Objectives: Most MCL patients relapse after first-line therapy, and disease progression after subsequent BTKi therapy (post-BTKi) often leads to poor outcomes. A systematic literature review and meta-analysis were conducted to estimate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) post-BTKi in patients with R/R MCL.

Methods: Databases (MEDLINE, EMBASE, Cochrane) were searched through January 2020 for studies reporting ORR and/or Kaplan-Meier curves for OS/PFS in patients with R/R MCL treated post-BTKi. The base-case meta-analysis included studies reporting outcomes for various systemic treatments (i.e. mixed treatments) and scenario analysis included additional single-therapy studies evaluating venetoclax, R-BAC, or RiBVD. A generalized linear mixed model was used for pooling ORR. For OS/PFS, alternative parametric survival models were fitted to the Kaplan-Meier curves and parameters of the best-fitting model (i.e. log-normal) were synthesized in a Bayesian framework to estimate between-study heterogeneity and pooled absolute treatment effects. Fixed-effect and random-effects (FE, RE) models were evaluated.

Results: Eight studies (n=7 retrospective observational; n=1 RCT) involving 297 post-BTKi patients (12-73 patients/study) were included in the meta-analysis (pooled characteristics: age 67 years, 77% male, median 2-4 prior therapies, 19% blastoid morphology, 77% Ki-67≥30%, 88% ECOG score 0/1). In the base-case (n=5 studies), the pooled ORR estimate from the RE model was 28% (95% CI: 23%, 34%). In scenario analysis (n=8 studies), the pooled ORR estimate was 43% (95% CI: 27%, 60%), with the RE model preferred due to between-study heterogeneity. Median OS and PFS were 9.5 (95% CI: 5.4, 20.5) months and 6.1 (95% CI: 3.5, 12.8) months, respectively. Across all OS scenarios (different treatments assessed, different start-time of OS measurements), median OS ranged between 8.1-10.7 months.

Conclusions: This meta-analysis of historical salvage therapy demonstrates poor responses and suboptimal survival outcomes with the limited therapeutic options available for post-BTKi R/R MCL.