Background: Mantle cell lymphoma (MCL) is incurable with standard chemotherapy. Although oral targeted agents are active in MCL, they fail to induce deep responses as monotherapy and are administered chronically. We developed a fixed-duration, multi-agent targeted regimen (ViPOR) and showed it to be safe and able to induce durable complete responses (CRs) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (Melani. NEJM. 2024). We hypothesized that simultaneously targeting multiple survival pathways with ViPOR will improve efficacy and time-limited, cyclic dosing will limit toxicities in MCL.

Methods: R/Rand treatment-naïve (TN) MCL pts >18y with adequate organ function are eligible. One prior study agent (excluding prednisone and CD20 Ab) is allowed. In Ph 1b, R/R MCL pts are treated at 2 dose-levels of venetoclax (VEN) (200 & 400 mg) PO D2-14 (starting C2) with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14 to determine the recommended phase 2 dose (RP2D). In Ph 2, 20 pts each with R/R and TN MCL are treated at the RP2D. ViPOR q21d x 6C is given without maintenance or consolidation. All pts are admitted for a 12d VEN ramp-up on C2 with tumor lysis syndrome (TLS) prophylaxis (ppx) and monitoring. All pts receive PCP ppx with VTE ppx per PI discretion. G-CSF ppx is given in all R/R pts and as needed in TN pts. Baseline CT, PET, and BM is performed with CT scans after C1, C2, C4, and C6 and PET after C6. Surveillance CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then annually x 2y. Minimal residual disease (MRD) is assessed in plasma ctDNA using clonoSEQ at baseline, during treatment, and in f/u.

Results: 36 MCL pts (16 R/R & 20 TN) have been enrolled. Median age is 67y (range, 41-82) with 69% male pts. Blastoid morphology and Ki-67 >30% was seen in 25% and 37% of pts, respectively. TP53 expression >50% was observed in 19% of pts with TP53 mutations and/or deletions in 32%. High-risk MIPI and MCL35 proliferation score was present in 33% and 20% of pts, respectively. Median prior therapies in R/R pts was 3 (range, 1-7), with prior BTKi in 50%. No pts received prior VEN or lenalidomide.

No dose-limiting toxicities occurred and VEN 400 mg was identified as the RP2D. G3-4 hematologic adverse events (AEs) (% cycles) included thrombocytopenia (14%), neutropenia (13%), and anemia (10%), with no febrile neutropenia observed across 204 total cycles. Common non-hematologic AEs (% pts) of any grade included hypokalemia (89%), diarrhea (67%), and rash (58%), with the only G3 non-hematologic AEs in >10% pts being hypokalemia (25%) and rash (11%). No TLS or treatment-related mortality occurred. Dose reductions and delays occurred in 5% and 11% of cycles, respectively, and 89% of pts completed all planned 6C of therapy.

All 35 (100%) MCL pts who are now off-treatment achieved CR, including 15 R/R and 20 TN pts. Median f/u across all pts was 24.1m. In TN MCL pts, 95% of CRs are ongoing with a 2y (95% CI) time to progression (TTP), progression-free survival (PFS), and overall survival (OS) of 95% (70-99), 95% (70-99), and 100%, respectively. In R/R MCL pts, 73% of CRs are ongoing with a 2y (95% CI) TTP, PFS, and OS of 91% (51-99), 75% (41-91), and 75% (41-91), respectively. 1 R/R pt received consolidative allo-HSCT. 1 TN pt with blastoid MCL relapsed in the skin and 2 R/R pts (1 blastoid & 1 TP53 mutated) relapsed in the CNS and blood, respectively. 2 R/R pts died in remission from COVID-19. 2y TTP was 100% in TP53 mutated/deleted, 81% in Ki-67 >30%, 80% in post-BTKi, and 74% in blastoid pts. In high-risk MIPI and MCL35 pts, 2y TTP was 100% and 80%, respectively.

Baseline ctDNA was identified in 97% (31/32) pts, with undetectable MRD (uMRD) after C1, C2, and at end-of-therapy in 13% (4/31), 81% (25/31), and 97% (28/29) of pts, respectively. 95% (18/19) of TN and 83% (10/12) of R/R pts remain in continued uMRD CR, with 1 TN MRD positive CR pt relapsing 1m post-treatment and 2 R/R uMRD CR pts experiencing molecular relapse prior to imaging.

Conclusion: Fixed-duration ViPOR x 6C without maintenance achieved CR in 100% and uMRD in 97% of MCL pts, with ongoing CR in 95% and 73% of TN and R/R pts, respectively, and only 1 R/R pt receiving consolidative allo-HSCT. This includes blastoid, TP53 mutated, and post-BTKi high-risk subsets. ViPOR with a 12d VEN ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia. Enrollment continues to better define the response and durability of ViPOR in MCL.

Disclosures

Muppidi:Astra-Zeneca: Other: spouse is employed. Rimsza:MCL35 assay: Other: Inventor of intellectual property for the MCL35 assay. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Simmons:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company.

Off Label Disclosure:

ViPOR is not FDA-approved as a combination for MCL.

This content is only available as a PDF.
2024
Sign in via your Institution