Combination of Ibrutinib with Rituximab (IR) in Previously Untreated Older Patients with Mantle Cell Lymphoma (MCL) - a Phase II Clinical Trial

Background - Older patients (pts) with mantle cell lymphoma (MCL) may exhibit poor functional status and become ineligible for intensive chemo-immunotherapy or stem cell transplantation. The advent of chemotherapy-free therapies are a significant advance in MCL. We investigated the safety and efficacy of combining ibrutinib and rituximab (IR) in previously untreated older pts (age ≥65 years) with MCL in a single center, phase II clinical trial.

Methods - We enrolled previously untreated pts with MCL ≥65 years (n=50) in this study (NCT01880567). Pts with Ki-67% ≥ 50%, blastoid/pleomorphic histology and those with clinically uncontrolled co-morbidities (including atrial fibrillation) were excluded from this study. Pts received ibrutinib 560 mg orally daily for 28 days (one cycle) continued until disease progression or discontinued for any reason. Rituximab was given on days 1, 8, 15 and 22 +/- 1 day by IV infusion at a fixed dose of 375 mg/m2 in cycle 1, followed by rituximab on day 1 of every cycle for cycles 3 - 8. Following cycle 8, rituximab was given on day 1 every 2 months for up to 2 years. The primary objective was to assess the safety and response of IR. For pts with evaluable samples, minimal residual disease (MRD) by flow cytometry at best response, whole exome (WES) and bulk RNA sequencing from baseline tissue samples was performed.

Results - Among 50 pts enrolled, the median age was 71 years (range 65-84), 76% were males, ECOG PS was (0) in 42 (84%) pts, 16% had high risk MCL international prognostic index, 48 (96%) pts had initial bone marrow involvement, and 19 (79%) of 24 evaluable pts had baseline GI involvement by MCL. The Ki-67% was low (<30%) in 38 (76%) and high (≥30-50%) in 12 (24%) pts, 21/47 pts had positive SOX-11, 3 pts had TP53 mutations (by targeted seq in 7 pts) and 4 pts had complex karyotype. Overall, the median number of IR cycles was 21 (range 1-59). At the time of last follow up, 24 pts remained on study and 26 (52%) discontinued therapy for various reasons - atrial fibrillation (n=10; 6 had new onset and 4 had prior history of atrial fibrillation), disease progression (n=4), bleeding (n=4; 2 were on systemic anticoagulation, 1 pt was on aspirin 81 mg and 1 pt had vitreous surgery), infections (n=2) and 1 pt each due to myocardial infarction, hypertension and chest pain, colitis, joint pains, esophageal cancer (unlikely related to drug) and patient choice). Dose reduction was performed in 29 (58%) pts for various reasons (7 atrial fibrillation, 5 infections, 5 bleeding, 5 myalgias and 7 miscellaneous). Overall 17/50 (34%) developed atrial fibrillation, 9/17 (53%) were pts without prior history of atrial fibrillation and 6/9 pts had baseline EKG abnormalities. Median time to onset of atrial fibrillation from the start of treatment was 9.4 months (range 1.3-48). Most frequent grade 3-4 toxicities were 22% atrial fibrillation 18% fatigue, 14% diarrhea, 14% myalgias, 14% shortness of breath, 8% neutropenia and 8% pain. None of the pts had any grade 5 toxicities. Three pts were not evaluable for response assessment. The best overall response (ORR) was 96% (66% CR, 30% PR, 4% stable disease). ORR and CR among pts who developed atrial fibrillation (n=17) were 76% and 47% while they were 97% and 70% in pts who did not develop atrial fibrillation (n=33). Median number of IR cycles to reach CR was 8 (range 3-51). Overall, the median follow up was 36.2 months (6-48). Four pts progressed (3 transformed to blastoid/pleomorphic MCL) on study after taking IR for 4, 9, 13 and 33 months. Two pts died (one due to disease progression and another unknown etiology). The median PFS and OS were not reached. Among pts with low and high Ki-67%, median PFS was not reached in both groups (p=0.21) and OS was not reached (p=0.009). Pts who achieved CR had a clear trend of longer PFS and OS compared to those who didn't achieve CR. Differential overexpression of genes CCND1, BIRC3, BANK1, AXIN2, RRAS2, SETBP1, FCGR2B and IL2RA was noted in PR (n=7) vs CR (n=9) pts where the data was evaluable.

Conclusions - IR combination is highly effective chemo-free option to treat elderly pts with MCL. The increased incidence of arrhythmia observed in our study is likely due to high number of cardio-vascular risk factors in this population. This suggests that baseline cardiac evaluation and cardiovascular risk factor modification should be added to IR therapy. Studies on molecular response predictors to ibrutinib will be reported.

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