Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide) in Relapsed/Refractory and Untreated Mantle Cell Lymphoma: Safety, Efficacy, and Molecular Analysis

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.3537-3537
• Main Authors: Melani, Christopher, Lakhotia, Rahul, Pittaluga, Stefania, Miljkovic, Milos D., Phelan, James D., Muppidi, Jagan R., Thomas, Craig J., Ceribelli, Michele, Juanitez, Anna Marie, Pradhan, Amynah, Hillsman, Amy, Steinberg, Seth M., Jaffe, Elaine S., Roschewski, Mark, Staudt, Louis M., Wilson, Wyndham H.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-147032

Background: Mantle cell lymphoma (MCL) is a biologically and clinically heterogenous B-cell lymphoma that is generally incurable with standard therapies. Novel targeted agents can disrupt key survival pathways in MCL such as regulation of apoptosis (BCL2: venetoclax), B-cell receptor signaling (BTK: ibrutinib), and NF-κB survival pathways (IRF4/SPIB: lenalidomide). As monotherapy, these agents fail to induce deep responses and doublet/triplet regimens often require continuous or maintenance therapy. ViPOR has been shown to be safe and active in non-MCL NHL pts without significant tumor lysis syndrome (TLS) (Melani et al. Blood. 2020; 136(Supplement 1):44-45). We hypothesized that combining agents that target multiple survival pathways with ViPOR will leverage efficacy and time-limited, cyclic dosing will limit toxicities in MCL. Methods: Relapsed/refractory (R/R) and untreated MCL pts with adequate organ function were eligible. In R/R MCL, a phase I “3+3” design was used to determine the maximum tolerated dose (MTD) of 2 dose-levels of dose-escalated venetoclax (200mg and 400mg) PO D2-14 (starting C2) in combination with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14. A phase II expansion in untreated MCL was included at the MTD. ViPOR q21d x 6C was given without maintenance or consolidation. All pts were admitted C2 for 12d venetoclax escalation and TLS monitoring. All pts received TLS prophylaxis (ppx) with IVFs and allopurinol as well as PCP and G-CSF ppx. VTE ppx was per investigator discretion. Baseline CT, PET, BM, and tumor biopsy was performed with CT scans after cycles 1, 2, 4, and 6 and PET after cycle 6 or at time of suspected complete response (CR). Surveillance CT was performed q3m for 1y, q4m x 1y, q6m x 1y, then annually x 2y. Plasma for ctDNA was collected at baseline, prior to each treatment cycle, at each follow-up visit, and at disease progression. Results: 11 pts have been enrolled and treated; 9 (82%) R/R in dose-escalation and 2 (18%) untreated in dose-expansion. Median age was 71y (range 57-79) with 73% >65y and 64% male. Low, intermediate, and high-risk MIPI occurred in 18%, 64%, and 18% of pts, respectively. Stage IV disease was seen in 91%, with BM involvement in 73%, extranodal disease in 82%, and both in 64%. Disease bulk >5cm occurred in 45% of pts. Blastoid morphology, Ki-67 >30%, and TP53 IHC >50% occurred in 27%, 36%, and 18% of pts, respectively. Me