A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent \u03b2-thalassaemia

Nirmani Yasara,Nizri Hameed,Nethmi Wickramarathne,Aresha Manamperi,Nirmani Wickramasinghe,Chamila Mettananda,Ishari Silva,Kumari Attanayaka,Sachith Mettananda,Lakshman Perera,Anuja Premawardhena,Rexan Rodrigo

doi:10.1038/s41598-022-06774-8

Nirmani Yasara, Nizri Hameed + Show 10 more

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https://doi.org/10.1038/s41598-022-06774-8

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Abstract

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.

Highlights

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease
Hydroxyurea alters epigenetics and proteomics to promote the synthesis of antioxidants, structural proteins, carbonic anhydrase and proteins required for protein repair, which may contribute to its beneficial effects on ineffective erythropoiesis[11]
Despite being one of the earliest diseases to be genetically characterised, β-thalassaemia remains a disease without a cure in most patients[21]

Summary

Introduction

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Patients with transfusion-dependent β-thalassaemia that includes β-thalassaemia major and severe haemoglobin E (HbE) β-thalassaemia require regular 2–5 weekly blood transfusions for life[3]. Luspatercept, an activin IIB receptor ligand trap that inhibits ineffective erythropoiesis, has recently been approved to treat adult patients with β-thalassaemia It showed only a 33% reduction in the transfusion b urden[6]. Treatment modalities that include gene therapy and genome editing have shown promise in preclinical studies and clinical t rials[7,8] None of these has progressed up to a level of standard patient care far. Hydroxyurea induces HbF and reduces the blood transfusion requirement in some patients with non-transfusion-dependent β-thalassaemia[13]. Hydroxyurea alters epigenetics and proteomics to promote the synthesis of antioxidants, structural proteins, carbonic anhydrase and proteins required for protein repair, which may contribute to its beneficial effects on ineffective erythropoiesis[11]

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