Hydroxyurea Dose Escalation Safe, More Effective Against Childhood Sickle Cell Anemia

By Gene Emery

June 26, 2020

(Reuters Health) - Raising the dose of hydroxyurea by roughly 50% for children with sickle cell anemia dramatically lowers the risk of sickle-cell complications, according to a new study of 187 Ugandan children published in the New England Journal of Medicine.

Researchers found that the higher dose cut the hospitalization rate by 79%, the transfusion rate by 70%, the odds of acute chest syndrome or pneumonia by 73%, and the risk of a vaso-occlusive pain crisis by 57%.

The rate of "laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia," the research team reports.

The trial was halted early because the findings were so clear-cut, and all the children were then offered the higher dose.

"Our data provide strong evidence that dose escalation is safe and provides considerably greater clinical benefits than standard dosing," the team, led by Dr. Chandy John of Indiana University, Indianapolis, writes in their report.

"You can get the extra benefit with increased dosing without added risk to the child," senior author Dr. Russell Ware, director of the division of hematology at Cincinnati Children's Hospital, in Ohio, said in a telephone interview with Reuters Health.

"This is a landmark paper and should decrease morbidity and improve outcomes in both low-resource and high-resource countries," said Dr. Elliott Vichinsky, medical director of hematology and oncology at the UCSF Benioff Children's Hospital Oakland, in California.

Dr. Vichinsky, who was not involved in the research, told Reuters Health by phone that the findings underscore his belief that "hydroxyurea is underutilized and hasn't met its potential in developed countries and countries with limited resources."

An estimated 300,000 children are born each year with the genetic defect that causes sickle cell disease, mostly in sub-Saharan Africa and India. Most go untreated, at least initially, because of lack of screening at birth or as newborns. Thus, 50% to 90% die before their fifth birthday.

Hydroxyurea works in part by sparking the production of fetal hemoglobin, which lacks the sickling defect. But the best dose to use in low-resource situations has continued to be uncertain, a gap in knowledge the new NOHARM MTD trial was designed to fill.

"Here's a drug that works, we know it boosts hemoglobin and inhibits sickling, but how hard do you push the dose? What if it's toxic and you have to draw labs all the time?" said Dr. Ware, expressing the concerns that had revolved around escalating the dose. "Oddly, the U.S. has been more eager to push the dose than Europe, where they want to use the least dose that makes the patient feel better."

The results may therefore have an impact far beyond the areas where sickle cell disease is most prevalent, he said.

"Particularly in low-resource settings such as sub-Saharan Africa, hydroxyurea therapy and periodic laboratory testing are often neither affordable nor feasible for most patients with sickle cell anemia and their families, so a simplified strategy for hydroxyurea dosing with minimal monitoring would be ideal," the researchers write. "Periodic monitoring, perhaps every 2 to 3 months, may be sufficient."

"We're trying to do an implementation study to see how feasible this is," said Dr. Ware. Quarterly monitoring is the goal.

The fact that the dose-limiting toxic effects were comparable in the two groups "indicates that dose escalation is not more toxic and does not require frequent monitoring after a stable dose is reached," the Ware team said.

The two hydroxyurea daily doses tested were approximately 20 milligrams per kilogram of body weight in the conventional treatment group and 30 mg/kg in the experimental group, although the dose could go to 35 mg/kg.

All the children were part of the original NOHARM study and had been receiving the 20 mg dose for at least several months.

In half the children, the dose was increased to 25 mg/kg for two months and then hiked again if lab tests showed no toxic effects. The test was scheduled to run for two years with laboratory monitoring every two to three months.

By the close of the trial, 37% in the standard fixed-dose group had achieved the primary outcome of a fetal hemoglobin level of 20% or more, or a hemoglobin level of at least 9.0 grams per deciliter. In the dose-escalation group, 86% met the primary outcome (P<0.001).

"Benefits conferred by higher doses of hydroxyurea were observable early in the trial, then continued to improve, and were maintained once a stable dose was reached," the Ware team said.

A lot of patients aren't getting the benefit of maximum dosing with hydroxyurea, said Dr. Vichinsky. "I think this study will reassure the health system that you can do that, and it will help."

Hydroxyurea costs about 50 cents per capsule, "and that's without anyone trying to mass produce it and bring the cost down," Dr. Ware said.

SOURCE: https://bit.ly/3fFrLcn The New England Journal of Medicine, online June 24, 2020.

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