Long-term outcomes in Waldenström macroglobulinemia (WM) patients who discontinue Bruton tyrosine kinase inhibitor (BTKi) therapy.

e19082 Background: BTKis have revolutionized the care of Waldenström macroglobulinemia (WM); however, treatment duration can be limited by adverse events (AEs) and disease progression (PD). Given the dearth of real-world data, we examined the outcomes of patients (pts) following BTKi discontinuation. Methods: We retrospectively analyzed data from all pts treated with BTKi at MD Anderson Cancer Center for frontline or relapsed/refractory (R/R) WM between 1/2014 to 3/2024. Outcomes were determined relative to first BTKi therapy; International Waldenstrom Macroglobulinemia Foundation (IWMF) criteria were used to assess clinical response. Results: Data from 153 pts (39% frontline, 61% R/R) were analyzed. Among all pts, 70% (106/152 pts) achieved a ≥partial response (PR) to 1 st BTKi therapy. With a median follow-up of 65 months (mos) from start of BTKi, median progression-free survival (mPFS) was 77 mos (5-year: 58%) and overall survival (mOS) was not reached (NR; 5-year: 77%). At last follow-up, 71% (108/153 pts) had discontinued (dc’d) treatment with their 1 st BTKi. Baseline demographics, IPSS-WM score, and disease-related factors were comparable between those who dc’d vs. remained on 1st BTKi; among those who dc’d 1 st BTKi more pts had received ibrutinib (88% vs 49%, p<0.001). Next-generation sequencing data (available in 44 pts) demonstrated comparable mutational incidences of MYD88 (85% vs 82%), CXCR4 (38% vs 28%), and TP53 (10% vs 14%) comparing dc’d vs. active BTKi groups (all p>0.05). The median time on therapy was 12 mos for pts who dc’d therapy, with reasons for discontinuation being AEs in 44% (47/108 pts), PD/large cell lymphoma transformation in 27% (29/108), physician/pt choice in 24% (26/108) and other in 6% (6/108). From the date of BTKi discontinuation, mOS was 106 mos, with comparable OS stratified by discontinuation reason (p=0.42): AE (106 mos), PD (NR) or physician/pt discretion (NR) (p>0.05). After discontinuation, 78% (n=84) received subsequent treatment; of these, 45% (38/84 pts) received chemotherapy + anti-CD20 antibody, 26% (22/84) an alternate BTKi-based regimen, 6% (5/84) rituximab alone, 10% (8/84) venetoclax, and 13% (11/84) other therapies. On next line after BTKi, 49% of pts achieved ≥ PR, and median PFS and major response rates were statistically comparable (all p>0.05) between next-line regimens (mPFS, ≥PR): BTKi (38 mos; 41% - 9/22 pts), chemo/anti-CD20 (20 mos; 53% -20/38), rituximab alone (85 mos; 60% - 3/5), venetoclax (10 mos; 50% - 4/8), and other (22 mos; 45% - 5/11). Conclusions: Following first BTKi therapy, pts can achieve prolonged long-term survival outcomes regardless of reason for discontinuation. For next line treatment, a comparably strong response rate was found with a variety of therapeutic strategies, including subsequent BTKi-based regimens. Large, randomized studies are needed to determine the best therapy post-BTKi.