Iron deficiency limits hydroxyurea-induced fetal hemoglobin and clinical efficacy in sickle cell disease

Abstract

Abstract Background Hydroxyurea (HU) is a widely used therapy for sickle cell disease (SCD) patients. HU reduces the frequency of acute complications, such as vaso-occlusive crises (VOCs) and acute chest syndrome (ACS), as well as mortality. Its mechanism of action is multifactorial, and patient response shows inter-individual variability. While some patients experience a significant increase in fetal hemoglobin (HbF%) levels, others show minimal change, although Mean Corpuscular Volume (MCV) increases in all patients. Studies have shown that iron deficiency may reduce intracellular hemoglobin S (HbS) concentrations in untreated patient. In this study, we assessed the relationship between iron status and HU response by analyzing biological and clinical parameters in SCD patients, based on the hypothesis that Iron metabolism plays a key role in modulating the therapeutic response. Materials and Methods We analyzed clinical and biological data from patients with HbSS and Sβ⁰-thalassemia genotype, in their steady state, collected between 2017 and 2024 at the Sickle Cell Referral Center of Henri Mondor University Hospital and enrolled in the FCDREP study. Inclusion criteria were: age ≥18 years, HbSS or Sβ⁰thalassemia, treatment with or without Hydroxyurea (HU), and no chronic transfusion (TF) or exchange TF program. Blood samples were collected during routine outpatient visits, at least 3 months after any TF, at least 1 month after vaso-occlusive crisis (VOC), and with a stable HU dose maintained for at least 3 months. Clinical and biological data were collected including: Hemoglobin (Hb), Fetal Hb percentage (HbF%), quantification of fetal hemoglobin (HbF) per red blood cell (HbF/cell), MCV, Mean Corpuscular Hemoglobin Concentration (MCHC), Mean Corpuscular Hemoglobin (MCH), Red Cell Distribution Width (RDW), Reticulocytes, serum ferritin, transferrin saturation, iron, and the number of VOC with hospitalizations. Iron deficiency was defined as transferrin saturation <20 %. All parameters were compared between patients with or without HU therapy and Iron deficiency. Results: We analyzed data from 278 adult SCD patients. Among them, 218 (79%) received HU therapy, while 60 (22%) were untreated. The median age of the patients was 39 years [IQR: 31–47.6], and 57.6% were women. The median HU dose was 17.6 mg/kg/day [IQR: 14.1–20.8]. We classified patients according to their iron deficiency status and HU therapy. Iron deficiency was observed in 43/218 (HU) and in 29/60 (non-HU) patients. Notably, among HU treated patients, iron deficiency was associated with a significant reduction in global %HbF, HbF/cell, MCV, MCH. Patients on HU with Iron deficiency experienced a significantly higher number of VOCs 2.0 [0.0-2.0] vs 0.8 [0.0-1.0] (p< 001), whereas no difference was observed in untreated patients 0.4 [0.0-1.0] vs 0.4 [0.0-0.0] VOCs (p=0.93). Correlation analyses have shown that iron deficiency reduces HbF synthesis more significantly than HbS and the ratio of cellular HbF/HbS decreases significantly in Iron-deficient patients on HU. This leads to increased intracellular HbS concentration and greater risk of sickling. However, using transferrin saturation rather than ferritin alone can partially help this issue, as ferritin may be falsely elevated in the inflammatory context of SCD. Conclusion: This study highlights the importance of iron in HbF production and its role in the efficacy of HU treatment. Iron deficiency can limit the response to HU, especially by reducing global HbF production, but also at the cellular level as well, and thereby raising the risk of sickling and VOC recurrence. Patients on HU and iron deficiency may lose the therapeutic benefits and may experience a recurrence of VOC. Treatment noncompliance and Iron deficiency are both associated with a decrease in MCV. Therefore, the screening for iron deficiency using transferrin saturation is essential in SCD patients and iron supplementation may be crucial to restore treatment efficacy for HU treated patients.