Vitamin D Supplementation and Treatment‐Free Survival in Early‐Stage CLL: A Real‐World Validation Study

ABSTRACT Background Patients with early‐stage chronic lymphocytic leukemia (CLL) are typically managed with a watch‐and‐wait strategy, and no intervention has been shown to modify the natural history of the disease. Methods We analyzed a large real‐world cohort derived from Clalit Health Services, including patients diagnosed with early‐stage CLL between 2000 and 2022 who were initially managed with active surveillance. Exposure was defined as vitamin D supplementation for at least 6 months during the watch‐and‐wait period. The primary endpoint was treatment‐free survival (TFS). Multivariable time‐dependent Cox models and inverse probability of treatment weighting were applied to adjust for baseline differences. Results The cohort included 5496 patients, of whom 1862 (34%) received vitamin D supplementation. Median age at diagnosis was 72.2 years, and 56% were male. Median follow‐up was 46 months. Patients receiving vitamin D demonstrated significantly longer TFS compared with nonusers (median 147 vs. 82 months, p <0.001). In multivariable time‐dependent Cox analysis adjusted for age, sex, and laboratory parameters, vitamin D exposure remained independently associated with improved TFS (HR: 0.87, 95% CI: 0.75–0.99; p = 0.027). Conclusions In this large real‐world validation cohort, vitamin D supplementation was associated with prolonged TFS in patients with early‐stage CLL managed with active surveillance. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.