Undetectable Hydroxyurea Levels in the Majority of Sickle Cell Disease Patients, Especially in Young Children.

Hydroxyurea (HU) is the most widely prescribed disease-modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z-score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy (n = 539), HU was detected in 39% (143/369) of HU-prescribed patients ≥ 10 years (median age 31.8 [10.0-69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2-9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV (p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU-prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.