Venetoclax or Pirtobrutinib in Relapsed/Refractory Waldenström Macroglobulinemia: Clinical and Molecular Predictors and Sequencing Implications

Venetoclax and pirtobrutinib have emerged as two chemotherapy-free options for relapsed or refractory Waldenström macroglobulinemia (WM). However, evidence to guide treatment sequencing or identify molecular subsets most likely to benefit from each agent remains limited. We retrospectively evaluated consecutive WM patients treated with venetoclax or pirtobrutinib. Major response rate (MRR) and progression-free survival (PFS) were assessed for each agent, with predictors of response and PFS analyzed using logistic and Cox regression. Comparative efficacy was examined in unmatched analyses and in a 1:1 matched cohort. Among 91 treatment exposures (64 venetoclax and 27 pirtobrutinib) across 80 unique patients, treatment discontinuation due to adverse effects occurred in 12 of 64 patients (19%) treated with venetoclax and in none treated with pirtobrutinib. In the venetoclax cohort, TP53 alterations were associated with shorter PFS (10.0 vs. 35.6 months; p < 0.001). In the pirtobrutinib cohort, CXCR4 mutations predicted lower MRR (40% vs. 91%; p = 0.01) and shorter PFS (8.3 months vs. not reached; p = 0.02). When transitioning from a cBTKi, IgM rebound occurred in 62% (8/13) of patients initiating venetoclax without overlap, whereas no rebound was observed with cBTKi-venetoclax overlap (0/5) or with pirtobrutinib initiation (0/15). In the matched cohort (n = 42), venetoclax and pirtobrutinib demonstrated comparable outcomes for MRR (p = 0.91) and PFS (p = 0.83). Despite the retrospective design and limited sample size, these findings indicate comparable efficacy between venetoclax and pirtobrutinib with distinct molecular vulnerabilities and support consideration of pirtobrutinib sequencing when transitioning from a cBTKi, as well as further exploration of combination strategies that may exploit complementary vulnerabilities.