Treatment with the iron chelator deferasirox for at least 3 years stabilized or improved liver fibrosis and necroinflammation and also reduced serum alanine aminotransferase levels in patients with beta-thalassemia and iron overload, Dr. Yves Deugnier and his colleagues reported in the October issue of Gastroenterology.
This improvement occurred independently of patients’ treatment response as measured by liver iron concentration, which suggests that some of the drug’s benefit is independent of its iron-clearing ability. The improvements also were seen regardless of patients’ hepatitis C virus (HCV) antibody status at baseline, said Dr. Deugnier of University Hospital Pontchaillou in Rennes, France, and his associates (Gastroenterology 2011 October [doi:10.1053/j.gastro.2011.06.065]).
"To our knowledge, this is the first analysis which demonstrates regression of fibrosis in patients with beta-thalassemia during iron chelation therapy," they noted. The study was sponsored by Novartis, maker of deferasirox.
"The overall improvement in liver fibrosis and necroinflammation with deferasirox treatment seen in this study is striking," given that there is scant evidence in the literature that any medication can reverse fibrosis.
The investigators performed a secondary analysis of data on 219 subjects participating in two 1-year trials. One trial involved patients with beta-thalassemia major who had received 1 year of either deferasirox or deferoxamine therapy, and the other involved patients with various transfusion-dependent anemias, including beta-thalassemia, who had received 1 year of treatment with deferasirox.
In Dr. Deugnier’s study, the subjects with beta-thalassemia were followed as they continued on deferasirox after the trials concluded, because the data collected so far showed that a 1-year course of therapy may not be long enough to reveal changes in the extent or severity of fibrosis.
All the study subjects were at least 2 years of age at baseline and were receiving eight or more blood transfusions per year. All underwent liver biopsy at baseline and after 3 years of deferasirox treatment, and 210 had evaluable biopsy samples.
A total of 134 patients were classified as response successes on the basis of their liver iron concentrations, while the other 76 were deemed to be response failures by this measure.
However, fibrosis staging scores improved in both groups – the response successes and failures. Overall, 122 patients, 56% of the entire study population, showed stabilization of liver fibrosis and another 59 (27%) showed regression of fibrosis.
Fibrosis stabilized in 60% of response successes and 49% of response failures, while it regressed in 26% of response successes and 30% of response failures.
This lack of correlation between liver iron concentrations and improvements in fibrosis suggests that deferasirox’s effect on fibrosis may be independent of its ability to remove iron. It is possible that the drug exerts a direct effect on the pathophysiologic mechanisms that moderate fibrosis, the researchers said.
"Recent studies have shown an inhibitory effect of deferasirox on the transcriptional nuclear factor NF-KB35, a protein which also has been shown to be implicated in the development of fibrosis of the lung. Further molecular biology studies are required to explore this hypothesis," they noted.
Deferasirox also improved liver fibrosis regardless of subjects’ HCV status. The fibrosis stabilized in 47% of HCV-positive and 57% of HCV-negative patients, and it regressed in 30% of HCV-positive and 27% of HCV-negative patients. Thus, infection with this virus does not appear to diminish the drug’s effectiveness.
Ishak necroinflammatory grading scores improved by a mean of 1.3 points in the study population overall. As with fibrosis, inflammation did not correlate with liver iron concentrations. And as with fibrosis, necroinflammatory scores improved in both HCV-positive and HCV-negative patients.
Patients who took deferasirox showed a mean decrease from 40.9 to 29.6 IU/L in mean serum alanine aminotransferase (ALT), a marker of hepatocellular damage. Improvements in ALT correlated with decreases in liver iron concentrations, so that only patients classified as response successes by this measure showed significant reductions in ALT as well.
The study findings "are encouraging and warrant further studies to investigate the potential effects of deferasirox in preventing iron-induced tissue fibrosis in organs other than the liver, such as endocrine organs or the heart. In support of this concept, recent preclinical data in which deferasirox treatment was administered to an iron-overloaded gerbil model were associated with attenuated cardiac fibrosis," Dr. Deugnier and his colleagues wrote.
Most of the authors disclosed relationships with Novartis; several authors are employees of the company and others receive honoraria, lecture fees, or grants from Novartis.