Associations between early on-treatment weight change and overall survival across targeted therapies in chronic lymphocytic leukemia.

Abstract

e19001 Background: Targeted therapies for chronic lymphocytic leukemia (CLL) include BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and the BCL-2 inhibitor venetoclax. We evaluated whether early on-treatment weight change after therapy initiation is associated with overall survival (OS) across agents. Methods: Using the nference nSights federated platform across multiple academic medical centers, we retrospectively identified adults with CLL (ICD-10 C91.1x) initiating ibrutinib, acalabrutinib, venetoclax, or zanubrutinib after diagnosis (>=3 encounters over >=30 days) with baseline weight within 90 days pre-initiation. Percent weight change from baseline was assessed at landmark months 1, 3, 4, and 6 post-initiation (nearest weight within +/-15 days). Cox proportional hazards models were fit by drug and timepoint for OS, adjusting for age, sex, baseline weight, baseline BMI, and diagnosis-to-treatment interval. Results: The cohort included 3,542 patients (ibrutinib 1,398; venetoclax 1,145; acalabrutinib 667; zanubrutinib 332). On-treatment weight gain was associated with improved OS for venetoclax at multiple landmarks (eg, month 3 HR 0.927; p<0.0001) and for ibrutinib at later landmarks (eg, month 6 HR 0.953; p<0.0001). Acalabrutinib and zanubrutinib were not significant at evaluated landmarks. Conclusions: On-treatment weight-trajectory metabotyping may provide a pragmatic clinical decision support signal in CLL, with drug-specific associations between weight gain and OS, strongest for venetoclax. Incorporating early weight-trajectory metabotypes into predictive risk stratification may help identify patients who could benefit from intensified supportive care, closer monitoring, or prognostic enrichment strategies during targeted therapy. Association between on-treatment weight change and OS for CLL patients. Drug Timepoint (Months) Patients C-Index HR (95% CI) p-value Ibrutinib 1 1057 0.606 0.994 (0.962-1.029) 0.747 Ibrutinib 4 889 0.612 0.968 (0.944-0.992) 0.011 Ibrutinib 6 803 0.634 0.953 (0.932-0.974) <0.0001 Acalabrutinib 6 329 0.65 0.979 (0.934-1.027) 0.386 Venetoclax 1 989 0.633 0.962 (0.926-1.000) 0.049 Venetoclax 3 888 0.657 0.927 (0.899-0.956) <0.0001 Venetoclax 4 855 0.641 0.937 (0.908-0.966) <0.0001 Venetoclax 6 678 0.652 0.933 (0.905-0.961) <0.0001 Zanubrutinib 6 178 0.716 0.928 (0.848-1.014) 0.099 HR represents risk per 1% weight change, with HR <1 indicating that weight gain is associated with reduced mortality. Only select rows with p-value<0.05 are shown.