Recent data from the first randomized trial on hydroxyurea treatment for preventing silent cerebral infarctions (SCIs) in infants with sickle cell disease (SCD) add support to early initiation of treatment. The findings, published in the American Journal of Hematology, also underscore the need for larger trials in this population.1
James F. Casella, MD, the Rainey Professor of Pediatric Hematology at Johns Hopkins School of Medicine in Baltimore and first author of the study, noted that neurologic complications, including stroke, are a major problem in SCD. By 15 months of age, about 13% of infants with SCD have SCIs that can be detected on brain imaging, increasing to 37% by age 14.2 Unlike stroke, these do not cause focal neurologic deficits, but such infarcts result in decreased IQ and accumulated cognitive dysfunction.
The largest randomized trial of hydroxyurea in infants with SCD was the BABY HUG study, in which Dr. Casella was also involved.3 Although it showed benefits for secondary endpoints such as pain crises, acute chest syndrome, need for transfusion, and hospitalization, the trial was not able to study SCIs as initially planned. Other data strongly suggest a preventive role of hydroxyurea for central nervous system (CNS) complications in SCD, in some situations for prevention of stroke, for example.
The current study reports results from HU Prevent, a double-blind, phase II feasibility/pilot study of hydroxyurea versus placebo for the prevention of CNS injury in children ages 12-48 months with SCD. The trial eventually included six patients in each group, all of whom initially had a normal neurologic exam, MRI, and cerebral blood flow velocities. Dr. Casella said a third of the patients they screened already had SCIs and thus could not be included in their study.1
As part of their analysis, Dr. Casella, Dana K. Furstenau, MD, MS, also of Johns Hopkins, and colleagues used a weighted score of stroke, transient ischemic attack, SCI, and elevated cerebral blood flow velocity to estimate the overall risks of suffering the consequences of a stroke, a measure they had validated previously.4 The mean Stroke Risk Consequences Score was 0.078 in the hydroxyurea group versus 0.312 in the placebo group, with a standard deviation of 0.174 in both groups; although the p value (0.072) did not quite reach statistical significance, it was below the level often used for follow-up phase III studies.
The team had hoped to use the data as an internal pilot as part of a larger phase III trial, but challenges with funding led them to release these results; the small size of the trial is a key limitation.
Current guidelines from the National Heart, Lung, and Blood Institute recommend offering hydroxyurea as an option to all children with SCD aged 9 to 42 months and engaging in shared decision-making with families to decide on its use.5 However, use of the therapy remains quite low at many centers and was as low as 9% in one study, for example.6
Dr. Casella said it can be challenging to convince parents to start hydroxyurea in their young children, particularly when they learn it is sometimes used as a cancer drug, causes side effects like hair loss, and requires special handling protocols. “My best clinical judgment is that all these children should be on it early, but you can’t tell parents what to do,” he said. “It’s sometimes difficult convincing someone with a well-looking child to take a medicine every day to prevent [an event like an SCI] that may not happen.”
Dr. Casella contended that even though the evidence for hydroxyurea in this population is already relatively good, the low utilization rates are an argument for the need for larger follow-up studies. These might prompt a new explicit recommendation in hematology guidelines and more emphatic recommendations from physicians to parents and family members.
Dr. Casella also underscored the importance of preventive approaches like this, even in the era when some patients might eventually obtain curative therapy. “If you don’t keep them in good shape until they get to gene therapy, they’re going to have to live with those adverse consequences for the rest of their lives.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Casella JF, Furstenau DK, Adams RJ, et al. Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-a randomized, placebo-controlled phase II feasibility/pilot study [published online ahead of print, 2024 July 2]. Am J Hematol. doi: 10.1002/ajh.27423.
- Runge A, Brazel D, Pakbaz Z. Stroke in sickle cell disease and the promise of recent disease modifying agents. J Neurol Sci. 2022;442:120412.
- Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377(9778):1663-1672.
- Casella JF, Adams RJ, Brambilla DJ, et al. Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease. Clin Trials. 2019;16(1):20-31.
- Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048.
- Barriteau CM, Murdoch A, Gallagher SJ, et A patient-centered medical home model for comprehensive sickle cell care in infants and young children. Pediatr Blood Cancer. 2020;67(6):e28275.
