Abstract Sickle cell disease (SCD) is a common and severe inherited hemoglobinopathy affecting millions worldwide. This chronic condition leads to red blood cell (RBC) deformation, chronic hemolytic anemia, and serious complications such as vaso-occlusive crises, stroke, and organ damage. Two therapeutic strategies are commonly used: chronic red cell exchange (RCE), which replaces abnormal RBC with healthy donor cells, and hydroxyurea (HU), which increases fetal hemoglobin (HbF) and reduces hemoglobin S (HbS). Although effective, RCE is invasive, resource-intensive, time-consuming (2- to 4-hour sessions every 4 to 8 weeks), and carries risks such as alloimmunization and iron overload. Since 2020, patients undergoing chronic RCE at our hospital have been systematically offered treatment intensification with HU. The goal is to increase the interval between RCE and reduce the overall treatment burden, while maintaining clinical and biological efficacy. This study aimed to systematically evaluate the real-world implementation of adding HU to chronic RCE in adults with SCD. We sought to: (1) quantify the impact of HU on transfusion burden by comparing the interval between RCE sessions and the number of transfused RBC units before and after HU initiation; and (2) assess the safety and feasibility of this combined strategy. This retrospective, single-center cohort study included all adults with SCD undergoing chronic RCE at our hospital who started HU between June 2020 and June 2025. The study followed a pre–post intervention design in which each participant served as their own control. Comparisons between the pre- and post-HU periods (two 12-month intervals, excluding the first 3 months post-initiation as a stabilization period) were performed using paired t-tests and a linear mixed-effects model (LMM), accounting for repeated measures within individuals. Forty-two patients met the inclusion criteria; 15 were excluded because of non-adherence to HU, and 27 were included in the final cohort, 70% (n = 19) of whom were men. Most participants were of the HbSS/HbSβ0 genotype (82%; n = 22), and the mean age was 44.5 years 24-73. The main indication for RCE was neurological complications (63%). Participants were on RCE for a mean of 127.9 months 44-245 prior to starting HU. Mean HU dose was 14.0 mg/kg at the beginning of the observation period and 18.3 mg/kg at the end. The intervals between RCE before and after HU initiation were 7.08 and 7.26 weeks (LMM, p = 0.1). No statistically significant difference was observed in the number of RBC units exchanged per session (9.97 units before vs 9.77 units after HU initiation; p = 0.60). However, the cumulative number of RBC units over 12 months decreased significantly, from a mean of 81.7 units per patient in the year prior to HU to 76.2 units afterward (p = 0.007). Mean pre-RCE hematocrit decreased significantly (31.1% vs 29.4%; p = 0.03), while post-RCE hematocrit remained stable (34.1% vs 34.2%; p = 0.79), in alignment with our institution's goal of 34% at that time. HbF increased significantly (1.5% vs 4.9%; p 0.001). The extended delays between RCE sessions did not result in an increase of HbS/C levels measured pre-RCE (41.2% vs 38.4%; p = 0.07). Ferritin increased significantly faster (426 vs 550; p = 0.006), while white blood cell count (p = 0.002) and neutrophils (p = 0.003) decreased significantly. Grade 3 leucopenia and neutropenia were observed in 4 (14.8%) and 5 (18.5%) patients, respectively. To our knowledge, this is the first study to evaluate the impact of HU intensification in adults with SCD undergoing chronic RCE. The pre–post design reduced inter-individual variability. Although we reviewed all charts for adverse events, the retrospective design may have nonetheless underestimated adverse outcomes due to the absence of standardized safety assessments and the exclusion of non-adherent patients from the final analysis. Furthermore, accurately measuring adherence posed a challenge, introducing a potential risk of exposure misclassification. In conclusion, systematic intensification of chronic RCE with HU was followed by a mild decrease in the transfusion burden in patients with SCD, with no observable compromise in RCE targets. Expected cytopenias observed in a minority of patients were manageable. Further studies are needed to identify those most likely to benefit from this promising approach and to assess its impact on iron balance, quality of life and long-term outcomes.
Pastore et al. (Mon,) studied this question.
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