Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.
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Melani Christopher, Lakhotia Rahul, Pittaluga Stefania, Phelan James D, Huang Da Wei, Wright George, Simard Jillian, Muppidi Jagan, Thomas Craig J, Ceribelli Michele, Tosto Frances A, Yang Yandan, Xu Weihong, Davies-Hill Theresa, Pack Svetlana D, Peer Cody J, Arisa Oluwatobi, Mena Esther, Lindenberg Liza, Bergvall Ethan, Portell Craig A, Farah Rafic J, Lee Seung Tae, Pradhan Amynah, Morrison Candis, Tadese Atekelt, Juanitez Anna Marie, Lu Crystal, Jacob Allison, Simmons Heidi, Figg William D, Steinberg Seth M, Jaffe Elaine S, Roschewski Mark, Staudt Louis M, Wilson Wyndham H
Аннотация
METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).