Introduction. Hydroxyurea treatment has proven safety, feasibility, and efficacy for children with sickle cell anemia living in sub-Saharan Africa. Even in malaria endemic regions, hydroxyurea is safe and has been shown to reduce vaso-occlusive events and lower mortality. The optimal dosing regimen is not known, however, and specifically whether a fixed dose at 15-20 mg/kg/day is better than escalation to maximum tolerated dose (MTD) at 25-30 mg/kg/day. Particularly in low-resource settings, additional drug-related toxicities and monitoring costs associated with dose escalation could outweigh potential laboratory and clinical benefits.

Methods. Children with sickle cell anemia previously enrolled in NOHARM (NCT01976416) received hydroxyurea at ~20 mg/kg/day during the open-label portion of that trial, after which they transitioned to commercial supply at that same daily dose. All were then offered enrollment in the NOHARM MTD trial (NCT03128515), a double-blinded trial with 1:1 randomization between continuing fixed-dose oral hydroxyurea (20 ± 2.5 mg/kg/day) versus dose-escalation to MTD (30 ± 2.5 mg/kg/day), using hydroxyurea tablets donated by Addmedica. The primary study outcome was the proportion of study participants who achieved either hemoglobin ≥9.0 g/dL or fetal hemoglobin ≥20% after 24 months of treatment. Secondary outcomes included sickle-related clinical adverse events, malaria events, and laboratory toxicities. We now present the main results of the NOHARM MTD trial.

Results. A total of 187 children enrolled and began study treatment: 94 children (4.8 ± 0.9 years, 55 males) received hydroxyurea at fixed dose versus 93 who received hydroxyurea with dose escalation (4.6 ± 1.0 years, 47 males). At Month 6 of study treatment the average doses were 19.3 ± 1.7 mg/kg/day and 29.0 ± 3.5 mg/kg/day, respectively, and these dose differences were continued through Month 12 and Month 18. The trial was terminated prematurely by the independent Data Safety Monitoring Board after 146 children had reached Month 18, when the clinical complications and interventions were significantly fewer among children randomized to MTD compared to fixed-dose. The incidence rate ratio (IRR) with 95% confidence intervals (CI) included the following: all sickle-related Adverse Events [IRR = 0.43, CI = (0.34, 0.56), P<0.00001]; vaso-occlusive crises [IRR = 0.43, CI = (0.33, 0.56), P<0.00001]; acute chest syndrome/pneumonia [IRR = 0.27, CI = (0.11, 0.55), P=0.001]; transfusions [IRR = 0.29, CI = (0.20, 0.43), P<0.00001]; and hospitalizations [IRR = 0.21, CI = (0.13, 0.34), P<0.00001]. The rates of Laboratory Adverse Events were similar between treatment arms [IRR = 0.83, CI = (0.60, 1.15), P=NS] and dose-limiting toxicities were equivalent [IRR = 1.01, CI = (0.66, 1.54), P=NS] without any episodes of severe neutropenia or thrombocytopenia. Superior laboratory benefits were observed in the dose-escalation arm, with higher hemoglobin (8.7 versus 8.3 g/dL, P=0.006) and fetal hemoglobin (30.5 versus 18.2%, P<0.0001), and lower reticulocyte counts (157 versus 261 x 109/L, P<0.0001) and neutrophil counts (3.4 versus 5.1 x 109/L, P<0.0001). At the time of study closure, more children on the dose-escalation arm had achieved the primary study endpoint compared to those on fixed-dose hydroxyurea (86% versus 37%, P<0.0001).

Conclusion. NOHARM MTD is the first randomized controlled clinical trial to compare hydroxyurea at fixed-dose versus escalation to MTD in either high- or low-resource settings. Hydroxyurea escalated to MTD at ~30 mg/kg/day had superior clinical and laboratory efficacy compared to fixed-dose treatment at ~20 mg/kg/day in this high-risk population, without any increase in toxicity. Optimal hydroxyurea dosing to MTD at ~30 mg/kg/day is therefore recommended for children with sickle cell anemia living in sub-Saharan Africa, which represents an important paradigm shift from the concept of low-dose daily treatment. Increasing access to hydroxyurea at optimal doses will require concerted efforts that include training and implementation strategies, to enable safe and effective hydroxyurea dose escalation for children in low-resource settings.


Ware:Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB.

Author notes


Asterisk with author names denotes non-ASH members.

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