Hydroxyurea Dose Escalation Effective for Children with Sickle Cell Anemia

Banu Aygun, MD

Credit: LinkedIn

Extended follow-up of an open-label, phase 1/2 trial revealed an escalation of hydroxyurea to the maximum tolerated dose (MTD) significantly improved clinical response and treatment outcomes, without increasing toxicities, in children with sickle cell anemia.¹

The non-randomized REACH study, conducted among ≥600 children in sub-Saharan Africa, showed a protocol-directed MTD strategy decreased the rate of important clinical events, including vaso-occlusive pain, acute chest syndrome (ACS), and death, compared with fixed-dose hydroxyurea.

“With non-communicable diseases now recognized as a key contributor to the global burden of disease, it is imperative that children with sickle cell anemia in low-resource settings have access to safe, effective, and affordable hydroxyurea at optimal doses,” wrote the investigative team, led by Banu Aygun, MD, a professor in the division of hematology, oncology, and cellular therapy, Cohen Children’s Medical Center.

Sickle cell anemia is a frequent and severe hemoglobinopathy worldwide–in the US, universal screening has identified 1000 to 2000 newborns each year with the condition, with more than 93% reaching adulthood.² Globally, the burden of sickle cell involves millions of patients, with nearly 300,000 newborns born annually in sub-Saharan Africa with the condition.

Hydroxyurea is a disease-modifying therapy approved by medicines agencies, including the US Food and Drug Administration (FDA), for children and adults with sickle cell anemia.³ Recent guidelines recommend starting hydroxyurea at 9 months, making it the standard of care for affected patients.

In the REACH trial, eligible children between 1 and 10 years old with documented hemoglobin SS or hemoglobin Sβ zero thalassemia were recruited from four clinical sites in sub-Saharan Africa.⁴ These patients received fixed-dose hydroxyurea of 17.5 mg/kg per day for 6 months, followed by 6 months of dose-escalation as tolerated, up to 20–35 mg/kg per day. Initial safety and feasibility results at 3 years of hydroxyurea with escalation to MTD in REACH reported fewer painful VOEs and ACS.

This analysis compared results on treatment responses, clinical events, and toxicity rates across the fixed-dose and MTD phases for up to 8 years.¹ Between July 2014 and November 2016, 635 children were enrolled in REACH, 606 initiated hydroxyurea, and 522 remained in the trial. As of October 2023, patients received treatment for a median of 93 months, representing 4340 patient-years of treatment.

With dose optimization, by that time point, the mean hydroxyurea dose was 28.2 mg/kg per day and responses were sustained during extended treatment. Mean hemoglobin concentration increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and the mean fetal hemoglobin level was raised from 10.9% at baseline to 24.1% at MTD and 23.3% at the last measurement. The average absolute neutrophil count (ANC) decreased from 6.8 x 109 cells per L at baseline to 3.6 x 109 cells per L at the last measurement.

Aygun and colleagues noted the clinical event rates over time and across dosing phases suggested significant improvements at higher doses of hydroxyurea, with extended treatment. Substantial reductions in incidence rate ratios (IRRs) were observed between MTD and fixed-dose hydroxyurea in clinical events, including:

• VOEs (IRR, 0.60; 95% CI, 0.52 - 0.70; P <.0001)
• ACS events (IRR, 0.21; 95% CI, 0.13 – 0.33; P <.0001)
• Recurrent stroke events (IRR, 0.27; 95% CI, 0.07 - 1.06; P = .061)
• Malaria infections (IRR, 0.58; 95% CI, 0.46 - 0.72; P <.0001)
• Non-malarial infections (IRR, 0.52; 95% CI, 0.46 - 0.58; P <.0001)
• Serious adverse events (IRR, 0.42; 95% CI, 0.27 - 0.67; P <.0001)
• Death (IRR, 0.70; 95% CI, 0.25 - 1.97; P = .50).

Dose-limiting toxicity rates were similar between the fixed-dose and MTD phases (24.1 vs 23.2 per 100 patient-years; IRR, 0.97; 95% CI, 0.70 - 1.35; P = .86), including numerically higher rates of neutropenia and reticulocytopenia and lower rates of anemia.

In an accompanying editorial, Julie Kanter, division of hematology and oncology, University of Alabama, Birmingham School of Medicine, described key issues accompanying the use of hydroxyurea at MTD in the context of clinical practice, particularly in sub-Saharan Africa.⁵

Kanter highlighted concerns about the key barriers to hydroxyurea use in the region, including poverty and lack of insurance, the low number of clinicians trained in the disease space, and costs, including frequent laboratory surveillance and medication expenses. The editorial also pointed to the potential for long-term increased risk of malignancy, requiring close monitoring of patients with long-term exposure to hydroxyurea therapy to investigate the association.

“As more people survive into adulthood, there needs to be a plan to manage a large population of adults with sickle cell anemia in low-resource regions and to ensure that these adults have a high quality of life as well as longevity,” she wrote.⁵

References

1. _{Aygun B Lane A Smart LR et al. Hydroxyurea dose optimisation for children with sickle cell anaemia in sub-Saharan Africa (REACH): extended follow-up of a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2024; (published online April 30.) https://doi.org/10.1016/S2352-3026(24)00078-4}
2. _{Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115(17):3447-3452. doi:10.1182/blood-2009-07-233700}
3. _{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 [published correction appears in JAMA. 2014 Nov 12;312(18):1932] [published correction appears in JAMA. 2015 Feb 17;313(7):729]. JAMA. 2014;312(10):1033-1048. doi:10.1001/jama.2014.10517}
4. _{John CC, Opoka RO, Latham TS, et al. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020;382(26):2524-2533. doi:10.1056/NEJMoa2000146}
5. _{Galadanci NA, Kanter J. Long-term data from the REACH study testing hydroxyurea to treat sickle cell anaemia in children in sub-Saharan Africa. The Lancet Hematology. April 30, 2024. Accessed May 3, 2024. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00096-6/fulltext?dgcid=raven_jbs_aip_email#%20.}