Real-world effectiveness and safety of hydroxyurea in adults with hemoglobin SC disease: A retrospective cohort study in Quebec, Canada

Abstract Background Hemoglobin SC disease (HbSC) is the second most prevalent genotype of sickle cell disease (SCD) worldwide and is associated with significant morbidity, including vaso-occlusive crises (VOC), acute chest syndrome (ACS), priapism, and organ damage. Therapeutic options are limited. Hydroxyurea (HU) is not routinely recommended in HbSC disease. Most clinical trials have excluded patients with HbSC, and concerns persist about potential hyperviscosity resulting from HU-induced hemoglobin increase. In Quebec, Canada, HU is used off-label in adults with SCD, yet its real-world impact in those with HbSC has not been systematically evaluated. Methods We conducted a retrospective, single-center pre-post cohort study at the Centre Hospitalier de l'Université de Montreal (CHUM). Adults with HbSC who initiated HU at our hospital between January 2010 and July 2025 were included in the efficacy analysis if they were followed by a hematologist in a Quebec hospital center for at least 12 months and whose number of VOC in the pre-HU period was documented. For safety analysis, patients who had no follow-up preceding the HU prescription and who did not necessarily complete the one-year post-HU period were also included. The primary endpoint was the change in frequency of VOC composite (VOCC), defined by a combination of VOC, ACS, priapism, and splenic or hepatic sequestration, between the 12 months pre-treatment and the 4th to 16th month post-HU initiation. Secondary endpoints included hematological and non-hematological adverse events (AE) graded according to CTCAE v5.0. An exploratory analysis was also performed to assess the influence of treatment response according to predefined cofactors, including age, sex, ethnicity, G6PD status, and presence of at least one alpha-gene deletion (alpha-thalassemia). Acceptability was measured via HU prescription patterns and discontinuation reasons. Results A total of 263 patients were assessed: 110 were included in the security analysis and 75 in the efficacy analysis. Women represented 51.8% of the sample, mean age was 33 years [18; 70], 37.3% had alpha-thalassemia and 7.3% had G6PD deficiency. Baseline hemoglobin was 118 g/L, ranging from 89 to 158 g/L and median HU dose was 17 mg/kg [4.20; 38]. HU was associated with a 56% reduction in the mean number of annual VOCC from 0.57 to 0.25 (-0.32 ± 0.84; 95% CI [-0.51; -0.13]; p = 0.0015) in the intent-to-treat analysis. Greater reductions were observed in patients aged 18-30 (-0.51 ± 0.98 [-0.85 ; -0.18]), those without G6PD deficiency (-0.31 ± 0.88 [ -0.53 ; -0.08]), and those with alpha-thalassemia (-0.41 ± 1.01 -0.77 ; -0.04]). There was no difference in VOCC reduction between sexes. The most frequent hematological AE was thrombocytopenia (32.7%), mostly grade 1, and requiring few interventions. Neutropenia (23.6%) and leukopenia (20.9%) were mostly grade 1. Within the limits of retrospective available data, no hyperviscosity-related complications were explicitly documented in the 10.9% of patients with an increase in hemoglobin above 120 g/L; however, one patient had grade 3 headaches in the months following HU introduction, and another patient had a splenic infarct, although upon review, the latter appeared unlikely to be related to hyperviscosity. Liver enzyme elevations were the most frequent non-hematological AE, with a maximum severity of grade 2, all asymptomatic and without clinical hepatotoxicity. Overall, HU was well tolerated, though 27.3% (n = 30/110) of patients discontinued treatment, reasons documented were primarily due to lack of awareness about prescription renewal (n = 10/30 = 33.3%) or AE (n = 8/30 = 26.7%), including 3 hematological AE, and 5 non-hematological AE (nausea, dizziness, pruritus, arthralgia). Conclusion This study contributes to the advancement of knowledge on HU in HbSC disease by quantifying its clinical impact, tolerability, and implementation feasibility in a North American population. Our findings may support guideline updates and optimize pharmacist engagement in SCD care. HU was associated with a clinically meaningful reduction in VOCC and demonstrated a favorable safety profile, with mostly mild AE. However, a significant proportion of treatment discontinuation highlights the need for improved patient education, measures of quality of life and adherence strategies to maximize therapeutic benefit.

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