A Pilot Study of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (VIPOR) for Diffuse Large B-Cell Lymphoma Involving the Central Nervous System

Background: Primary diffuse large B-cell lymphoma (DLBCL) of the CNS (PCNSL) and secondary CNS involvement with DLBCL (SCNSL) have an overall poor prognosis. High-dose chemotherapy cures a subset of younger patients, but those who relapse after or are ineligible for intensive therapy are rarely cured. The molecular biology of PCNSL and non-GCB SCNSL involves chronic active BCR signaling targetable by BTK-inhibitor (BTKi) based therapy. We developed the multi-targeted therapy combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (VIPOR) and demonstrated curative potential in relapsed and refractory systemic non-GCB DLBCL (Melani et al. N Engl J Med 2024). VIPOR is a synergistic combination that overcomes resistance to both chemotherapy and prior treatment with BTKi. Here, we show results of a pilot study testing VIPOR in pts with CNS lymphoma who have relapsed after or are ineligible for high-dose chemotherapy.

Methods: Pts with PCNSL or non-GCB SCNSL, and adequate organ function were eligible. Pts had either relapsed after or were ineligible for high-dose methotrexate (HD-MTX) (advanced age, effusions, renal dysfunction). Prior BTKi was allowed. Staging included baseline MRI brain, CSF flow cytometry, PET/CT brain and body, eye exam, and bone marrow. In the original study design, pts first received nivolumab 200mg IV x 1 and lenalidomide 15mg x 14 days in a 21-day window, followed by up to six 21-day cycles of nivolumab 200mg IV D1, venetoclax 800mg PO D2-14, ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. No doses were escalated. The study was later amended to remove the 21-day window, and all pts received up to 6 cycles of VIPOR alone without maintenance or planned consolidation. Response assessments with brain MRI and PET/CT scans were done after cycles 1, 3, and 6. All complete responses by brain MRI were confirmed with PET brain and CSF analysis. Surveillance imaging with brain MRI and CT body were performed q3m for 1y, q4m for 1y, q6m for 1y, then annually. The primary objective was to assess the safety and tolerability of VIPOR in CNS lymphomas. Secondary objectives included overall response rate and duration of response.

Results: Overall, 14 pts were enrolled, including 9 with PCNSL and 5 with SCNSL. In the PCNSL cohort, 5 (56%) had brain only involvement and 4 (44%) had both brain and CSF involvement. In the SCNSL cohort, 3 (60%) had CNS only involvement and 2 (40%) had both systemic and CNS involvement. Median age was 66 (range 54-86) and 9 (64%) pts were male. Nine (64%) pts were White, 4 (29%) were Black, and 1 (7%) was Asian. Ten (71%) patients had primary refractory disease. Median prior lines of therapy was 2 (range 1-6), including 10 (71%) pts with prior BTKi, 9 (64%) with prior HD-MTX, 4 (29%) with prior autologous stem cell transplant, and 1 (7%) with prior CAR-19. After 4 pts enrolled, a pt developed grade 4 autoimmune hepatitis during window and did not receive VIPOR (response unevaluable). The study was amended to treat with VIPOR only without nivolumab and no window. Of 56 cycles administered, G3-4 thrombocytopenia occurred in 9 (16%), neutropenia in 5 (9%), anemia in 2 (3%), and febrile neutropenia in 1 (2%) pt. Grade 3 or higher non-hematologic toxicities were uncommon and included hypokalemia in 3 (21%) pts. Ten (71%) pts had grade 1 or 2 diarrhea that required anti-diarrheal agents, and 7 (50%) pts required potassium supplements. Eight (57%) pts stopped therapy prematurely due to progression (N=4), myocardial infarction (N=1, unrelated), renal insufficiency (N=1, unrelated), pneumonia (N=1, related), and autoimmune hepatitis (N=1, related). Of 13 evaluable pts, 8 (62%) responded including 4 (31%) who achieved a CR. In 9 pts treated with prior BTKi, 6 (67%) responded including 2 (22%) pts who achieved CR. Two patients who achieved a CR remained free from progression, both of whom had not received prior BTKi. Both patients with concomitant systemic disease and CNS involvement responded in both compartments.

Conclusion: VIPOR is safe in CNS lymphoma without any additional toxicities than those observed in systemic DLBCL. VIPOR can overcome treatment resistance to both HD-MTX and BTKi-based therapy, although durable remissions may be more likely in BTKi-naïve patients. Further studies testing multi-targeted combination regimens are warranted in both PCNSL and SCNSL.