TY - JOUR
T1 - Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma
AU - Melani, Christopher
AU - Lakhotia, Rahul
AU - Pittaluga, Stefania
AU - Phelan, James D.
AU - Huang, Da Wei
AU - Wright, George
AU - Simard, Jillian
AU - Muppidi, Jagan
AU - Thomas, Craig J.
AU - Ceribelli, Michele
AU - Tosto, Frances A.
AU - Yang, Yandan
AU - Xu, Weihong
AU - Davies-Hill, Theresa
AU - Pack, Svetlana D.
AU - Peer, Cody J.
AU - Arisa, Oluwatobi
AU - Mena, Esther
AU - Lindenberg, Liza
AU - Bergvall, Ethan
AU - Portell, Craig A.
AU - Farah, Rafic J.
AU - Lee, Seung Tae
AU - Pradhan, Amynah
AU - Morrison, Candis
AU - Tadese, Atekelt
AU - Juanitez, Anna Marie
AU - Lu, Crystal
AU - Jacob, Allison
AU - Simmons, Heidi
AU - Figg, William D.
AU - Steinberg, Seth M.
AU - Jaffe, Elaine S.
AU - Roschewski, Mark
AU - Staudt, Louis M.
AU - Wilson, Wyndham H.
N1 - Publisher Copyright:
© 2024 Massachusetts Medical Society.
PY - 2024/6/20
Y1 - 2024/6/20
N2 - Background The 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. 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.)
AB - Background The 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. 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.)
UR - http://www.scopus.com/inward/record.url?scp=85196696769&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2401532
DO - 10.1056/NEJMoa2401532
M3 - Article
C2 - 38899693
AN - SCOPUS:85196696769
SN - 0028-4793
VL - 390
SP - 2143
EP - 2155
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 23
ER -