Efficacy of acalabrutinib in treatment-naive Mantle Cell Lymphoma: A systematic review and meta-analysis

Abstract Background: Mantle cell lymphoma (MCL) is a rare and typically aggressive subtype of non-Hodgkin's lymphoma. While MCL is largely incurable, survival rates have improved with advancements in therapy, and new treatment options are being actively explored for patients with untreated disease. Acalabrutinib is a next-generation, potent, and selective Bruton's tyrosine kinase inhibitor (BTKi) that offers advantages over ibrutinib and other BTKis due to its improved safety profile. This systematic review and meta-analysis evaluates the pooled efficacy of acalabrutinib-based combination therapy in treatment-naïve (TN) MCL, focusing on overall response rate (ORR), complete response rate (CRR), overall survival (OS), and progression-free survival (PFS). Methods: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. A comprehensive literature search was performed across PubMed, Embase, and the Cochrane Library. From 302 identified articles, 256 unique records were screened, and 36 full-text articles were assessed for eligibility. Studies reporting efficacy outcomes of acalabrutinib-based combination regimens in TN MCL were included. In cases of duplicate trial reporting across different phases, the version with the longest follow-up or the most comprehensive data was selected. The ROB-2 tool was used to assess risk of bias. Pooled proportions and 95% confidence intervals (CIs) were estimated using a random-effects model with inverse variance weighting. Heterogeneity was evaluated using I² and Chi² tests. Results: Ten studies assessing 802 patients were included in the analysis of treatment endpoints. The pooled ORR was 95.34% (95% CI: 92.76–97.46) with low heterogeneity (I² = 18.4%, p = 0.2739), indicating consistent and favorable activity. The pooled CRR was 78.56% (95% CI: 68.44–87.29), though heterogeneity was high (I² = 86.9%, p < 0.0001), suggesting variability in complete remission rates across studies. The pooled OS from eight studies was 91.26% (95% CI: 84.53–96.43) with moderately high heterogeneity (I² = 64.4%, p = 0.0063). The pooled PFS from seven studies was 82.14% (95% CI: 71.41–90.98), with moderate heterogeneity (I² = 67.7%, p = 0.0049). Overall, acalabrutinib-based combination therapy demonstrated strong efficacy across all endpoints, supporting its role in the frontline setting.Conclusion: This meta-analysis provides evidence supporting the efficacy of acalabrutinib-based combination therapy in newly diagnosed MCL, as demonstrated by the high overall and complete response rates. The prolonged PFS and favorable OS further indicate optimal therapeutic potential and underscore its capacity to achieve durable remissions. These findings suggest that acalabrutinib-containing regimens may offer meaningful clinical benefit when introduced earlier in the treatment course. Nonetheless, certain limitations warrant consideration, including the relatively small number of studies, variability in combination partners, and differences in follow-up duration across trials, which may influence pooled estimates. In conclusion, acalabrutinib-based combinations demonstrate substantial therapeutic promise in the frontline treatment of MCL, with a favorable safety profile and consistent efficacy across key clinical endpoints. These results support further evaluation in randomized controlled trials and provide a rationale for incorporating acalabrutinib into future first-line treatment strategies.