Abstract
Background: Sickle Cell Disease (SCD) is a known risk factor for hematologic malignancies, but age-related variation in this risk remains underexplored. We examined how relative and absolute malignancy risks differ across age strata. Our findings clarify disease mechanisms and inform age-specific surveillance strategies to better manage SCD-associated hematologic malignancies.
Methods: We utilized real-world data from a multicenter electronic health record network to perform a propensity score-matched cohort analysis. Patients with SCD were matched 1:1 with non-SCD controls across three distinct age groups: under 30 years, 30 to 50 years, and over 50 years. We analyzed the 5-year cumulative incidence of hematologic malignancies, specifically leukemia and myelodysplastic syndromes (MDS), calculating relative risk (RR), odds ratio (OR), absolute risk difference, and 95% log-normal confidence intervals (CIs). Hydroxyurea exposure was identified as a baseline characteristic and included in descriptive analyses.
Results: Among 81,312 matched individuals, key findings revealed age-stratified differences in malignancy burden. In individuals aged 30 to 50, the RR for any hematologic malignancy was highest at 3.50 (95% CI: 2.49–4.93), followed by RR 2.42 (1.93–3.04) in those >50 and RR 2.30 (1.63–3.26) in those <30. Similarly, leukemia risk was most pronounced in the 30–50 age group with an RR of 5.29 (2.99–9.35), followed by RR 3.43 (2.29–5.15) in >50 and RR 2.81 (1.88–4.21) in <30. Although the relative risk peaked in middle age, absolute risk differences were most significant in the >50 cohort: 1.8% for hematologic malignancy and 0.9% for leukemia, compared to 0.7% and 0.4% in the 30–50 group and 0.3% each in the <30 group. Myelodysplastic syndromes were only assessable in individuals >50, where the RR reached a striking 6.20 (CI: 3.18–12.08), with an absolute risk difference of 0.7% (0.8% vs. 0.1%). Hydroxyurea exposure was recorded in 3,221 (39.6%) of patients under 30, 2,879 (35.4%) of patients aged 30–50, and 1,122 (13.8%) of patients over 50. Despite these differences, its distribution was not significantly associated with variations in malignancy incidence within each age group.
Discussion: The disproportionate increase in relative risk during midlife may reflect a convergence of cumulative marrow stress due to chronic hemolysis, inflammation, and transfusional iron overload, intersecting with relatively intact immune competence. This amplifies susceptibility in comparison to non-SCD peers. Although absolute risk continues to climb in older adults, the relative risk diminishes, likely due to increasing background malignancy incidence in the general population. The uniquely elevated risk of MDS in the older SCD population suggests an age-dependent vulnerability to clonal myeloid disorders. These findings support the hypothesis that SCD-related marrow pathology evolves, eventually manifesting in increased susceptibility to hematologic transformation. Hydroxyurea exposure, recorded in many patients, may influence this trajectory. While hydroxyurea is a cornerstone of SCD management and may reduce sickling complications and inflammatory stress, its long-term effects on clonal hematopoiesis and malignancy risk remain uncertain. Although hydroxyurea use was captured in this study, subgroup analyses did not demonstrate a clear association with reduced or increased malignancy risk. Further dedicated studies are required to elucidate its potential role, whether protective, neutral, or leukemogenic, in the evolution of malignancy in SCD.
Conclusion: Our study has shown that SCD significantly elevates the risk of hematologic malignancies across all adult age groups, but the magnitude and nature of this risk vary by age. The 30–50 age group displays the highest relative risks, signaling a critical period of vulnerability. In contrast, the oldest group experiences the most significant absolute increases in malignancy incidence, underscoring the additive burden of aging on SCD marrow. The exceptionally high RR for MDS in older adults further highlights the long-term hematopoietic consequences of SCD. These findings underscore the urgent need for age-tailored malignancy surveillance and prevention strategies in SCD care, and they call for hematology guidelines to evolve accordingly. Our study's implications emphasize the importance of these strategies in improving the management of SCD-related hematologic malignancies.
