Ibrutinib‐rituximab and venetoclax (irv) followed by risk‐stratified r‐hypercvad/mtx in young patients with untreated mantle cell lymphoma—phase‐ii window‐2 trial

Introduction: We investigated the efficacy and safety of ibrutinib, rituximab (IR) and venetoclax (IRV) followed by risk-stratified short course R-HCVAD/MTX-ARA-C as consolidation and IRV maintenance in previously untreated young patients (pts) (≤65 yrs) with MCL (mantle cell lymphoma). We anticipated that using a triplet chemotherapy-free induction would minimize chemotherapy exposure. Methods: We enrolled 50 previously untreated pts in this single institution, single arm, phase II clinical trial—NCT03710772. Pts received IR induction (Part-1) and added dose ramp-up venetoclax (400 mg) at cycle 5. Pts were stratified into three risk groups: high, moderate and low risk from baseline data and assigned to R-HCVAD/MTX-ARA-C as consolidation in part 2 (4 cycles, 2 cycles, or no chemotherapy for high, medium and low risk pts respectively). Low risk pts (Ki-67 ≤30%, tumor mass <3 cm, low MIPI score and no high risk features), High risk pts (Ki-67 ≥50%, mutations in the TP53, NSD2 or in NOTCH genes, or tumor diameter >5 cm or blastoid/pleomorphic histology). Medium risk pts did not belong to low or high-risk categories. After part 2 consolidation, all pts received 2 years of IRV maintenance. The primary objective was to assess CR rates after IRV induction. Adverse events were coded as per CTCAE version 4. Results: Among the 50 pts, the median age was 58 years (range: 35–65). There were 21 pts in the high-risk group, 18 pts in the intermediate-risk group and 11 pts in the low-risk group. Forty-eight pts received IRV. Two pts couldn’t start venetoclax due to progression on IR and on-study death prior to venetoclax. Best response to IRV was 100% and CR of 100%. The median number of cycles of triplet IRV to reach best response was 8 cycles (range 2–12). Sixteen pts (30%) did not receive part 2 chemotherapy (11 were low risk and 5 pts other reasons). With a median follow up of 41 (range: 25–50) months, median PFS and OS were not reached (3 year 85% and 86% respectively). Median PFS and OS were not reached and not significantly different in pts with high and low Ki-67% or with/without TP53 aberrations or among pts with low, medium or high-risk categories. Twenty-seven pts (54%) came off study—20 for adverse events (9 COVID related and 11 non-COVID related), 3 deaths, and 4 patient choice. Overall, 7 pts died (2 on trial, one off study with progression and 4 due to COVID pneumonia in CR). Grade 3–4 toxicities on part 1 included 10% myelosuppression and 10% each with fatigue, myalgia and rashes and 3% mucositis. One pt developed grade 3 atrial flutter during part 1. None had grade 3–4 bleeding/bruising. Encore Abstract—previously submitted to regional or national meetings (up to <1’000 attendees) The research was funded by: Janssen and abbvie Keywords: combination therapies, molecular targeted therapies Conflicts of interests pertinent to the abstract M. Wang Consultant or advisory role: Consultancy—InnoCare, Loxo Oncology, Juno, Oncternal, CStone, AstraZeneca, Janssen, VelosBio, Pharmacyclics, Genentech, Bayer Healthcare Honoraria: Janssen, Acerta Pharma, OMI, Physicians Education Resources, Dava Oncology, CAHON, Hebei Cancer Prevention Federation, Clinical Care Options, Mumbai Hematology Group, Anticancer Association, Newbridge Pharmaceuticals Research funding: Pharmacyclics, Janssen, AstraZeneca, Celgene, Loxo Oncology, Kite Pharma, Juno, BioInvent, VelosBio, Acerta Pharma, Oncternal, Verastem, Molecular Templates, Lilly, Innocare