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Hydroxyurea benefits children from sub-Sahara Africa with sickle cell anemia
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SAN DIEGO — Children from sub-Saharan Africa with sickle cell anemia treated with hydroxyurea for 6 months demonstrated reductions in sickle-related clinical events, transfusions and rates of malaria and mortality, according to results of the prospective multicenter REACH trial presented during the plenary session of the ASH Annual Meeting and Exposition.
This analysis provides the first prospective data supporting the safety and efficacy of hydroxyurea for the treatment of children in sub-Saharan Africa, the area of greatest global sickle cell anemia burden.
“Our results show that we have to use [hydroxyurea] in most of the patients with sickle cell anemia living in Africa,” Leon Tshilolo, MD, PhD, of Centre Hospitalier Monkole in Kinshasa, Congo, told HemOnc Today. “We hope it will be more available, but we are not able to produce it locally.”
Researchers treated 606 children (median age at enrollment, 5.4 years; interquartile range, 3.4-7.4) with sickle cell anemia from four separate sites with hydroxyurea at an average dose of 17.5 mg/kg daily.
After 6 months, the dose of hydroxyurea increased 2.5 mg/kg to 5 mg/kg per day for 8 weeks until the patient reached mild marrow suppression, defined as an absolute neutrophil count less than 4 x 109/L or absolute reticulocyte count less than 150 x 109/L.
A total of 515 patients received an average maximum tolerated dose of 22.5 ± 4.5 mg/kg per day. The average time to maximum tolerated dose was 11 months.
The primary endpoints included feasibility (enrollment, retention, adherence), safety (hematological toxicities, infections, maximum tolerated dose), and benefits (lab parameters, sickle-related clinical events, transfusions, death). Incidence of hematological dose-limiting toxicities among the first 133 children at each site served as the study’s primary safety endpoint.
Only 5% of children dropped out due to study withdrawal or death.
Researchers reported that hydroxyurea was well tolerated overall, with 0.22 toxicities a year during 1,438 patient-years of treatment.
Only 4.9% of children experienced a dose-limiting toxicity during the first 3 months.
The benefits of hydroxyurea included increases in hemoglobin concentration, mean corpuscular volume and fetal hemoglobin, as well as decreases in white blood cell count, neutrophils and reticulocytes. Researchers also reported a nearly 50% decrease in vaso-occlusive pain, acute chest syndrome and transfusions during the treatment phase of the trial.
The rate of malaria decreased overall from 47.8 events to 22.3 events per 100 patient-years, which Tshilolo noted was a surprising finding. Clinically severe malaria — defined as grade 3 or above — fell from 9.9 events to 2.5 events per 100 patient-years.
“I can say it was a real event that we observed the reduction of malaria and nonmalaria infection in all our patients that were submitted to hydroxyurea,” Tshilolo said during a press conference. “We don’t know the cause of these reductions in malaria incidents, [but] I suppose it would be due to the high level of fetal hemoglobin.”
All-cause mortality rates also dropped from 3.6 deaths per 100 patient-years during screening to 1.1 deaths per 100 patient-years during the treatment phase.
Tshilolo told HemOnc Today that he believes this study would show similar results in sub-Sahara Africa if the trial was expanded.
“I’m sure we would have similar results because the four countries we used have the highest prevalence of malaria,” he said. “We worked in both the western and eastern parts [of the continent] where the more aggressive parasite Plasmodium falciparum is present.” – by John DeRosier
Reference:
Tshilolo et al. Abstract 3. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures :
Tshilolo reports no relevant financial disclosures. One researcher reports a consultant role with Nova Laboratories; research funding from Addmedica, BioMedomics, Bristol-Myers Squibb and Novartis; and advisory board or board of directors roles with Agios and Global Blood Therapeutics.
Perspective
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Ifeyinwa Osunkwo, MD, MPH
The biggest fear we had about bringing hydroxyurea to Africa was whether these patients then were going to die of malaria. The fact that these investigators showed a decrease in malaria rates shows we truly can treat individuals in Africa with sickle cell disease.
I don’t think hydroxyurea access will be a very formidable challenges. With support from groups like ASH, WHO and others, these results will motivate the international market to acknowledge this approach is feasible and figure out how to make it happen. Without these data, they couldn’t even imagine this could happen because everyone was afraid of the infection rate. Now we know it can be done. If HIV drugs are available in every African country, they can use the same infrastructure with hydroxyurea for sickle cell disease.
I love that the principal investigator of this study is from Africa. We have had challenges before when an American becomes the PI of a study in Africa. That doesn’t build trust and relationships. It doesn’t create the buy-in patients need to stay on the study. That is not unique to Africa. The same challenge would apply in the United States or anywhere else in the world. In this case, investigators were able to get 600 patients enrolled on this study for 3 years. That has never happened in that region.
We make a lot of assumptions about Africa regarding what can happen there and what cannot happen. This study shows that, despite the political instability and the poor resources, you can do a clinical trial with integrity and have strong results. We cannot discount any country because of preconceived notions. We have to go in and do feasibility and find solid partners we can work with. We should not discount any under-resourced country when it comes to providing the opportunity to participate in research because, when people participate in research, their lives get better and health care gets better.
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