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Selected Summaries Indian Pediatrics 1999; 36:738-740 |
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Deferiprone for Thalassemia Major |
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[Olivieri NF, Birtttenham GM, McLaren CE, Templeton DM, Cameron RG, McChelland RA, et at. Long term safety and effectiveness of iron chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998; 339: 417-423]. Patients with thalassemia major require repeated blood transfusions for survival and subsequently suffer from the ill effects of iron deposition in various vital organs especially liver and heart. Desferoxamine, an iron chelator has been in use for a long time but compli- ance in patients is difficult to achieve owing to , its parenteral mode of administration. Thus search .continues for an ideal iron chelator which is effective orally, cheap and devoid of serious adverse effects. One such drug deferiprone (1,2 dimethyl 3 hydroxypyridin 4 one L1) was introduced for clinical use(1). Studies on serum ferritin concentration and direct assessment of body iron have shown a favorable effect of deferiprone on iron balance(2). The long term effects of this drug are largely unknown. Studies in animals have shown that it is capable of causing hepatic fibrosis(3) and clinical efficacy may decrease with continued use. The current study evaluated the effects of prolonged deferiprone therapy (4.6:t 0.3 years) in 19 patients of thalassemia major receiving blood transfusions and with hemoglobin concentration regularly above 9.5 g per deciliter. In this 7 year study, hepatic iron was measured yearly by chemical analysis of liver biopsy specimens, magnetic spectrometry or both. Three histopathologists who were un- aware of the patients clinical condition examined the iron content of the 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver biopsy specimens obtained from 20 patients treated with desferoxamine for more than one year were valuated. A he- patic iron concentration of less than 80 J1mol per gram of liver net weight was considered to indicate effective iron-chelator therapy and a concentration of 80 J1mol or more per gram of liver was considered poor chelator therapy. Among the 18 patients in whom the effective- ness of deferiprone could be evaluated, the mean (:t SE) hepatic iron concentration de- creased from 88.7:t 12.1 to 65.5:t 7.9 J1mol per gram of liver, wet weight (normal value about 1.6) after a mean of 4.6 :t 0.3 years of therapy (range 2 to 7). This decrease of 23.2 :t 10.9 J1mol of iron per gram of liver was not significant. In nine of the patients, the serum ferritin concentration exceeded 2500 J1g per litre the threshold used to distinguish effective from ineffective chelation therapy. Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could evaluated for progression of hepatic fibrosis, and 5 had progression of fibrosis (median time 3.2 years) on biopsy as compared to desferoxamine treated patients who did not demonstrate any progression of hepatic fibrosis in any specimen examined. The deferiprone treated patients had a significantly higher mean initial hepatic iron concentration than the desferoxamine treated patients. No significant adverse hematological effects were observed during deferiprone therapy. The results of this study show that prolonged deferiprone therapy may cause progression of hepatic fibrosis as the hepatic iron concentrations in these patients did not de-monstrate an increase. This was not observed in patients receiving desferoxamine therapy. Comments Repeated blood transfusions and consequent iron overload are frequently seen in patients of thalassemia major and this abnormal deposition in vital organs like heart and liver is a major cause of mortality in there patients. Each 250 ml of blood transfused adds 250 mg of elemental iron and this accumulates owing to the limited ability of the body to excrete it. The aim of all chelator therapies is to keep heaptic iron concentration below 400 µmol per gram of liver, dry weight (22.4 mg per gram) as cirrhosis occurs in all patients once this level is exceeded. Thus effective chelator therapy not only prolongs life of these patients but also'improves their quality if timely introduced at therapeutic doses. The introduction of desferoxamine brought some hope for these patients. However, its high cost, parenteral mode of therapy, almost daily contipuous in- fusion, which is inconvenient and multiple ad- verse effects led researchers to discover other ideal drugs without these limitations. The introduction of d eferiprone is a step in this direction. At doses of 75 mg per kilogram per day it causes negative iron balance and urinary excretion of iron is similar to that seen with desferoxamine. The continued long term efficacy of this drug and its effects on hepatic histology are stilI far from clear. Few studies(4,5) have reported that hepatic iron in- creases over time with prolonged deferiprone therapy though one study reports a decrease. In the current trial Olivieri et at. reported progression of hepatic fibrosis in 5 of 14 deferiprone treated patients, while patients receiving desferoxamine did not develop this complication. Long term therapy with desferoxamine has halted the progression of hepatic fibrosis in patients with thalassemia major(6,7). This study employed too small numbers and hence definite conclusions are difficult to formulate. Though urinary excre- tion of desferoxamine and deferiprone are comparable it is intriguing as to why deferiprone should become ineffective with time. The mean baseline hepatic iron concentration in the deferiprone treated patients was significantly higher than in the desferoxamine treated ones. This is plausible that deferiprone treated patients had a higher risk of fibrosis than the desferoxamine due to the higher initial hepatic iron levels. Further the histopathology of hepatic fibrosis caused by deferiprone is identical to that caused by hepatic siderosis. Also four of the five patients were older and had antibodies to hepatitis C and these risk factors may be contributory in initiating hepatic fibrosis rather than deferiprone therapy per se. Many large randomized multicentric trials are required before any firm conclusions can be reached. It is slightly premature to conclude that deferiprone hastens hepatic fibrosis in patients of thalassemia major receiving this drug on a long term basis for iron chelation. The convenient oral administration along with its lower cost may prove extremely cost effective in developing countries like India.
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