Landmark natural history studies, including the Cooperative Study of Sickle Cell Disease1 and the Jamaican Cohort Study,2 generated the seminal observations that fetal hemoglobin (HbF) is a critically important laboratory parameter for individuals with sickle cell anemia (SCA). Higher HbF levels are associated with better clinical outcomes including reduced mortality,3-5 and if present at sufficient levels with pancellular distribution, higher HbF levels can lead to a benign condition.6
Because HbF declines rapidly in the postnatal period, it should theoretically be possible to inhibit or reverse the physiologic suppression of HbF production. The search for pharmacologic modifiers to boost HbF began in the early 1980s with the recognition that γ-globin genes were likely silenced due to methylation of the promoter sequences. Initial treatment with the demethylating agent 5-azacytidine was found to increase HbF production in a patient with SCA, but was predictably toxic.7 In studies by Nathan and colleagues, hydroxyurea was tested as an S-phase–specific cytotoxic/cytostatic agent that does not influence DNA methylation and, unexpectedly, was found to boost F-cells dramatically, first in anemic monkeys8 and then in human patients.9
Since these initial proof-of-principle publications in 1984, hundreds of articles have been published, which collectively have firmly established hydroxyurea as the first and best disease-modifying treatment of SCA. As illustrated in Figure 30-1, a large number of phase I/II and III trials have been conducted in adults, children, and even infants that together document the safety and efficacy of hydroxyurea. Over the past decade, trials have focused on the use of hydroxyurea in specific clinical settings, including the long-term effects on organ function and preservation in babies and young children; the prevention or stabilization of established cerebrovascular disease such as conditional or abnormal transcranial Doppler ultrasound (TCD) velocities; and the safety and feasibility of treatment for patients living in low-resource settings including sub-Saharan Africa. The cumulative data provide compelling evidence for hydroxyurea, leading to evidence-based recommendations for treatment across the life span.10
Hydroxyurea clinical trials over the past 35 years. From the initial 1984 proof-of-principle study in 2 adults to the randomized double-blind NOHARM MTD trial in Africa that found increased benefit from escalated hydroxyurea dosing, hydroxyurea has been carefully investigated in many settings and study designs. Green shading indicates phase I/II trials, whereas red shading indicates phase III trials. The purple boxes indicate the years in which hydroxyurea was US Food and Drug Administration approved for adults (1997) and then for children (2017). CVA, cerebrovascular accident; MTD, maximum-tolerated dose; PD, pharmacodynamics; PGx, pharmacogenomics; PK, pharmacokinetics; TCD, transcranial Doppler. See text for trial acronyms.
The primary disease-modifying mechanism of hydroxyurea occurs via the induction of HbF, which interferes with HbS polymerization. Hydroxyurea is a potent ribonucleotide reductase (RR) inhibitor that has ...