Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics‐guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia

Abstract

Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (nearpancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

Clinical Utility of the Addition of Molecular Genetic Testing to Newborn Screening for Sickle Cell Anemia

“…Now, the increasing use of early, pre-symptomatic disease-modifying therapy (e.g., hydroxyurea initiation at 6 months of age) has made this critical diagnostic distinction time-sensitive ( 9 , 12 ). For infants with SCA, hydroxyurea should be started to prevent and reverse this early decline in HbF rather than waiting for the HbF level to decline to some arbitrary level ( 13 ). However, treating children who have HbS/HPFH with hydroxyurea is not indicated and exposes them to unnecessary risks, expenses, laboratory monitoring, and inconvenience.…”

Precision Medicine and Sickle Cell Disease

“…Perhaps the best approach to a more precise use of hydroxyurea in SCA involves using pharmacokinetic measurements to individualize the dose of hydroxyurea and rapidly achieve the maximum tolerated dose, 61 which has been shown to offer the most clinical benefit. 9 Traditionally, patients have been started on moderate dose of hydroxyurea and the dose gradually increased over months and years until there is clinical benefit or evidence of myelosuppression, as suggested by some degree of neutropenia.…”

“…This approach is fairly slow, with many patients never reaching optimal doses. Quinn et al, 61 showed that high HbF levels could be rapidly achieved by starting children on the maximum tolerated dose from the onset, as predicted by pharmacokinetic methods. This approach has not been widely adopted yet, partly because of limited availability of hydroxyurea pharmacokinetic measurements, although there is a trend toward starting children on higher doses rather than gradually building up.…”

Assessment of donor cell engraftment after hematopoietic stem cell transplantation for sickle cell disease: A review of current and future methods

“…The RBC transfusions and hydroxyurea 22 are mainstays of therapy, but are not without risk and do not eradicate the disease. Newer treatments such as L-glutamine, 23 voxelotor, 24 and crizanlizumab 25 offer disease modification but must be taken indefinitely.…”