According to results from the NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) maximum tolerated dose (MTD) trial, dose-escalated hydroxyurea controlled complications associated with sickle cell disease (SCD) more effectively than a lower fixed dose of hydroxyurea in sub-Saharan African children, and both dosing strategies were associated with similar safety.
While there are several new FDA-approved treatments for SCD available in the U.S., none are yet suitable for use in sub-Saharan Africa due to cost and testing requirements, the authors, led by Chandy C. John, MD, from the Ryan White Center for Pediatric Infectious Diseases and Global Health at Indiana University School of Medicine, noted.
With the NOHARM MTD trial, investigators sought to determine whether dose escalation to hydroxyurea’s MTD was associated with greater benefits than a conventional fixed weight-based dose and whether these benefits outweigh any treatment-related toxic effects. “Although hydroxyurea has been used successfully to treat children and adults with sickle cell disease for many years, there are still many unanswered questions, including the optimal dose,” study coauthor Russell Ware, MD, PhD, of the Cincinnati Children’s Hospital Medical Center, told ASH Clinical News.
This analysis is a continuation of the initial NOHARM trial, which enrolled 187 children with SCD from a hospital in Kampala, Uganda. Patients in this prior blinded portion of the NOHARM trial received either hydroxyurea or placebo for 1 year, followed by open-label treatment with once-daily hydroxyurea 20 mg/kg for 1 year.
At the end of the trial, children were prescribed once-daily hydroxyurea 20 mg/kg, which was administered for several months prior to the NOHARM MTD trial. Patients were then randomized to either:
- hydroxyurea at a fixed standard dose of 20 mg/kg rounded to the nearest capsule size (n=94)
- hydroxyurea at escalating doses until the MTD (based on peripheral blood counts), up to a maximum of 35 mg/kg (n=93)
Only the pharmacist knew the actual treatment group assignments. The mean ages of participants in the fixed-dose and dose-escalation groups were 4.6 and 4.8 years, respectively. At baseline, the mean hemoglobin (Hb) levels were 8.4 g/dL in the fixed-dose group and 8.4 g/dL in the dose-escalation group.
At 8 months, the actual mean daily hydroxyurea doses were 19.2 mg/kg and 29.5 mg/kg in the fixed-dose and dose-escalation groups, respectively.
After 70 children in the fixed-dose group and 76 children in the escalating-dose group had completed 18 months of trial treatment, an independent data and safety monitoring board halted the study, noting that there were significantly fewer clinical complications in the patients assigned to dose escalation. These children also did not experience any increase in toxic effects compared with those in the fixed-dose group.
At the time of trial closure, 86% of patients who received hydroxyurea at escalating doses achieved an Hb level of ≥9.0 g/dL or a fetal Hb level of ≥20% after 24 months (the study’s primary outcome). In the fixed-dosing group, only 37% of children achieved the primary endpoint.
Children randomized to the dose-escalation group also had significantly fewer clinical adverse events (AEs) compared with children randomized to fixed dosing, including:
- all sickle cell–related events (105 vs. 245; incidence rate ratio [IRR] = 0.43; 95% CI 0.34-0.54)
- vaso-occlusive pain crisis (86 vs. 200; IRR=0.43; 95% CI 0.34-0.56)
- acute chest syndrome or pneumonia (8 vs. 30; IRR=0.27; 95% CI 0.11-0.56)
No difference was found between the two groups in terms of sickle cell–related serious AEs (IRR=0.84; 95% CI 0.24-2.79; p=0.77). There were also no differences between the two groups in terms of dose-limiting toxic effects, such as anemia, reticulocytopenia, neutropenia, and thrombocytopenia.
The study authors also noted that dose escalation was associated with fewer key medical interventions, including transfusions (34 vs. 116; IRR=0.30; 95% CI 0.20-0.43) and hospitalizations (19 vs. 90; IRR=0.21; 95% CI 0.13-0.34).
“With direct comparison of fixed-dose hydroxyurea with dose escalation, our data provide strong evidence that dose escalation is safe and provides considerably greater clinical benefits than standard dosing,” the investigators concluded. However, they added that hydroxyurea is not routinely available for most patients living in sub-Saharan Africa, so routine dose escalation will require an increased drug supply and cost-effectiveness analysis.
Despite the fact that the study was limited to only children who resided in Uganda, Dr. Ware noted that the findings from this trial are likely applicable to all children with SCD. He added that these patients had previously received hydroxyurea, but the findings would likely be applicable for the pediatric patient population with previously untreated SCD.
In addition to the clinical findings of this trial, Dr. Ware said that the results demonstrate “the power of global health research and confirm that high-quality research can be conducted in low-resource settings.”
The authors report no relevant conflicts of interest.
John CC, Opoka RO, Latham TS, et al. Hydroxyurea dose escalation for sickle cell anemia in sub-Saharan Africa. N Engl J Med. 2020;382:2524-2533.