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ASH 2018: Large Single-Arm Trial of Hydroxyurea for Sickle Cell Anemia in Sub-Saharan Africa

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Key Points

  • A total of 515 participants (85%) achieved MTD at an average dose of 22.5 ± 4.9 mg/kg/d; the average time to MTD was 11 months from treatment initiation.
  • The benefits of hydroxyurea included clinically significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin as well as plus significant decreases in white blood cell count, neutrophils, reticulocytes, rates of vaso-occlusive pain, acute chest syndrome, and transfusions.
  • Rates of all-cause mortality decreased from 3.6 deaths per 100 patient-years during screening to 1.1 deaths per 100 patient-years with hydroxyurea.

The largest prospective trial of hydroxyurea for sickle cell anemia (SCA) has shown that this treatment—long the standard of care for treating SCA in developed countries—is feasible, accepted, well tolerated, and safe for children living in sub-Saharan Africa. Tshilolo et al reported that there are distinct clinical benefits for children receiving hydroxyurea at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 3).

After a median of 2.5 years of treatment, children in the trial experienced less pain and anemia, fewer episodes of malaria and other infections, and lower rates of transfusions and death compared with rates during the pretreatment screening phase of the trial.

“Because of its positive impact on anemia, clinical events, and quality of life, hydroxyurea can now be considered for routine care of children with sickle cell anemia in Africa,” said lead study author Leon Tshilolo, MD, PhD, of the Centre Hospitalier Monkole in Kinshasa, Democratic Republic of the Congo, in a statement. Although some previous studies had suggested that hydroxyurea treatment might put children at higher risk for malaria by suppressing the immune system, this study found that not to be the case.

“We’re very encouraged by the fact that we saw reductions in the rates of malaria and other infections,” said Dr. Tshilolo. “This suggests that hydroxyurea doesn’t cause suppression of the immune system in treated children and therefore doesn’t increase their risk for malaria or other infectious diseases.”

Ample data support the value of hydroxyurea treatment for children with SCA who live in high-resource countries such as the United States, the United Kingdom, and European countries, Dr. Tshilolo said. However, prior to this study, data were lacking on the drug’s benefits for children living in sub-Saharan Africa, where the burden of SCA is highest and the rates of malaria and other infectious diseases, as well as undernutrition and poverty, are extremely high.

Study Methods

A total of 635 children between the ages of 1 and 10 (median age at enrollment = 5.4 years) from 4 African countries—Angola, the Democratic Republic of the Congo, Kenya, and Uganda—were enrolled in the trial. Four children died during a 2-month screening period before treatment began; 25 other children withdrew from the trial for other reasons during the screening period.

The remaining 606 children began 6 months of hydroxyurea treatment at an average dose of 17.5 ± 1.8 mg/kg/d. After 6 months, if no adverse effects were observed, the dose was escalated by 2.5 to 5.0 mg/kg/d every 8 weeks until mild marrow suppression, typically absolute neutrophil count < 4.0 x 109/L, or absolute reticulocyte count < 150 x 109/L based on weight and other criteria, to a maximum tolerated dose (MTD).

Key Findings

A total of 515 participants (85%) achieved MTD at an average dose of 22.5 ± 4.9 mg/kg/d; the average time to MTD was 11 months from treatment initiation.

The benefits of hydroxyurea included clinically significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin as well as significant decreases in white blood cell count, neutrophils, reticulocytes, rates of vaso-occlusive pain, acute chest syndrome, and transfusions.

Rates of all-cause mortality decreased from 3.6 deaths per 100 patient-years during screening to 1.1 deaths per 100 patient-years with hydroxyurea.

Five percent of treated patients dropped out of the trial or died. Of the remaining patients, 97% completed all scheduled study visits, and 94% completed all the required laboratory tests. The rate of toxicities was similar between the screening period and the treatment phase. Patients received the hydroxyurea capsules, all lab tests, and transportation to clinic visits at no charge, which may have contributed to the high rates of retention and adherence to treatment. The close monitoring for adverse effects that children received throughout the trial may also have contributed to the benefits of treatment observed in the study, Dr. Tshilolo said.

Next Steps

Dr. Tshilolo and his colleagues plan to continue to follow the children in this study for several years to observe the effects of hydroxyurea treatment on their growth and sexual development, as well as on the function of organs such as the brain, liver, spleen, and kidneys, and the children’s intellectual performance as they get older.

The cost of hydroxyurea treatment and associated laboratory monitoring will be a major factor limiting more widespread use of the drug to treat SCA in Africa. “The current cost of treatment is beyond the daily wage of most families living in sub-Saharan Africa,” Dr. Tshilolo said. “We hope that treatment will be made available to more patients through outside financial support.”

Disclosure: See the study authors’ full disclosures at ash.confex.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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