Hydroxyurea for Non-Transfusion-Dependent β-Thalassemias: A Meta-Analysis

Abstract Background Non-transfusion-dependent (NTD) β-thalassemia syndromes consist of β-thalassemia intermedia and moderate Hemoglobin E/ β thalassemias. They are characterized by varying degrees of chronic anemia and a wide spectrum of complications due to ineffective erythropoiesis and iron overload from chronic transfusions. Hydroxyurea, an oral chemotherapeutic drug, is anticipated to decrease disease severity by raising hemoglobin (Hb) levels and reducing transfusion requirements. Objectives To examine the evidence for clinical efficacy and safety of hydroxyurea in NTD β-thalassemia patients of any age. Search strategy We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ongoing trials registers, and major preceding conferences. Hand searches were also conducted using reference lists from primary studies. All searches were updated to June 5, 2014. Selection criteria Randomized controlled trials (RCTs) and observational studies (sample size ≥ 5) assessing the clinical efficacy of hydroxyurea alone for three months or longer, for the treatment of patients with NTD β-thalassemia were included. Data collection and analysis Two authors acted as reviewers and independently assessed study quality and extracted data from the included studies. Authors of included studies were contacted if further information was required. NTD β-thalassemia was sub-classified into two groups; mild (no or < 4 transfusion per year) and severe (≥4 transfusions per year). The effect size was estimated as a proportion (responders over sample size). For Mild-NTD-β-thalassemia, response rate (RR) was identified as a ≥10g/dL increase in Hb. In Severe-NTD-β-thalassemia, overall response rate (ORR) was defined as ≥ 50% reduction in transfusion need and complete response rate (CRR) was defined as complete cessation of regular transfusion. All data was analyzed using Stata, Version 13.0. Results For Mild-NTD β-thalassemia, a total of 14 studies (1 RCT and 13 observational studies) involving 344 patients met inclusion criteria. Hydroxyurea therapy was effective in raising Hb by 10g/dL from baseline in 56% (95% CI, 46-67%). In Severe-NTD-β-thalassemia, 8 studies (1 RCT and 7 observational studies) involving 305 patients were included. Hydroxyurea was associated with a statistically significant decrease in transfusion need with CRR of 53% (95% CI, 37-70%) and ORR of 79% (95% CI, 68-91%). All of the studies had several limitations, such as small sample size, lack of comparison group, under-reporting of data and methods, and the majority having been observational studies. Adverse events (AEs) were transient and improved with temporary cessation of the drug and/or adjustment of the dose. Author’s conclusion Hydroxyurea appears to be effective in the management of NTD β-thalassemia (both mild and severe forms) by raising the Hb by at least 10g/dL and decreasing the need for chronic blood transfusions completely or partially, respectively, in the majority of patients. It appears to be well tolerated and associated with mild and transient AEs. Patients with NTD β-thalassemia may benefit from a trial of hydroxyurea, though large RCTs assessing efficacy should be done to confirm the findings of this meta-analysis. Disclosures Off Label Use: Hydroxyurea for β-Thalassemia.

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