Safety and efficacy of ten years of hydroxyurea treatment for young children with sickle cell anemia in Uganda

Abstract Introduction. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM, NCT01976416) was a randomized placebo-controlled clinical trial of hydroxyurea for very young children with sickle cell anemia (SCA) living in Uganda. A total of 207 children with SCA (95 girls, 112 boys) were enrolled and treated at an average age of 2.3 ± 1.0 years (range 1.0 - 3.8 years). In the initial randomized treatment phase, hydroxyurea (Siklos®, donated by Theravia) at 20 mg/kg/day conferred no increased risk of malaria compared to placebo (primary study endpoint), while also providing striking laboratory and clinical benefits without excess dose-limiting toxicities (DLT). Subsequently, all NOHARM participants received open-label hydroxyurea at 20 mg/kg/day per protocol, until a second trial re-randomized these children either to continue fixed-dose hydroxyurea at 20 mg/kg/day or escalate to maximum tolerated dose (MTD). In that follow-on NOHARM-MTD trial (NCT03128515), children randomized to dose escalation to MTD received a higher hydroxyurea dose of ~30 mg/kg/day, and were more likely to achieve the primary study endpoint of hemoglobin (Hb) ≥ 9.0 g/dL and/or fetal hemoglobin (HbF) ≥ 20.0% (86% versus 37%, p <0.0001). Children with dose escalation to MTD also had significantly fewer clinical adverse events (AE), serious adverse events (SAE), transfusions, and hospitalizations compared to children on fixed-dose hydroxyurea. Methods. This unique cohort of children has continued to receive open-label hydroxyurea at MTD with dose optimization, designed to provide modest myelosuppression defined as an absolute neutrophil count (ANC) of ~3.0 x 109/L. We reviewed the entire NOHARM treatment database, analyzing dosing trends, laboratory values, DLT, SAE, transfusions, hospitalizations, and important AE. The Incidence Ratio (IRR) and 95% Confidence Intervals was calculated, comparing the MTD phase to the fixed-dose phase. Results. Of the original treated NOHARM cohort, there are currently 175 children (85%) still on protocol-directed treatment for 10 years, at an average current hydroxyurea dose of 29.0 ± 4.5 mg/kg/day and average hydroxyurea treatment duration of 9.8 ± 0.6 years (range 8.9 - 10.8 years). The most recent laboratory values for this cohort include Hb = 8.6 ± 1.3 g/dL, HbF = 26.3 ± 10.1 %, MCV = 99 ± 12 fL, ANC = 3.3 ± 2.0 x 109/L, and platelets = 439 ± 265 x 109/L. DLT are infrequent and typically occur during a febrile illness. With a cumulative total of 1808 patient-years of hydroxyurea treatment exposure, there were significantly greater clinical benefits at MTD with optimized dosing than at fixed dose. For all SAE, the IRR = 0.37 (95% CI = 0.17 - 0.80, p = 0.011); for hospitalizations, the IRR = 0.19 (95% CI = 0.12 - 0.30, p <0.0001; for transfusions, the IRR = 0.64 (95% CI = 0.39 - 1.05, p = 0.077); and for death, the IRR = 0.27 (95% CI = 0.09 - 0.80, p = 0.018). Serial transcranial Doppler (TCD) screening has documented normal velocities in 93.3% of 1426 completed scans, conditional velocities in 6.3%, and abnormal velocities in 0.5% of scans, with only two clinical strokes (one on fixed dose, one at MTD) during the entire treatment period with a low cumulative primary stroke rate of 0.11 per 100 patient-years. There have been no episodes of cancer or marrow dysplasia identified, and no pregnancies to date. The NOHARM cohort is currently 12.6 ± 0.9 years of age (range 11.0 - 14.6 years) and entering adolescence. Ongoing surveillance includes periodic blood counts with assessments of growth and development every six months as the cohort enters puberty. Conclusion. The NOHARM cohort is the youngest group of children in Africa treated prospectively with hydroxyurea for ten years in a controlled clinical trial, documenting sustained safety and efficacy, and the first study to document a statistically significant reduction in mortality using MTD with optimized dosing compared to a fixed dose regimen. We plan to enroll this cohort into a new clinical monitoring trial, Extension of NOHARM into Adolescence with Comprehensive Testing (ENACT) to assess the benefits of early initiation and long-term hydroxyurea exposure on the organ dysfunction in the brain, spleen, kidney, and bones. Continued follow-up of the NOHARM cohort will determine if early, optimized, and sustained hydroxyurea treatment can further ameliorate or prevent chronic organ damage and change the clinical outcomes of SCA in low-resource settings.

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