Background

Relapsed and refractory large B-cell lymphomas (r/r LBCL) remain a therapeutic challenge, particularly after CAR-T cell therapy or bispecific antibodies, where prognosis is dismal with no standard treatment. VIPOR(P) is a biologically guided, multi-targeted regimen combining venetoclax (V), ibrutinib (i), prednisone (P), obinutuzumab (O), and lenalidomide (R) ± polatuzumab vedotin (P). The pivotal phase 1b/2 trial achieved an overall response rate (ORR) of 54% and a complete response (CR) rate of 38%, with preferential activity in ABC-DLBCL and high-grade B-cell lymphomas (HGBCL) harboring MYC and BCL2 rearrangements (Melani et al NEJM 2024). The use of multi-targeted agents prompted concerns about the real-world use of VIPOR(P) due to cumulative toxicity, particularly infections in late-line patients. Moreover, the potential of VIPOR(P) as a bridge-to-CAR-T, especially in chemotherapy-refractory patients, remains unexplored.MethodsWe conducted a retrospective, multicenter study of 56 patients with r/r LBCL treated with VIPOR (77%) or VIPOR(P) (23%) across 18 German and Austrian centers between March 2021 and December 2024 (intention to treat [ITT] cohort). Patients were analyzed in the ITT cohort (n=56), and two subcohorts: i) sustained therapy ≥2 cycles (n=24), and ii) bridge-to-CAR-T (n=17). Response assessment by CT/PET-CT, toxicities per CTCAE v5.0. Whole transcriptome and whole exome sequencing were performed to define cell-of-origin (COO) and genetic subtypes (DLBclass and LymphGen).ResultsWithin the ITT cohort, the median age was 60 years (28–76). Patients were heavily pretreated with a median of 4 prior lines (range 1–12) and poor prognostic features: stage III–IV in 91% and elevated LDH in 93%. Overall, 91% had IPI ≥3 before VIPOR(P), 82% were refractory to the last therapy, and 39% had prior CAR-T cell exposure. Histologies included DLBCL, NOS (57%, thereof 69% ABC, 31% GCB), HGBCL with MYC/BCL2 and/or BCL6 rearrangements (30%), HGBCL, NOS (11%), THRLBCL (2%) and transformed indolent lymphomas (27%, also in other histological subgroups as appropriate).Toxicity exceeded pivotal trial rates, reflecting the late-line, frail population, but was manageable with supportive care. Specifically, hematologic toxicity predominated: neutropenia (grade 3/4 56%), thrombocytopenia (grade 3/4 50%), anemia (grade 3/4 40%), and febrile neutropenia (30%, all grades). Grade 3/4 infections occurred in 25% (4 fatal). Two further patients died of a pulmonary embolism and renal failure. Non-hematologic toxicities included transaminitis (61%), hypokalemia (55%), and nausea (27%) and vomiting (28%).VIPOR(P) induced meaningful responses despite high-risk disease characteristics. ORR/CR rates were 45%/13% (ITT), 61%/22% (sustained), and 50%/0% (bridge-to-CAR-T). Molecular stratification underscored the selectivity of VIPOR(P) for specific LBCL subtypes: Responses were enriched in ABC-DLBCL: ORR 71% (ITT), 80% (sustained), and 100% (bridge-to-CAR-T), while no GCB-DLBCL patients responded. Transformed lymphomas demonstrated few delayed but durable responses exceeding 18 months (ORR: 22%). Among 18 WES-profiled patients, 11 pts had high-risk C2 DLBCLs, with biallelic TP53 inactivation and chemo resistance. A trend toward longer PFS was seen in HGBCL-BCL2 and triple-hit cases as well as transformed lymphoma, while HGBCL-NOS responded poorly.Median follow-up was 6 months; median progression-free survival (PFS) and overall survival (OS) in the ITT cohort were 4 and 5 months, respectively. Twelve-month PFS for imaging-assessed patients was 43% (95% CI: 28-67) (ITT), 55% (35-88) (sustained), and 55% (30-100) (bridge-to-CAR-T), and 12-month OS was 25% (95% CI: 13-46), 42% (22-80), and 42% (20-86), respectively. VIPOR(P) successfully bridged 36% of patients to CAR-T and 9% to allo-HSCT, and 22 patients remained alive at data cutoff.ConclusionsVIPOR(P) demonstrated clinically meaningful activity and a manageable safety profile in r/r LBCL refractory to chemo-immunotherapies. Responses dominated in ABC-DLBCL, aligning with the biologically guided design. Despite higher hematological toxicity observed in more heavily pretreated patients than in the pivotal trial, durable responses in sustained responders and successful bridging of chemo-refractory patients to CAR-T cell therapy highlight the relevance of multi-targeted, chemo-free combination therapies for the treatment of r/r LBCL.

*contributed equally as first author

This content is only available as a PDF.
2025
Sign in via your Institution