A Randomized Controlled Trial Comparing the Combination Therapy of Deferiprone (DFP) and Desferrioxamine (DFO) Versus DFP or DFO Monotherapy in Patients with Thalassemia Major.

Several clinical studies have shown that the combination of deferiprone (DFP) with desferrioxamine (DFO) is efficacious with regard to decrease in serum ferritin (SF), reduction of liver iron concentration (LIC) and increase in urinary iron excretion (UIE) in patients (pts) suffering from thalassemia major (TM). However, there is lack of randomized controlled trials comparing the efficiacy and safety of the combination therapy versus DFP or DFO monotherapy.

This is the first randomized controlled trial analyzing and comparing changes of LIC and total iron excretion (TIE) in pts treated with the combination therapy versus pts treated with DFP or DFO monotherapy during a study period of one year. A total of 95 pts with TM were randomized into one of the following three treatment arms: DFP was given orally at a daily dose of 75 mg/kg either alone, in combination with s.c. DFO (40–50 mg/kg twice weekly) or DFO was given alone at a dose of 40–50 mg/kg 5 days a week (control arm). All pts had been treated with DFO prior to the study.

LIC was measured in biopsies at baseline and after one year. TIE / day was calculated as (iron transfused during study period (mg) + (LIC at T₀ - LIC at T_1y) x 10.6 x body weight in kg) / number of days on treatment between biopsies. Biochemistry measurements including SF and liver enzymes were performed at 3-monthly intervals. Blood counts were analyzed weekly for 8 weeks and thereafter bi-weekly. Cardiac function (ECHO) was assessed 6-monthly. UIE was measured quarterly; in pts receiving combination therapy on two different days, i.e. during DFP and combination therapy.

Compliance was excellent in all three treatment arms. In total, 14 pts (15%) dropped out from the study: one due to biopsy failure at baseline, five withdrawals from informed consent, four non-compliance to treatment, one due to jaundice, one died from arrhythmia induced heart failure, and two (2.1%) developed agranulocytosis. The most common adverse events were transient increase in liver enzymes, nausea and arthralgia.

The average change in LIC after one year was most pronounced in the combination arm (−47%; p=0.001), but LIC was also significantly lowered after one year monotherapy with DFO (−23%; p=0.13) or DFO (−45%; p=0.003). A reduction of the liver iron score acc. to Sciot was observed in all three treatment arms and the change after one year compared to baseline was statistically significant in the combination arm (p=0.0013). Further, the combination regimen was associated with the highest TIE (mean±SD: 0.46±0.22 mg/kg/d; p=0.00003). The majority of pts in all treatment arms showed a clear decrease in SF and the mean SF was significantly reduced in the combination arm after one year (−2′120μg/L; p=0.0003). The left ventricular ejection fraction increased during combination therapy (+3.4% absolute units; p=0.19), whereas it slightly decreased (−2.1% absolute units; p=0.41 and p=0.55, respectively) after either DFP or DFO treatment. The mean daily UIE was higher in DFP-containing regimens than with DFO single agent therapy. UIE on days of combination (0.90±0.33 mg/kg/24h) was significantly higher than on days of DFP monotherapy (0.53±0.26 mg/kg/24h) (p=0.0003).

This study indicates that the combination of daily DFP and twice weekly DFO at standard doses is a highly efficacious and safe chelation therapy for pts with TM.