Abstract Introduction: Oral targeted agents are active in MCL; however, most fail to induce deep or durable remissions as monotherapy. We developed the multi-agent ViPOR regimen to target B-cell receptor (BCR) signaling, BCL2, and CD20, and showed it to be safe and able to induce durable remissions in R/R DLBCL (Melani et al. NEJM. 2024). We hypothesized that fixed-duration ViPOR would be able to induce durable remissions in pts with MCL due to its dependence on BCR signaling and BCL2. Methods: TN and R/R MCL pts with adequate organ function were eligible. Venetoclax 400mg was given PO D2-14 on C2-6 with an initial 12d ramp-up on C2, with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14 on C1-6. ViPOR q21d x 6C was given without maintenance. TLS prophylaxis was given to all pts and R/R pts received G-CSF. Baseline CT, PET, BM, and tumor biopsy were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, and q12m x 2y. MRD was assessed in ctDNA from paired plasma and PBMC samples using clonoSEQ at baseline, during treatment, and in f/u. Results: 41 pts (21 R/R 30%, and TP53 aberration was noted in 27%, 37%, and 38%, respectively. High-risk MIPI and MCL35 proliferation score was seen in 32% and 20%, respectively. Median (range) prior therapy in R/R was 3 (1-7), with prior BTKi in 43% and 52% of pts refractory to last treatment. Among all pts, heme AEs included G3-4 (% cycles) thrombocytopenia (14%), neutropenia (13%), and anemia (10%), with no febrile neutropenia observed across 216 cycles. G3 non-heme AEs in 10% pts included hypokalemia (28%) and rash (13%). Common any grade non-heme AEs (% pts) included hypokalemia (92%), diarrhea (65%), and rash (54%). G3 A. fib and G3 VTE occurred in 2 pts each, with no major bleeding noted. No TLS or treatment-related mortality occurred. Dose reductions occurred in 27%, and 90% of pts completed all 6C. ORR and CR rate were 100% (21/21) and 95% (20/21), respectively, in R/R and both 100% (20/20) in TN MCL. CRs occurred across all MIPI and MCL35 risk groups and high-risk subsets. With a median f/u of 43m, 80% of CRs are ongoing, with a 3y TTP and PFS of 70% and 53%, respectively, in R/R, and both 95% in TN MCL. Among all pts, 3y TTP was 60% in pts with elevated Ki-67 30%, 70% in blastoid, and 71% in pts with TP53 aberration. MRD was evaluable in 98% (40/41) of pts, with undetectable MRD (uMRD) achieved in 18%, 79%, and 95% of pts after C1, C2, and at EOT, respectively. Median (range) duration of uMRD was 24m (0-53), and all 5 pts with relapse after CR experienced molecular relapse prior to imaging, with a median (range) lead-time of 4m (0-6). Conclusions: Fixed-duration ViPOR x 6C induces a high rate of uMRD CRs in R/R and TN MCL, including high-risk subsets. ViPOR with a 12d venetoclax ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia. Citation Format: Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, James D. Phelan, Jagan Muppidi, Max Gordon, Yandan Yang, Weihong Xu, Theresa Davies-Hill, Da Wei Huang, Craig J. Thomas, Michele Ceribelli, Frances A. Tosto, Anna M. Juanitez, Amynah Pradhan, Atekelt Tadese, Colleen A. Ramsower, Lisa M. Rimsza, Allison Jacob, Elaine S. Jaffe, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson. Combination targeted therapy with ViPOR in relapsed/refractory (R/R) and treatment-naïve (TN) mantle cell lymphoma (MCL): Analysis of safety, efficacy, and minimal residual disease (MRD) abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A027.
Melani et al. (Wed,) studied this question.