Vitamin D Use Tied to Longer Treatment-Free Survival in Early-Stage CLL

Patients with early-stage chronic lymphocytic leukemia (CLL) who took vitamin D supplements during a watch-and-wait period experienced significantly longer treatment-free survival than those who did not, according to a real-world validation study published in EJHaem.¹

The findings, drawn from a large Israeli health system database, corroborate results from a previous independent cohort published in 2024,² strengthening the case for a reproducible association between vitamin D use and delayed disease progression in this population.

In this real-world cohort, patients who received vitamin D had a median treatment-free survival of 147 months, compared with 82 months among nonusers (P <.001). This difference remained consistent after multivariable adjustment for potential confounders. The earlier dataset showed a similar pattern, with median treatment-free survival of 169 months in vitamin D users vs 84 months in nonusers (P ≤.004).² Adjusted hazard ratios were closely aligned between the 2 cohorts—0.866 in the current analysis and 0.912 in the earlier study—supporting consistency of the association across different populations and health care systems.

“The consistency of findings across [2] independent real-world cohorts strengthen the biological plausibility and clinical relevance of this association,” authors Tadmor et al wrote in the publication.¹

Study Background and Patient Characteristics

Patients with early-stage CLL are typically managed with active surveillance, and no intervention has been shown to modify the disease’s natural course. Investigators used data from Clalit Health Services to evaluate 5496 patients with early-stage CLL diagnosed between 2000 and 2022 who were initially managed with a watch-and-wait approach. Of these, 1862 patients (34%) received supplementary vitamin D for a minimum of 6 months during surveillance, while 3634 did not.

The median patient age at diagnosis was 72.2 years, and 56% of the cohort was male. Median follow-up was 46 months (range, 19-89). Notably, baseline vitamin D levels were similar between the supplementation and nonsupplementation groups (P =.315), indicating that use of the supplement was not driven by documented deficiency at diagnosis.

Limitations and Implications

Despite this concordance between cohorts, the authors cautioned that residual confounding cannot be excluded. Differences in supplementation practices and health-seeking behavior between sexes were noted as a particular source of potential bias, and although models adjusted for measured covariates, unmeasured factors may have contributed to the observed differences in outcomes.

The authors also addressed the feasibility of prospective confirmation. "A prospective randomized study is unlikely to be feasible for several reasons," they wrote, citing the high prevalence of vitamin D insufficiency in the general population and the routine use of vitamin D supplementation among postmenopausal women as part of standard clinical care, which complicates the ethical and practical design of a placebo-controlled trial.

Given the retrospective, observational nature of the study, the authors noted that the design reflects the practical constraints of studying a widely available, over-the-counter supplement in a population where deficiency is common and supplementation is already routinely recommended for other indications.

Taken together, the findings add to a growing body of real-world evidence suggesting that vitamin D supplementation may be associated with a longer interval before treatment initiation in patients with early-stage CLL under active surveillance, though the observational nature of the data limits causal inference.

REFERENCES

1. Tadmor T, Arbel R, Razi T, and Rokach L. Vitamin D Supplementation and Treatment-Free Survival in Early-Stage CLL: A Real-World Validation Study. eJHaem 7. 2026;4;e70336. doi:10.1002/jha2.70336

2. Tadmor T, Melamed G, Alapi H, Gazit S, Patalon T, Rokach L. Vitamin D supplement for patients with early-stage chronic lymphocytic leukemia is associated with a longer time to first treatment. Blood Advances. 2024;8(14):3840-3846. doi:10.1182/bloodadvances.2023011458