Risk Clinical Stratification of Sickle Cell Disease in Nigeria, Assessment of Efficacy/Safety of Hydroxyurea Treatment

Summary

The vast majority of births with sickle cell disease (SCD) occur in Africa and 90% are thought to die before the age of five. Hydroxyurea (HU) is the only drug approved by the FDA for the treatment of sickle cell anemia. Although HU is used to treat small numbers of patients in Africa, cost, fear of toxicity, and lack of awareness and availability limit its use. The leukopenia that may be seen with HU raises the possibility of increased susceptibility to infection. Risk stratification - i.e., identification of patients most likely to benefit- could focus therapy and provide confidence that the risk:benefit ratio is favorable. Several clinical measures of future risk are well defined and findings on modifier genes in the US, primarily related to fetal hemoglobin (HbF), have further improved risk prediction. Whether the genetic variants predict severity in Africa is not known. The investigators have established a SCD cohort in Ibadan, Nigeria. In the first phase of this research the investigators will implement clinical risk examinations and assess the relationship between clinical characteristics (including levels of HbF) and known genetic markers. As a proxy for a birth cohort, the investigators will compare the frequency of the genetic markers in adult patients (i.e., "survivors") to children. In the second phase the investigators will randomize 40 high risk adult patients to fixed low dose HU or no HU treatment in a crossover design and monitor hematologic and physiologic parameters to document hematologic effects and safety. This work will lay the basis for a large-scale trial to document safety and efficacy.

Timeline

Start

2014-12

Primary completion

2017-09

Completion

2022-12

Publications

• Background Saraf SL, Akingbola TS, Shah BN, Ezekekwu CA, Sonubi O, Zhang X, Hsu LL, Gladwin MT, Machado RF, Cooper RS, Gordeuk VR, Tayo BO. Associations of alpha-thalassemia and BCL11A with stroke in Nigerian, United States, and United Kingdom sickle cell anemia cohorts. Blood Adv. 2017 Apr 25;1(11):693-698. doi: 10.1182/bloodadvances.2017005231.
• Results Tayo BO, Akingbola TS, Saraf SL, Shah BN, Ezekekwu CA, Sonubi O, Hsu LL, Cooper RS, Gordeuk VR. Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. Am J Hematol. 2018 May 14:10.1002/ajh.25143. doi: 10.1002/ajh.25143. Online ahead of print. No abstract available.
• Results Akingbola TS, Tayo BO, Ezekekwu CA, Sonubi O, Zhang X, Saraf SL, Molokie R, Hsu LL, Han J, Cooper RS, Gordeuk VR. "Maximum tolerated dose" vs "fixed low-dose" hydroxyurea for treatment of adults with sickle cell anemia. Am J Hematol. 2019 Apr;94(4):E112-E115. doi: 10.1002/ajh.25412. Epub 2019 Feb 6. No abstract available.

Drugs

Indications