Long-Term Data Provide Reassurance for Hydroxyurea Management
Hydroxyurea is well established as a cornerstone of disease-modifying therapy for children with sickle cell anemia. As treatment options continue to evolve, long-term evidence about its safety, durability and optimal dosing remains important to clinical decision making.
Two decade-long international studies led by Russell E. Ware, MD, PhD, director of the Division of Hematology and the Global Health Center at Cincinnati Children’s, provides some of the strongest prospective evidence to date supporting prolonged hydroxyurea treatment in children with sickle cell anemia.
Published May 27, 2026, in The New England Journal of Medicine, the study followed 207 Ugandan children enrolled in the NOHARM trial. Participants began hydroxyurea at a young age and continued treatment through successive extension studies, ultimately accumulating approximately 10 years of follow-up.
The findings provide reassurance that hydroxyurea can remain an effective component of disease-modifying therapy throughout childhood when accompanied by appropriate monitoring and dose optimization.
Maximum-Tolerated-Dose Therapy Shows Sustained Benefit
One of the most clinically relevant findings is the long-term performance of hydroxyurea when each child receives their maximum tolerated dose.
After the original randomized trial, participants entered extension studies in which dosing was increased based on individual response and laboratory monitoring. The goal of maximum-tolerated-dose therapy is to maximize treatment benefits, including fetal hemoglobin production, while maintaining hematologic safety.
Across approximately 10 years of treatment, investigators documented sustained elevations in fetal hemoglobin along with lower rates of serious adverse events, hospitalizations, blood transfusions and death compared with children receiving lower fixed-dose treatment. In addition, height and weight percentiles increased for both girls and boys, documenting improved growth among the treated children.
Importantly, investigators found no evidence of cumulative toxicities that have historically raised concerns about prolonged hydroxyurea treatment, including no reported cases of cancer or marrow dysplasia.
Infection Safety Findings Support Hydroxyurea Dose Optimization
Additional findings from the Realizing Effectiveness Across Continents with Hydroxyurea (REACH) trial provide further reassurance about the infection-related safety of hydroxyurea in children with sickle cell anemia.
Published October 7, 2026, in The Lancet Haematology, the study evaluated clinically diagnosed infections among 606 children and young adults receiving hydroxyurea across four African countries. Participants initially received fixed-dose treatment for six months before escalation to maximum tolerated dose.
Despite widespread concerns that hydroxyurea-related neutrophil suppression could increase susceptibility to infections, investigators found no increase in the incidence or severity of clinically diagnosed infections, including malaria. Instead, infection risk decreased with increasing hydroxyurea dose, with reported reductions of 51% for malaria and 38% for non-malarial infections.
These findings provide additional long-term safety evidence for hydroxyurea dose optimization, particularly in settings where the infectious disease burden is high and access to healthcare resources is limited.
Long-Term Research Has Advanced Hydroxyurea Management
These findings build on more than a decade of international research involving Cincinnati Children's investigators examining hydroxyurea safety, dosing and outcomes in children with sickle cell anemia.
Through studies including NOHARM and REACH, Dr. Ware and his colleagues have expanded the evidence supporting safe and effective hydroxyurea treatment in sub-Saharan Africa. Together, these research efforts have advanced understanding of individualized dosing, long-term clinical outcomes and infection-related safety, helping inform evidence-based sickle cell management. Although these studies were conducted in low-resource settings, the findings and conclusions are highly relevant to all populations including children with sickle cell anemia in the US.
What the Findings Mean for Pediatric Sickle Cell Care
For pediatric hematologists, the NOHARM and REACH findings provide complementary evidence supporting continued hydroxyurea therapy, individualized dose optimization and long-term treatment safety.
Maximum-tolerated-dose management requires periodic laboratory monitoring and follow-up to that with a fixed-dose approach. However, the sustained treatment response and reduction in serious complications observed in NOHARM support the value of that higher dosing for appropriate patients. Findings from REACH offer further reassurance that dose escalation is not associated with increased clinically diagnosed infections, even in settings with a high infectious disease burden.
Together, these studies strengthen the evidence supporting individualized hydroxyurea dosing and long-term treatment safety. While new pharmacologic, gene therapy-based and potentially curative therapies continue to expand treatment options, hydroxyurea remains an important component of pediatric sickle cell management because of its extensive evidence base and established safety profile. For low-resource settings, it is the only affordable option.
When Specialty Consultation May Help
For many children with sickle cell anemia, hydroxyurea treatment can be effectively managed by their existing hematology team. Consultation with a comprehensive sickle cell program may help when significant complications persist or when questions arise about dose optimization and additional therapies.
Physicians may consider consultation for patients with:
- Persistent vaso-occlusive pain or acute chest syndrome despite therapy
- Frequent hospitalizations or transfusion requirements
- Suboptimal clinical or laboratory responses to hydroxyurea
- Difficulty achieving or maintaining an optimal hydroxyurea dose
- Treatment-limiting toxicity or other complex management considerations
Cincinnati Children’s specialists can partner with referring hematologists to evaluate treatment response, optimize disease-modifying therapy and consider additional treatment options or clinical trials while supporting continuity with the patient’s existing care team.
Connect with a Sickle Cell Expert
Cincinnati Children’s partners with pediatric hematologists and other referring physicians to support individualized hydroxyurea management and comprehensive sickle cell care.
To discuss a patient, treatment approach or potential consultation, contact Russell E. Ware, MD, PhD, at russell.ware@cchmc.org.
(Published November 2026)
