effective treatment for sickle cell anemia

The new england journal of medicine

n engl j med 380;2 nejm.org January 10, 2019 121

established in 1812 January 10, 2019 vol. 380 no. 2

From Centre Hospitalier Monkole, Kin- shasa, Democratic Republic of Congo (L.T.); the Department of Medicine, Uni- versity Health Network and Mt. Sinai Hospital, and the University of Toronto, Toronto (G.T.); the Kenya Medical Re- search Institute (KEMRI)–Wellcome Trust Research Program, Kilifi, Kenya (T.N.W.); the Department of Medicine, Imperial College London, London (T.N.W.); Hos- pital Pediátrico David Bernardino, Luanda, Angola (B.S.); Mbale Clinical Research Institute and Mbale Regional Referral and Teaching Hospital–Busitema Univer- sity, Mbale, Uganda (P.O.-O.); the Divi- sion of Hematology, Department of Pedi- atrics, Cincinnati Children’s Hospital (A.L., S.E.S., T.S.L., P.T.M., R.E.W.),

University of Cincinnati College of Medicine (A.L., P.T.M., R.E.W.), and the Global Health Center, Cincinnati Children’s Hospital Medical Center (S.E.S., P.T.M., R.E.W.), Cincinnati; and Cohen Children’s Medical Center, New Hyde Park, and the Zucker School of Medicine at Hofstra/Northwell, Hempstead — both in New York (B.A.). Address reprint requests to Dr. Ware at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, or at russell . ware@ cchmc . org.

*A complete list of the REACH Investiga- tors is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on December 1, 2018, at NEJM.org.

N Engl J Med 2019;380:121-31. DOI: 10.1056/NEJMoa1813598 Copyright © 2018 Massachusetts Medical Society.

BACKGROUND Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hy- droxyurea in low-resource settings. METHODS We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation.

The end points assessed feasibil- ity (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival). RESULTS A total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels.

laboratory variables

Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient- years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence in- terval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72),

malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88). CONCLUSIONS Hydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, in- fections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731.)