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Hydroxyurea shows promise for stroke prevention in pediatric patients with sickle cell anemia
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ORLANDO, Fla. — The maximum tolerated dose of hydroxyurea appeared noninferior to chronic transfusions for maintaining transcranial Doppler velocities and preventing stroke in high-risk children with sickle cell anemia, according to findings from the TWiTCH trial presented during the plenary session at the ASH Annual Meeting and Exposition.
Transcranial Doppler screening is used for children with sickle cell anemia to identify abnormal elevation of cerebral artery flow velocity, which increases the risk for primary stroke. Patients with this abnormality often receive chronic transfusions as prophylaxis, but the transfusions must continue indefinitely and lead to iron overload.
Russell E. Ware
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, and colleagues conducted the TWiTCH trial, a phase 3 multicenter randomized trial, to compare 24 months of standard transfusions to hydroxyurea for the prevention of stroke in children with sickle cell anemia.
“Stroke in sickle cell anemia is a huge problem, specifically in pediatrics,” Ware said at a press conference prior to presenting his findings at the plenary session of the ASH meeting. “It’s one of the most sever clinical events that occurs in children.”
Ware said that historically, approximately 10% of children with sickle cell anemia will develop a stroke.
“Lifelong transfusions can be used to prevent stroke but have associated morbidity with their use,” Ware said. “Transcranial Doppler has been used for the past 20 years as a way of screening children to identify those at high risk for developing stroke, and in that setting transfusions 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.”
Ware and colleagues conducted the study to determine if hydroxyurea can represent an effective alternative to indefinite transfusions for the prevention of primary stroke in this high-risk population.
Researchers randomly assigned 121 children to standard transfusions (n = 61) or hydroxyurea (n = 60). The hydroxyurea arm included an overlap period where the patients still received transfusions until a stable maximum tolerated dose of hydroxyurea was reached, at which point the transfusions were replaced by serial phlebotomy.
Patients in both arms were balanced by specific characteristics, including maximum transcranial Doppler velocity, age, duration of transfusion, serum ferritin and liver iron concentration.
The patients in the transfusion arm maintained an average HbS of less than 30% throughout the study period, whereas those in the hydroxyurea arm reached the maximum tolerated dose of an average of 27 mg/kg daily after 7 ± 2 months. Expected hematological changes occurred, including HbF of approximately 25% throughout the treatment period.
After 37% of the patients exited the study, an interim analysis suggested that the primary endpoint — or the 24-month transcranial Doppler velocity obtained from a linear mixed model, controlling for baseline values with a noninferiority margin of 15 cm/second — had been reached. The study continued until 50% of the patients exited.
The final analysis included data from 42 patients in the transfusion arm who completed the treatment protocol. Of the remaining patients on this arm, 11 had shortened treatment and eight patients withdrew.
In the hydroxyurea arm, 41 patients completed treatment, 13 had a truncated treatment and six patients withdrew.
The final transcranial Doppler velocity was 143 ± 1.6 cm/second in the transfusion arm and 138 ± 1.6 cm/second in the hydroxyurea arm (P for noninferiority = 8.82 x 10-16; P for superiority = .046).
Overall, there were 29 neurological events, but researchers observed no strokes in the cohort. Six transient ischemic attacks occurred, three in each arm. One child in the transfusion arm was withdrawn after developing on-study transcranial Doppler velocities of greater than 240 cm/second. No new parenchymal abnormalities occurred; however, one child developed a new vasculopathy.
Serious adverse events related to sickle cell anemia were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15); however, these adverse events were not related to the study treatment or procedures.
Patients in the hydroxyurea arm experienced a greater overall improvement in iron overload vs. patients in the transfusion arm, as measured by change in serum ferritin (–1,085 ng/mL vs. –38 ng/mL in the transfusion arm; P < .001) and liver iron concentration (average –1.9 mg/g dry weight liver vs. 2.4 mg/g dry weight liver; P = .001).
“After a period of transfusion, which we defined as at least 12 months, children with sickle cell anemia and abnormal transcranial Doppler velocity … in this setting can substitute hydroxyurea for chronic transfusions to maintain transcranial Doppler velocities and to help prevent primary stroke,” Ware said. – by Anthony SanFilippo
Reference:
Ware RE, et al. Abstract 3. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: There was off-label use of hydroxyurea for children with sickle cell anemia in this study. The researchers report consultant/advisory roles, speakers bureau roles and employment with; research funding from; and other financial arrangements with ApoPharma, Baxter, Bayer Pharmaceuticals, Biomedomics, BioRad Labs, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, ISIS, Janssen, Novartis, Sancillo, Shire Pharmaceuticals and Sideris Pharmaceuticals.
Perspective
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Alexis A. Thompson, MD, MPH
This truly is one of the abstracts that can be defined as practice changing. There are many families who have had great difficulty accepting the realities of their children being transfused lifelong. These are children who are found to have an abnormal transcranial Doppler on their screening test and are otherwise in school and appear to be normal. It has been a great challenge for some families to look at the prospect of lifelong transfusions. Given this in a noninferiority trial, this clearly offers a family a choice to continue with transfusions if they so choose, but to be confident that if they choose to switch to hydroxyurea that their child will not be at an increased risk for a stroke.
Perspective
Back to TopJulie A. Panepinto, MD, MSPH
Cerebral infarction is a devastating complication of sickle cell disease that results in impairment in physical functioning, impairment in cognitive function and decrease in quality of life that affects these patients for the rest of their lives.
Historically, we know that overt stroke occurs in up to 10% of children and it has a high recurrence rate if left untreated — as high as 80%.
More recently we have learned that silent cerebral infarction occurs in up to 30% of children and it too, if left untreated, has a high recurrence rate for silent cerebral infarction and a risk for overt stroke.
Landmark research that began more than 20 years ago looking at strategies and prevention for overt and silent stroke using such methods as transcranial Doppler screening and MRI have resulted in significant decrease in cerebral infarction.
Now, more than ever, there is a need for new treatments for the prevention and recurrence of cerebral infarction. Red blood cell transfusions have been the mainstay of therapy, decreasing the amount of sickle hemoglobin indefinitely. However, with effective transfusion, there is still an increased risk for cerebral infarction. In addition, there is risk for iron overload and alloimmunization.
Further, but as important, the availability and safety of red blood cell transfusions globally is not yet widely available for those with sickle cell disease. Hematopoietic stem cell transplantation has shown to be curative and to prevent cerebral infarction and recurrence of infarction; however, that procedure too is limited by donor availability and the accessibility of this therapeutic option across the world for all patients with sickle cell disease.
It is not only vital to our field, but it also is very exciting for those of us who care for patients with sickle cell disease that Ware and colleagues have presented their work for alternative treatments for prevention of cerebral infarction.
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Julie Kanter, MD
Chronic red cell transfusion therapy prevents stroke in children with sickle cell anemia who have abnormal flow velocity on transcranial Doppler ultrasound (TCD). However, no safe stopping point for chronic red cell transfusion therapy has been previously identified, committing at-risk individuals to indefinite monthly transfusions.In the TWiTCH study, Ware and colleagues found that a select group of at-risk patients could be safely transitioned to hydroxyurea in place of chronic red cell transfusion therapy without increasing the risk for stroke.
Although exciting, these results must be interpreted and implemented with caution. Eligible patients underwent thorough screening to ensure they did not have risky vascular disease and were monitored closely to ensure adherence to hydroxyurea. Thus, the majority of children identified with abnormal TCD or those with previous stroke should still be continued indefinitely on chronic red cell transfusion therapy — or at least until the next study.
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