Effectiveness of hydroxycarbamide in children with sickle cell disease - Analysis of dose-response metrics in a large birth cohort in a tertiary sickle cell centre.

BACKGROUND: Despite the well-established efficacy of hydroxycarbamide in the management of sickle cell disease (SCD), the paucity of real-world clinical data limits the establishment of a practical dosing strategy. The aim of this study was to analyse the dose-response metrics of hydroxycarbamide associated with the minimum effective dose protocol - specifically, between dose groups and differing degrees of myelosuppression.

DESIGN/METHODS: A retrospective cohort study was conducted on 93 patients who were initiated on hydroxycarbamide between 2005 and 2017 at a tertiary haemoglobinopathy centre in London, UK. The burden of acute SCD-related complications was defined by the annualised rates of emergency department attendances and hospital admissions. Secondary outcomes included haematological, biochemical, liver, renal and transcranial Doppler velocity status. Comparisons were performed upon stratification via dose (<20 mg/kg/day, 20-24 mg/kg/day and ≥25 mg/kg/day) and sustained absolute neutrophil count (ANC) values (ANC <4 × 109 /L and ANC ≥4 × 109 /L).

RESULTS: Clinical outcomes were not predicted by dose or ANC values. Whilst laboratory indices between dose groups were also non-statistically significant, patients maintained on ANC <4 × 109 /L were shown to achieve superior responses in haemoglobin, haemoglobin F, absolute reticulocyte count and liver function. Toxicities occurred idiosyncratically, with minimal reports of transient neutropaenia and thrombocytopaenia.

CONCLUSIONS: Objective clinical responses may be achievable without intensive dose escalation. Our finding that greater myelosuppression is associated with greater improvements in laboratory markers of clinical benefit is consistent with prior clinical trials, but ongoing effectiveness studies are needed to determine whether these benefits can be reliably demonstrated in routine clinical practice using different dosing protocols.