Background: Recent population-based studies have shown that Black patients (pts) with CLL have worse overall survival (OS) than White pts with CLL. These studies could not account for the use of modern therapies, CLL prognostic variables, or comorbidity and thus the root cause of this disparity remains unclear. Here, we use the Flatiron Health Database (FHD) to study this disparity, while accounting for disease-specific variables and treatment (tx) received. Methods: Retrospective analysis of pts with CLL in the FHD treated between 2002 to 2022 was performed. Pt characteristics such as age at diagnosis (dx), year (yr) of dx, months (mos) from dx to first tx, race, sex, IGHV status, ECOG performance status (PS), and use of small molecule inhibitors at any time (including BTK inhibitors, venetoclax, PI3K inhibitors, and lenalidomide) were collected and analyzed. OS was measured from tx start. Multivariable cox regression (MVA) was used to determine adjusted odds of survival. Results: 13646 pts with CLL were identified. Mean age at dx was 65.3 yrs, and mean time from dx to tx was 32.3 mos. 81.2%, 8.4%, and 10.4% of pts were White, Black, or other race, respectively, and 63.2% of pts were male. 61.4% of pts were IGHV unmutated, and 89.1% of pts had a ECOG PS 0/1. 58.7% of pts were treated with a small molecule inhibitor at any point during their tx. After a median follow-up of 5.3 yrs, the median OS was 10.5 yrs (95% CI: 10.2-10.8). Black pts were younger at dx (63.1 vs 65.4), had shorter time to first tx (23.6 mo vs 34 mo), were more likely to be IGHV unmutated than White pts (83% vs 60.1%), and had more small molecule inhibitor use (69% vs 58.5%). These differences were all statistically significant (p <0.01). 90.8% and 89.1% of Black and White pts had an ECOG PS of 0/1, respectively. Median OS for Black pts was 10 yrs (95% CI: 9.1-11.1) vs 10.5 yrs (95% CI: 10.2-10.8) for White pts. On MVA, Black pts had higher risk of death than White pts of the same age despite increased use of small molecule inhibitor (Table). However, the interaction between age and race was also significant, indicating a decreasing disparity between Black and White race as pts aged. Time to first tx, IGHV unmutated status, and ECOG PS were also independently associated with worse OS. Conclusions: Black race especially at younger age was independently associated with worse OS despite the use of small molecule inhibitors, IGHV status, and ECOG PS.

*Controlled for gender and region.