• Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, James D Phelan, Da Wei Huang, George Wright, Jillian Simard, Jagan Muppidi, Craig J Thomas, Michele Ceribelli, Frances A Tosto, Yandan Yang, Weihong Xu, Theresa Davies-Hill, Svetlana D Pack, Cody J Peer, Oluwatobi Arisa, Esther Mena, Liza Lindenberg, Ethan Bergvall, Craig A Portell, Rafic J Farah, Seung Tae Lee, Amynah Pradhan, Candis Morrison, Atekelt Tadese, Anna Marie Juanitez, Crystal Lu, Allison Jacob, Heidi Simmons, William D Figg, Seth M Steinberg, Elaine S Jaffe, Mark Roschewski, Louis M Staudt, and Wyndham H Wilson.
• From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management Section (S.M.S.), Center for Cancer Research, the Laboratory of Pathology, Clinical Center (S.P., T.D.-H., S.D.P., E.S.J.), and the Biometric Research Program, Division of Cancer Treatment and Diagnosis (G.W.), National Cancer Institute, the Division of Pre-Clinical Innovation Chemistry Technologies, National Center for Advancing Translational Sciences (C.J.T., M.C., F.A.T.), and the Clinical Center Pharmacy Department (C.L.), National Institutes of Health, Bethesda, and Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore (S.T.L.) - all in Maryland; the Division of Hematology and Oncology, University of Virginia, Charlottesville (C.A.P.); Mario Lemieux Center for Blood Cancers, University of Pittsburgh School of Medicine, Pittsburgh (R.J.F.); and Adaptive Biotechnologies, Seattle (A.J., H.S.).
• N. Engl. J. Med. 2024 Jun 20; 390 (23): 214321552143-2155.

BackgroundThe identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.MethodsWe 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.ResultsIn 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.ConclusionsTreatment 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.).Copyright © 2024 Massachusetts Medical Society.

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