PracticeUpdate Conference Series ASH 2018

Hydroxyurea a Feasible Sickle Cell Therapy in Sub-SaharanAfrica But financial barriers to widespread use in Africa remain. T he use of hydroxyurea for sickle cell disease, which is the standard of care in the developed world, is also Congo, Kenya, and Uganda), and involves 635 children aged 1 to 10 years.

with patients and their families. In addition, the hydroxyurea, lab tests and transporta- tion to clinics were free of charge. As for safety, the primary safety endpoint was hematological dose-limiting toxici- ties in the first 133 children at each site. Dr. Tshilolo and his colleagues found that just 5.1% of the children in the study had a dose-limiting toxicity within the first 3 months of the study, which they reported was well below the predicted 20% to 30%. Overall, they reported that hydroxyurea was well tolerated with no excess lab toxicities. As for the clinical benefits of hydroxyurea in this study population, the rates of vaso- occlusive pain, acute chest syndrome and transfusions were all reduced by about 50% during the course of treatment. One of the concerns with hydroxyurea treatment is the effect it might have on the incidence of malaria, since sickle cell disease is known to provide its carrier with some protective advantage against that mosquito-borne disease. However, said Dr. Tshilolo during his presentation, “an unexpected result was a reduction in malaria.” Specifically, the rate and severity of malaria (grade 3 or above) decreased from 9.9 to 2.5 events per 100 patient years during treatment. The group of patients on hydroxyurea also saw all-cause mortality decrease from 3.6 deaths per 100 patient years during screening to 1.1 deaths per patient years while on treatment. “Hydroxyurea is feasible, safe and an effective treatment for African children with sickle cell [disease],” concluded Dr. Tshilolo. “Wider access to hydroxyurea [for sickle cell disease] has the potential to save millions of lives in Africa.” As for the possibility of making the drug more widely available in Africa, Dr. Tshilolo suggested that it will probably depend on the pharmaceutical industry’s ability to provide it at an affordable price. “There are companies in Africa that are manufacturing hydroxyurea, but it’s not cheap,” said Ify Osunkwo, MD, of Carolinas Healthcare System in Charlotte, North Carolina, who was moderating the session on sickle cell disease. “It’s prob- ably cheap by American standards, but not cheap by African standards. So, it will be part of efforts going forward to make it more available to a larger variety of patients in the continent.”

Of those 635 children, 4 died during a 2-month screening period before the treatment with hydroxyurea began, while another 25 withdrew from the trial for other reasons. The remaining 606 children began treatment with a modest daily dose of hydroxyurea (15–20 mg/kg/day), which was gradually adjusted based on weight and other criteria to a maximum tolerated dose. After month 6, the dose was esca- lated by 2.5 to 5.0 mg/kg/day every 8 weeks until mild marrow suppression was achieved, typically an absolute neutrophil count <4.0 x 10 9 /L or absolute reticulocyte count <150 x 10 9 /L. Since the trial began, 5% of patients have either died or dropped out of the trial. Of the remaining patients, retention and adherence rates were high, with 97% completing all study visits, while 94% com- pleted all required tests. During his presentation Dr. Tshilolo sug- gested there are several reasons for the high retention and adherence rates in this trial. For example, he said, the trial was well-organized and healthcare workers were able to develop good relationships

effective, safe, accepted, and feasible in children in sub-Saharan Africa, according to research presented at ASH 2018. Unfortunately, explained Leon Tshilolo, MD, of Centre Hospitalier Monkole in Kinshasa, Democratic Republic of the Congo, who presented the study, hydroxyurea is rarely available to sickle cell patients in Africa even though about 75% of the global burden of the disease occurs in sub-Saharan Africa. While data have long supported the use of hydroxyurea in sickle cell patients in areas like the United States, the United Kingdom, and Europe, there are few data regarding its use in sub-Saharan Africa, where not only is the sickle burden extremely high but the health of these patients is also complicated by malnutrition, poverty and other diseases like malaria. The REACH study, which is being coordi- nated by Cincinnati Children’s Hospital, is a phase I/II open-label trial designed to determine the feasibility, effectiveness and safety of hydroxyurea in sub-Saharan Africa. It is being conducted in four sites (Angola, the Democratic Republic of the

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© ASH/Rodney White 2018

PRACTICEUPDATE CONFERENCE SERIES • ASH 2018 10