration in patients with comorbidities or high tumor burden.
- Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236.
- Eichhorst B, Niemann C, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia (CLL) of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Blood. 2021;138(suppl 1):71.