Long-Term Iron Chelation Therapy with Deferiprone in Patients with Thalassemia Major and Low Iron Load

Introduction and Objectives: Iron chelators are effective in reducing iron burden and in improving clinical outcomes in patients with transfusional iron overload. However, limited data are available on their efficacy and safety in transfusion-dependent patients with low iron overload, due mainly to concerns of chelation toxicity observed with deferoxamine (DFO) in patients with serum ferritin (SF) < 1500ug/L. Deferiprone (DFP) has markedly lower affinity for iron (pFe³⁺ log stability constant = 19.9) than that of deferoxamine (26.6), and may provide a better safety profile in patients with low iron overload. The objective of this study is to evaluate the safety and efficacy of DFP in patients with thalassemia major (TM) and SF <500 ug/L.

Methods: A total of 32 patients with TM (15 males) who had achieved SF <500 ug/L while on chelation with combined DFO and DFP (n=30) or on deferasirox (DFX) (n=2) had their chelation switched to DFP monotherapy (75-100mg/kg/day). All patients received 50 mg of oral zinc sulfate once a week for the duration of the study. Iron overload was assessed using SF and MRI T2* of liver and heart within 3 months of switch and then 6-12 monthly thereafter. Renal and liver function tests were performed monthly and trace elements (serum magnesium, copper, zinc and selenium) were also assessed.

Results: Patients were followed for a median of 4.5 years (Range: 1-11 years). The median age at time of switch was 22.7 years (Range 11-28). The mean packed red blood cell volume transfused during the study was 197 mL/kg/year (Range: 157-282 mL). There was no significant increase in the SF (Baseline 392 ug/L; Last assessment 418 ug/L; p value 0.55) or the liver iron concentration (Baseline 3.44 mg/g dw; Last assessment 3.1 mg/g dw; p value 0.54) during the follow up. On the contrary, there was a statistically significant improvement in the cardiac T2* (Baseline 30 ms; Last assessment 38 ms; p <0.001). DFP was discontinued in 28% of patients (Ineffective in 3; Agranulocytosis in 1; Pregnancy in 1; Bone marrow transplantation in 2; Deaths in 2). The two deaths were unrelated to the chelation therapy (Decompensated HCV related liver cirrhosis and severe hypoglycaemia in a patient with diabetes mellitus). Two patients had mild asymptomatic hypocalcemia, and one had low copper levels. All three patients normalized their results with no treatment and without stopping DFP. No patient reported gastrointestinal disturbances or arthralgia, and none had elevation of liver enzymes or serum creatinine.

Conclusion: Long-term DFP therapy in patients with TM and low iron overload was effective in stabilizing SF and LIC and was associated with improvement in the myocardial iron. The safety profile was consistent with those observed during therapy in patients with more severe iron burden and there were no increase in the unexpected adverse drug reactions.