Retrospective study of venetoclax or pirtobrutinib in relapsed or refractory Waldenström macroglobulinemia

Venetoclax and pirtobrutinib are two chemotherapy-free options for relapsed or refractory Waldenström macroglobulinemia (R/R WM). A retrospective study at Dana-Farber Cancer Center (Boston, MA) compared these two treatments. Among 91 treatment exposures (64 venetoclax and 27 pirtobrutinib) across 80 consecutive patients, treatment discontinuation due to adverse events occurred in 19% of patients treated with venetoclax and none treated with pirtobrutinib. In the venetoclax cohort, TP53 alterations were associated with shorter progression-free survival (PFS; median 10.0 versus 35.6 months; p<0.001), whereas in the pirtobrutinib cohort, CXCR4 mutations predicted lower major response rate (MRR; 40% versus 91%; p=0.01) and shorter median PFS (8.3 months versus not reached; p=0.02). When transitioning from a covalent BTK inhibitor, IgM rebound occurred in 62% of patients initiating venetoclax without overlap, whereas no rebound was observed with cBTKi-venetoclax overlap or with pirtobrutinib initation. In a 1:1 matched cohort of 42 patients, venetoclax and pirtobrutinib demonstrated comparable outcomes for MRR (p=0.91) and PFS (p=0.83). The auithors conclude that these findings indicate comparable efficacy between venetoclax and pirtobrutinib with distinct molecular vulnerabilities.