Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.
BACKGROUND
Deferiprone is an orally active iron-chelating agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis.


METHODS
Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 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 parenteral deferoxamine for more than one year were similarly reviewed.


RESULTS
Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (+/-SE) of 4.6+/-0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 micromol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment.


CONCLUSIONS
Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis.
Department of Medicine, University of Toronto, ON, Canada.
N F
NF
Olivieri
G M
GM
Brittenham
C E
CE
McLaren
D M
DM
Templeton
R G
RG
Cameron
R A
RA
McClelland
A D
AD
Burt
K A
KA
Fleming
D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D000077543:Deferiprone; D003676:Deferoxamine / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D006801:Humans; D007501:Iron / Q000032:analysis; D007502:Iron Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019190:Iron Overload / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000737:chemistry; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D016015:Logistic Models; D008297:Male; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure; D017086:beta-Thalassemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron; D003676:Deferoxamine