Both Hydroxyurea (HU) as a single agent or in combination with Erythropoietin (rHuEPO) became a therapeutic option for β-Thalassemia intermedia(TI) over last 2 decades. However superiority and safety of combination therapy over HU alone needs further evaluation. Aim: to assess the increase of hemoglobin levels in TI patients by at least 1g/dl above baseline during therapy using combined HUO and rHuEPO compared to single HUO therapy, also to report decline in transfusion requirements, quality of life (QoL), and any drug related adverse events. Patients and methods: An interventional prospective randomized open-labeled study; was approved from the local ethical committee and was registered in the Clinical Trials. Goverment (NCT01624038 ). Eighty Patients 18 years or less will be assigned into one of 2 groups using a random allocation method. Group A: Forty TI patients (age range: 5–18 years) considered as interventional arm 1 and received combined daily HUO (25 mg/kg/day orally) and rHuEPO (1000 IU/kg/week subcutaneously divided in three times/week). Group B: Forty TI patients (age range: 4–18 years) considered as arm 2 (control arm) and received daily single HUO therapy of 25 mg/kg/day. Both groups were followed up both clinically and laboratory for a mean period of one year with assessment of transfusion requirements, blood pressure weekly, liver and renal functions, Hemoglobin (Hb), HbF monthly, basal serum erythropiotin levels and QoL was assessed at study entry and end using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Diagnosis of TI was based on both genetic mutations and absence of transfusion during the 1st 2 years of life. Exclusion criteria were: evidence of active hepatitis (ALT>5 times) or renal impairment. Results: There were a significant improvement in the QoL in 80% and 60% of patients on combined compared to single therapy(p<0.05). There was a significant increase in both Hb and HbF (p <0.001), and the increments were strongly correlated (r =0.84; p <0.001) in both groups more in group A patients. The median Hb level in groups A and B during the study was 9.1 and 7.9 g/dL, respectively (p=0.03). In 68% (n=27) of TI patients group (A) were responded by a 0.5–3 g/dl increase in Hb level. There was significant difference between the 2 groups as only 20% (n=8) of patients in group B show intended improvement in their hemoglobin levels (p<0.01). In studied thalassemics 40%(n=16) of group A compared to 15%(n=6) of group B (p=0.01) became transfusion independent with 20% in group A showed decrease in their transfusion requirements with significant decrease in transfusion index compared to group B thalassemics (p<0.001). There was no significant change in absolute Hb-F, and serum ferritin levels during treatment. splenectomized patients and those with serum EPO less than 500 mU/mL, and intial HbF% > 40% had best response to combined therapy. Side effects from rHuEPO included bone pain in 2 patients, headache in 4 patients, however no uncontrolled hypertension was reported. Gastrointestinal irritation was observed in 3 patients and resolved when the dose was given at bedtime. No renal or hepatic toxicity were reported. A single case of mild neutropenia was reported and recovered within one week of temporary discontinuation Conclusions: Hu was effective in management of TI however combination with erythropiotin had an additive therapeutic effect and was well tolerated with no further serious adverse events.
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