Hydroxyurea Prevents Stroke in Pediatric Sickle Cell Anemia

Roxanne Nelson, BSN, RN

December 15, 2015

Orlando, Florida — Stroke is a devastating complication of sickle cell anemia that occurs in young children, and while blood transfusions protect against primary stroke, they must be continued indefinitely and have associated morbidity.

But findings from a new study, presented here at the plenary session of the American Society Hematology (ASH) 57th Annual Meeting, showed that oral agent hydroxyurea was noninferior and possibly superior to long-term transfusions.

This truly is one of the abstracts that can be defined as practice changing. Dr Alexis A. Thompson

"This truly is one of the abstracts that can be defined as practice changing," commented Alexis A. Thompson, MD, MPH, professor of pediatrics at the Ann & Robert H. Lurie Children's Hospital of Chicago, Illinois. "There are many families who have had great difficulty accepting the realities of their children being transfused lifelong."

"Given this is a noninferiority trial, this clearly offers a family a choice of continuing on transfusions if they so choose, but certainly for many families, to be confident that if they choose to switch to hydroxyurea that their child will not be at an increased risk for a stroke," said Dr Thompson, who moderated a press briefing where highlights of the study were presented.

Sickle cell disease is an inherited, chronic disorder affecting nearly 100,000 Americans. Stroke is one of the most severe clinical events in children with this disease and historically occurs in about 10% of all affected children and has a high recurrence rate.

The advent of transcranial Doppler (TCD) screening allows identification of high?risk children and transfusion therapy to prevent primary stroke, explained lead author Russell E. Ware, MD, PhD, director of the Division of Hematology at Cincinnati Children's Hospital and professor in the department of pediatrics at University of Cincinnati in Ohio.

"Lifelong transfusions can be used to prevent stroke but have associated morbidity with their use," Dr Ware said. "Transcranial Doppler has been used for the past 10 or 20 years as a way of screening children to identify those at high risk for developing stroke, and in that setting transfusion can be used to prevent the stroke, but there are associated morbidity and complications of that treatment. Treating a 3-year-old with chronic transfusions lifelong is a very big undertaking."

Study Details

Hydroxyurea is approved by the US Food and Drug Administration for adults with severe sickle cell anemia and is also used in several types of cancer, including chronic myelogenous leukemia and squamous cell carcinomas. In this study Dr. Ware and colleagues examined whether hydroxyurea was noninferior to transfusions and could offer similar, effective protection against primary stroke in children with sickle cell anemia and abnormal TCD velocities.

The TCD with Transfusions Changing to Hydroxyurea (TWiTCH) study is a phase 3 multicenter, randomized clinical trial conducted in 26 pediatric programs across the United States and Canada. The participants, 121 children with sickle cell anemia who were currently receiving monthly transfusions for abnormal TCD but without severe vasculopathy, were randomly assigned to receive standard transfusions (n = 61) or hydroxyurea (n = 60). The two interventions were monitored over 24 months.

The primary endpoint was the 24-month TCD velocity, obtained from a linear mixed model controlling for baseline values, with a noninferiority margin of 15 cm/sec.

The hydroxyurea group included an overlap period with transfusions until a stable maximum tolerated dose of hydroxyurea was reached, at which point the transfusions were replaced by serial phlebotomy to reduce iron overload.

Children in the transfusion group maintained a hemoglobin S value less than 30% throughout the trial, and elevated liver iron concentration was managed with chelation. Participants in the hydroxyurea group reached maximum tolerated dose after 7 ± 2 months at an average dose of 27 mg/kg per day, with expected hematologic changes including fetal hemoglobin of about 25% throughout the treatment period.

Early Termination and Endpoint Reached

. The first interim analysis, carried out after a third of the patients had exited from the trial, demonstrated noninferiority, suggesting that the primary study endpoint was likely to be achieved. The study continued until 50% of the children exited, at which time the statistical analysis was confirmed and the study was terminated. All of the remaining participants then moved into the exit phase.

The final analysis included 42 patients in the transfusion arm who completed all treatment, 11 with truncated treatment, and 8 who withdrew early. In the hydroxyurea group, 41 children completed all treatment, 13 had truncated treatment, and 6 withdrew.

The final calculated TCD velocities (mean ± standard error) in the transfusion and hydroxyurea groups were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively (by intention-to-treat analysis, P for noninferiority = 8.82 × 10–16; by post hoc analysis, P for superiority = .046).

The primary study endpoint was achieved, said Dr Ware, in that TCD velocities were maintained in both treatment groups and noninferiority was demonstrated at the first data analysis.

Secondary endpoints were also reached. There were no strokes, although six transient ischemic attacks occurred (three in each group). One child in the transfusion group was withdrawn after developing on-study TCD velocities greater than 240 cm/sec. No new parenchymal abnormalities were documented, but one child in the transfusion group developed new vasculopathy.

Sickle cell–related serious adverse events were more common among children receiving hydroxyurea (23 vs 15), but none were related to study treatment or study procedures, the researchers reported.

Liver iron decreased more in the hydroxyurea group, as measured by changes in serum ferritin (–1085 ng/mL vs –38 ng/mL in the transfusion group; P < .001) and liver iron concentration (average, –1.9 mg/g dry weight liver vs 2.4 mg/g dry weight liver; P = .001).

"In this setting, hydroxyurea can substitute for chronic transfusions to maintain transcranial Doppler velocities and to help prevent primary stroke," Dr Ware concluded.

The study was funded by the National Heart, Lung, and Blood Institute. Dr Ware has disclosed relationships with Bristol-Myers Squibb, BioMedomics, Bayer Pharmaceuticals, Addmedica, and Eli Lilly and DSMB membership. Several coauthors have also declared relationships with industry as noted in the abstract.

American Society Hematology (ASH) 57th Annual Meeting. Presented December 6, 2015. Abstract 3


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.