Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed/Refractory (R/R) and Treatment-Naive (TN) Mantle Cell Lymphoma (MCL)

Introduction: MCL is incurable with standard chemotherapy. Although oral targeted agents are active in MCL, they fail to induce deep responses as monotherapy and require extended duration. We developed a multi-agent targeted regimen (ViPOR) and showed it to be safe and able to induce durable CRs in R/R B-cell lymphomas (Melani et al. Blood. 2020). Here, we present data for the MCL cohort of the ongoing ViPOR study. Methods: R/R and TN MCL pts with adequate organ function were eligible. In Ph1, R/R pts were tx at 2 DLs of VEN (200 and 400 mg) to identify the RP2D. VEN was given PO D2-14 on C2-6 with an initial inpatient 12d ramp-up on C2, with fixed-dose IBRUT 560 mg PO D1-14, PRED 100 mg PO D1-7, OBIN 1000 mg IV D1-2, and LEN 15 mg PO D1-14 on C1-6. In Ph2, R/R and TN MCL pts were treated at the RP2D. ViPOR q21d × 6C was given without maintenance. TLS, G-CSF, and PCP ppx was given to all pts and VTE ppx was per PI discretion. Baseline CT, PET, BM, and tumor bx was performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m × 1y, q4m × 1y, q6m × 1y, and q12m × 2y. MRD was assessed in plasma ctDNA using clonoSEQ at baseline, during tx, and in f/u. Results: 24 MCL pts (11 R/R & 13 TN) have been enrolled. 71% were male with a median (range) age of 67y (41–82). Blastoid morphology, Ki-67 ≥30%, and TP53 mutations occurred in 29%, 38%, and 26%, respectively. High-risk MIPI and MCL35 proliferation score was noted in 21% and 19%, respectively. Median (range) prior tx in R/R was 3 (1–4) with prior BTKi in 45% and 73% refractory to last tx. No DLTs occurred and VEN 400 mg was used in Ph2. Heme AEs were most common and included G3-4 (% cycles) thrombocytopenia (17%), anemia (9%), and neutropenia (9%), with no febrile neutropenia across 126 cycles. The only non-heme G3 AE in >10% pts was hypokalemia (22%), with any grade observed in 78%. Other common non-heme AEs (% pts) included diarrhea (65%) and rash (52%). G3 A.fib occurred in 2 pts with 1 G3 VTE and no major bleeding. No TLS or tx-related mortality occurred. Dose reductions occurred in 25%, and 86% completed all 6C. All 21 (100%) off-tx pts achieved CR, including 7 blastoid, 5 TP53 mutated, 5 post-BTKi, and 8 refractory pts (Figure 1A). CRs occurred across all MIPI and MCL35 risk groups. With a median f/u of 17m, 78% of responses are ongoing (Figure 1B), with a 1y TTP, PFS, and OS of 87%, 74%, and 80%, respectively. 1y TTP was 88% in R/R, 90% in TN, 42% in blastoid, and 67% in TP53 mutated MCL. Baseline ctDNA was identified in 95% (21/22) pts, with 95% (19/20) MRD- at EOT. Median (range) duration of MRD negativity was 6m (0–25). All 3 pts with relapse after CR experienced molecular relapse prior to imaging, with a median (range) lead-time of 4m (1–6). The research was funded by the intramural program of the National Cancer Institute of the National Institutes of Health. Keywords: Indolent non-Hodgkin lymphoma, Minimal residual disease, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. L. M. Rimsza Other remuneration: Named inventor on the MCL35 assay. A. Jacob Employment or leadership position: Adaptive Biotechnologies. H. Simmons Employment or leadership position: Adaptive Biotechnologies.