First- versus second-generation Bruton tyrosine kinase inhibitors in Waldenstrom's Macroglobulinemia: A systematic review and meta-analysis

Bruton tyrosine kinase inhibitors (BTKi) are important treatment options in Waldenstrom's macroglobulinemia (WM). Whether second-generation BTKi are associated with improved outcomes and/or better safety profile remains unclear. We did a systematic review and meta-analysis of clinical trials that reported data on the outcomes of patients with WM who received either first- or second-generation BTKi in the period between January 2010 and August 2021. Studies with twenty or fewer patients were excluded. The primary outcomes were efficacy measured by response and survival data. Eleven studies met the eligibility criteria and were included in the final analysis (n = 730 patients). A total of 298 patients received 1st-generation BTKi and 432 received a 2nd-generation BTKi. Pooled overall response rate (ORR) and major response rate (MRR) for both generations were similar (94.2% and 78.5% in 1st vs. 88.9% and 75.1% in 2nd, respectively). MRR for both generations was higher in MYD88 Mut/CXCR4 WT patients compared to MYD88 Mut/CXCR4 Mut patients (odds ratio [OR]: 3.9, 95% CI: 2.2 to 5.5). Pooled 18-mo progression-free survival (PFS) was similar for both generations (88.5% vs. 87.3%). Grade 3/4 atrial fibrillation was higher in 1st-generation BTKi (3.1% vs. 0.4%); however, grade-3/-4 infections and neutropenia were more frequent in 2nd-generarion BTKi (20.9% vs. 13.2%, 17.7% vs. 12%, respectively). The efficacy of 1st- and 2nd-generation BTKis is comparable. The 1st-generation BTKi were associated with a higher risk of atrial fibrillation, whereas infections and neutropenia occurred more frequently in 2nd-generation BTKi.