PHASE I STUDY OF BENDAMUSTINE, RITUXIMAB, IBRUTINIB, AND VENETOCLAX IN RELAPSED, REFRACTORY MANTLE CELL LYMPHOMA

Abstract

Introduction: Bendamustine (B) and rituximab (R) with ibrutinib (IBR) was well-tolerated and efficacious (Maddocks Blood 2015). Ibrutinib and venetoclax (VEN) were synergistic and active in relapsed, refractory (R/R) MCL (Tam NEJM 2018). VEN increases apoptotic priming and can act as a chemosensitizing agent. The aim of this phase I study was to define the safety and tolerability of VEN with BR-IBR in R/R MCL (Clinical trial: NCT03295240). Methods: Patients (pts) with R/R MCL received six 28-day cycles of BR-IBR-VEN in a 3+3 dose escalation design. Dose level 1 (DL1) included B 90 mg/m2 day (d) 1 and 2, R 375 mg/m2 d1, and IBR 560mg daily. For cycle 1, VEN dose ramp-up was 20, 50, 100, and 200mg daily weekly. During cycles 2-6, VEN 400mg daily was given d1-5. Dosing cohorts with longer duration of VEN (7d and 10d) were planned. The study was amended to include dose level-1 (DL-1) with B at 70mg/m2, d1 and 2. Results: As of March 2021, 7 pts were treated with BR-IBR-VEN at DL1 and 3 pts at DL-1. Baseline characteristics were median age 68 years (range 60-81);90% male;80% with Ki67 ≥30%;10% blastic MCL;40% TP53 mutant, and 100% one prior line of treatment (tx). One dose limiting toxicity (DLT) was observed at DL1: grade 3 thrombocytopenia lasting >14 days. At DL1, 2 pts had only 5 cycles of BR-IBR-VEN due to cytopenias (grade 3 neutropenia and grade 2 thrombocytopenia) despite B dose reduction. The frequent tx-related adverse events (AEs) were thrombocytopenia (n = 7), constipation (n = 6), fatigue (n = 4), neutropenia (n = 3), and nausea (n = 4). The grade 3-4 AEs were neutropenia (n = 1) thrombocytopenia (n = 3), and rash (n = 1). There was one tx-related serious AE: an elderly pt was briefly hospitalized during VEN ramp-up for volume overload and diuretic tx. Most pts had count recovery post-tx, but one had persistent neutropenia. Given cytopenias observed at DL1, the study was amended to include DL-1. At DL-1 (n = 3), there were no DLTs, dose reductions or delays, significant cytopenias, or ≥grade 3 txrelated AEs. The overall response rate (ORR) was 80% (8/10), all complete responses (CRs). For TP53 mutant MCL, the ORR was 50% (2/4), all CRs. There were 5 deaths (Fig 1). Two TP53 mutant MCL pts with primary refractory disease died of disease rapidly. A 17p deleted MCL pt achieved a CR and underwent allogeneic stem cell transplant and died of pneumonia (PNA) 10 mos after. A pt in CR with post-tx neutropenia died of PNA. The TP53 mutant MCL pt with a DLT after 2 cycles of BR-IBR-VEN received single-agent BTKi for 27 mos until progression and then died of COVID. Conclusions: BR-IBR-VEN showed acceptable safety and tolerability and preliminary efficacy at DL-1. During the COVID pandemic, enrollment for this immunosuppressive 4-drug regimen with intravenous tx was challenging. The study was closed after enrolling 3 of 6 pts at DL-1 and a definitive maximum tolerated dose was not determined. Future study is needed to determine the role of BR-IBR-VEN in MCL.