Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma

Abstract

Purpose: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years).

Methods: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed.

Results: The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response.

Conclusion: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

Trial registration: ClinicalTrials.gov NCT01880567 NCT02427620.

FIG 1.

Flowchart of patient treatment and disposition. The induction treatment consisted of ibrutinib administered at 560 mg once daily on days 1-28 of a 28-day cycle and rituximab weekly for 4 weeks during cycle 1 and then 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. Of the 50 patients enrolled, 28 came off study for various reasons.

FIG 2.

Survival outcomes after a median follow-up of 45 months. (A) The median PFS in all patients was not reached. (B) PFS by Ki-67% was not significantly different in high (Ki-67% ≥ 30%) versus low Ki-67% (< 30%) although higher hazard of progression was noted in those patients with high Ki-67%, HR of 2.62, P = .190. (C) PFS by CR status. Patients who achieved CR as the best response to IR therapy had a significantly better PFS compared with those patients without CR as the best response, P = .003. (D) The median OS in all patients was not reached. (E) OS by Ki-67% was not significantly different between low and high Ki-67% categories (P = .356). (F) OS by CR status. Patients who achieved CR as the best response to IR therapy had a significantly better OS compared with those patients without CR as the best response, P = .002. CR, complete response; HR, hazard ratio; IR, ibrutinib-rituximab; OS, overall survival; PFS, progression-free survival.

FIG 3.

Somatic mutation profile by WES and transcriptomic profile by bulk RNA sequencing and differential gene expression in patients, on the basis of achieving CR (C1) or PR (C2) after treatment with ibrutinib-rituximab. (A) The landscape of somatic mutations from pretreatment MCL samples (n = 25). The bottom panel shows somatic mutations and gene-level copy number alterations by sample (column) and by gene (row). The middle tracks display the clinical characteristics. The histogram on the top shows the number of alterations accumulated on 28 listed genes in each individual patient. The right bar plots show the composite of all mutations between CR (C1) and PR (C2) groups. Fisher's exact test, P < .05. (B) Composite of copy number profiles between CR and PR groups, with gains in red and losses in blue. The regions that showed a difference in the frequency of copy number alterations between two subtypes are shaded in light red rectangles, and within which the names of cancer-related or biologically important genes are labeled (STAB1, FAT1, FAT4, KMT2C, MALT1, SMARCA4, ROS1, NCOR2, and RB1). (C) Transcriptomic profile of baseline tumor specimens from 16 patients with MCL is shown, CR (C1) and PR (C2). Unsupervised hierarchical clustering of DEGs on RNA-seq analysis is shown. Genes with log₂(fold change) > 1 and a FDR q < 0.05 were applied to filter DEGs. Biologically important genes are labeled on the right of the plot. The top tracks show clinical characteristics among the samples. A Fisher's exact test is used to identify significant clinical factors; response was significantly correlated with the DEGs (P = .003). (D) Violin plot indicates biologically important DEGs among the three clusters. BM, bone marrow; CR, complete response; DEG, differentially expressed gene; FDR, false discovery rate; MCL, mantle cell lymphoma; PR, partial response; WES, whole-exome sequencing.