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Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa.
N Engl J Med. 2020 06 25; 382(26):2524-2533.NEJM

Abstract

BACKGROUND

Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.

METHODS

In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.

RESULTS

Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia.

CONCLUSIONS

Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.).

Authors+Show Affiliations

From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).From the Ryan White Center for Pediatric Infectious Diseases and Global Health, Department of Pediatrics, Indiana University, Indianapolis (C.C.J.); the Department of Pediatrics and Child Health, Makerere University (R.O.O., H.A.H., C.N., P.K., C.M.N.), Global Health Uganda (R.O.O., C.N.), and Mulago Hospital (P.K.) - all in Kampala, Uganda; the Division of Hematology, Department of Pediatrics (T.S.L., A.L., R.E.W.), and the Global Health Center (R.E.W.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (A.L., R.E.W.) - all in Cincinnati; and the Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal (H.A.H.).

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32579813

Citation

John, Chandy C., et al. "Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa." The New England Journal of Medicine, vol. 382, no. 26, 2020, pp. 2524-2533.
John CC, Opoka RO, Latham TS, et al. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020;382(26):2524-2533.
John, C. C., Opoka, R. O., Latham, T. S., Hume, H. A., Nabaggala, C., Kasirye, P., Ndugwa, C. M., Lane, A., & Ware, R. E. (2020). Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. The New England Journal of Medicine, 382(26), 2524-2533. https://doi.org/10.1056/NEJMoa2000146
John CC, et al. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020 06 25;382(26):2524-2533. PubMed PMID: 32579813.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. AU - John,Chandy C, AU - Opoka,Robert O, AU - Latham,Teresa S, AU - Hume,Heather A, AU - Nabaggala,Catherine, AU - Kasirye,Phillip, AU - Ndugwa,Christopher M, AU - Lane,Adam, AU - Ware,Russell E, PY - 2020/6/25/entrez PY - 2020/6/25/pubmed PY - 2020/7/9/medline SP - 2524 EP - 2533 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 382 IS - 26 N2 - BACKGROUND: Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown. METHODS: In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events. RESULTS: Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia. CONCLUSIONS: Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.). SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/32579813/Hydroxyurea_Dose_Escalation_for_Sickle_Cell_Anemia_in_Sub-Saharan_Africa L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa2000146?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -