Growth and Puberty in African Children with Sickle Cell Anemia Treated with Hydroxyurea

Most untreated children with sickle cell anemia (SCA) have poor growth. Puberty is often delayed by 1-2 years, with boys more affected than girls. Studies with sufficient patient numbers are few and most focus on high resource regions. REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731) is a prospective trial designed to determine the feasibility, efficacy, and safety of hydroxyurea for SCA children in sub-Saharan Africa. We aim to describe growth and pubertal development in young SCA patients treated with hydroxyurea.

Patients were enrolled at 4 sites in sub-Saharan Africa, treated with open-label hydroxyurea, and followed longitudinally. Auxology (height, weight) and pubertal (Tanner) staging were obtained by local investigators at enrollment and serially through 5 years of hydroxyurea therapy. Serum IGF-I was measured using the Immuno Diagnostic Systems® immunoassay. Height, weight, and body mass index (BMI) were compared with age-matched normative data from the World Health Organization (WHO). Auxological data (n=10,117 observations) from an additional (untreated) Africa-specific SCA patient cohort (n=864) between 1 and 18 years of age has been developed and will also be used for further comparisons.

A total of 606 children started hydroxyurea treatment in REACH and had growth parameters measured periodically for at least 5 years. Baseline mean age was 5.9 years (range, 1.6-10.2) for girls (n=296) and 5.5 years (range, 1.3-10.1) for boys (n=310). Mean baseline (n=287) and follow-up (n=279) WHO height-for-age z-scores were -1.0 SDs and -1.2 SDs, respectively for girls. Mean baseline (n=299) and follow-up (n=275) WHO height-for-age z-scores were -1.0 SDs and -1.3 SDs, respectively for boys. Mean baseline and follow-up WHO BMI-for-age z-scores were -0.7 and -0.9 SDs, respectively for girls. Mean baseline and follow-up WHO BMI-for-age z-scores were -0.5 and -1.1 SDs, respectively for boys. On-treatment BMI-for-age z-scores were better than pre-treatment at all ages. Because all WHO percentiles plot much higher than the percentiles for untreated SCA patients, the improvement in BMI z-scores with hydroxyurea therapy for all ages was much more noticeable when compared to the untreated SCA cohort. On-treatment height-for-age z-score improvements were evident in all ages but better in the youngest children (1.0-3.9 years). Regarding sexual development in the REACH cohort, the median age at breast Tanner stage 2 was 12.1 years, while median age at testes Tanner stage 2 was 12.8 years. In girls who reached at least age 13 years, 27% had not yet developed Tanner stage 2 breasts. In boys who reached 14 years of age, 27% had not yet developed Tanner stage 2 testes. Mean IGF-I levels in girls was -1.5 SDs at baseline and -1.4 SDs at follow-up. Mean IGF-I in boys was -2.3 SDs at baseline and -2.2 SDs at follow-up.

Growth is very delayed in African children with SCA and serum IGF-I concentrations are low in many study participants. Pubertal development is comparably delayed in girls and boys. Our data indicate that hydroxyurea likely mitigates further growth delay in SCA. Analyses from the ongoing REACH extension study will be required to assess the full impact of hydroxyurea therapy on growth and puberty. In addition, the availability of longitudinal growth data for a large, untreated cohort of SCA children from sub-Saharan Africa will allow better assessment of the impact of hydroxyurea therapy on the growth and development of REACH participants.

Tomlinson:Editas Inc: Consultancy; Spectral Inc: Consultancy. Tshilolo:Novartis: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy. Ware:Merck Pharmaceuticals: Other: Medical Advisory Board; Novo Nordisk: Other: Health Equity Advisory Board; Nova Laboratories: Other: Medical Advisory Board; Theravia: Other: Medical Advisory Board.