Study Design and Patient Population
This is an investigator-initiated, institutional review board–approved, open-label, single-institution, single-arm, phase II clinical trial. The study was originally designed to investigate the efficacy and safety of the IR combination in relapsed MCL (reported previously) and was modified in 2015 to include a cohort of newly diagnosed elderly patients with MCL. In this study, we report the results of the 50 previously untreated elderly patients with MCL who participated in this clinical trial after obtaining informed consent as per the Declaration of Helsinki. The key eligibility criteria included the following: previously untreated elderly patients with MCL, age ≥ 65 years with nonblastoid or pleomorphic histology and/or with a Ki-67% < 50% (chosen to avoid inadequate therapy for very aggressive MCL), and an Eastern Cooperative Oncology Group performance status of ≤ 2. Patients with a history of controlled atrial fibrillation were included (Protocol, online only).
Ibrutinib was administered orally at 560 mg once daily in 28-day cycles with rituximab. Rituximab was administered as intravenous infusion at a fixed dose of 375 mg/m2 once weekly for 4 weeks in cycle 1 followed by day 1 of every cycle starting in cycles 3–8. After cycle 8, rituximab was given on day 1 of every 2 months for up to 2 years, and after 2 years, ibrutinib was administered in continuous cycles until disease progression or unacceptable toxicity or any other reason of discontinuation. None of the patients received stem-cell transplantation.
ORR included partial response (PR) and CR according to the Lugano 2014 criteria. Response assessments were performed using computed tomography scanning every two cycles until cycle 8, followed by assessments every 4 months. After achievement of CR and for patients receiving ibrutinib treatment after 2 years, response assessments were performed every 6–12 months. A 18F-fluorodeoxyglucose–positron-emission tomography (PET) scan was performed at baseline and to confirm the CR at best response. Best response is the best response that the patient had achieved while on therapy. Deauville scoring, with scores ranging from 1 to 5, with a score of 1 to 3 indicating a complete metabolic response, was used. Bone marrow examination using flow cytometry–based assay with a minimum sensitivity of 0.01%-0.1% was performed at best response, among evaluable patients who had initial evidence of bone marrow involvement by MCL. Adverse events were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0).
Among evaluable patients, DNA and RNA extraction was performed from archived formalin-fixed paraffin-embedded tissues baseline tissue samples (node, extra-nodal tissue, gastrointestinal tract, or bone marrow biopsies) with > 30% cellularity with MCL and germline samples (when available). Whole-exome sequencing (WES) and bulk RNA sequencing were performed to assess the somatic mutation profile, copy number abnormalities, and differential gene expression (DEG), and gene set enrichment analysis was performed among various response categories to identify genomic predictors of response and resistance to IR. All WES sequencing was performed with a NovaSeq6000 SP-XP flow cell using the 150bp paired end format, whereas for RNA sequencing, Illumina HiSeq4000 using the 76bp paired end configuration was used (detailed methods are given in the Data Supplement, online only).
The primary objective was to estimate ORR. The secondary objectives included PFS and overall survival (OS). PFS was measured from the treatment start date until disease progression or death whichever occurs earlier. OS was measured from the treatment start date to the date of death or last follow-up. Safety assessment was performed during every patient visit. Time to event outcomes were estimated using the Kaplan-Meier method. All statistical tests were based on a two-sided alpha level of .05. Statistical analyses were performed using Stata/SE version 16.0 statistical software (Stata Corp LP, College Station, TX).
J Clin Oncol. 2022;40(2):202-212. © 2022 American Society of Clinical Oncology