Safety and efficacy of ibrutinib as a first line agent for Mantle Cell Lymphoma : A systematic review and meta-analysis Free

Background

Mantle cell lymphoma (MCL) accounts for approximately 5% of all non-Hodgkin lymphomas and is characterized by an aggressive clinical course, with a median overall survival of about 5.9 years. While standard first-line chemotherapy regimens include rituximab and bendamustine or cytarabine containing regimens, Bruton tyrosine kinase inhibitors (BTKis), such as ibrutinib and zanubrutinib, have demonstrated efficacy in relapsed or refractory MCL and are now being explored as frontline options. Notably, acalabrutinib in combination with bedamustine and rituximab has received FDA approval for treatment-naïve MCL patients who are ineligible for autologous hematopoietic stem cell transplantation (HSCT). In this systematic review and meta-analysis, we evaluate the efficacy and safety of ibrutinib as a first-line treatment for patients with MCL.

Methods

We followed PRISMA guidelines to conduct a systematic review and meta-analysis. A comprehensive search of PubMed and the Cochrane Library was performed up to July 2025 using the terms “mantle cell lymphoma” and “ibrutinib.” Eligible studies included phase II and III trials evaluating ibrutinib as monotherapy or in combination for treatment-naïve patients. Phase I trials and studies focused on relapsed/refractory MCL were excluded. We pooled objective response rates (ORR) and adverse event (AE) incidences using a DerSimonian–Laird random-effects model on logit-transformed proportions. Heterogeneity was assessed via I² and τ² statistics. Forest plots illustrated individual and pooled estimates. Sensitivity analyses included leave-one-out testing and model comparisons. Funnel plots were used to assess publication bias. All analyses were conducted in Stata v18.

Results

We included eight eligible studies comprising four phase II single-arm trials, three randomized controlled trials, and one real-world study, with a total enrollment of 1,434 patients. While one study assessed ibrutinib monotherapy, seven evaluated combination therapy. The age range extended from 38 to 94 years, and the study population was predominantly men (74%). Follow-up durations ranged from 15.6 to 84.7 months. Bone marrow involvement was reported in five studies, affecting approximately 82% of patients. The pooled ORR was 90% (95% CI: 86%–95%), indicating high efficacy, though substantial heterogeneity was present (I² = 91.16%, p < 0.001).The pooled incidence of atrial fibrillation was 10% (95% CI: 4%-17%) with substantial heterogeneity (I²=91.05%, p<0.001). The funnel plot inspection of both the outcomes showed asymmetry, suggesting possible publication bias or small-study effects, which may be partially explained by underlying heterogeneity. Using regression analysis, the coefficient for complete response rate (CR) was found to be 0.015 (p value 0.137) with age as the covariate, 0.05 (p value 0.167) with follow up period as the covariate and 0.001 (p value 0.432) with bone marrow involvement as the covariate.

Conclusions

Ibrutinib-based regimens demonstrate a high objective response rate and an acceptable safety profile when used as a first-line treatment for MCL. However, the substantial heterogeneity and potential publication bias is identified.