Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 52nd Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 4-7, 2010

Due to the limited ability of ferritin, the key iron storage protein, to contain excess loads of iron, chelation is essential to prevent organ damage whenever a disease or a treatment leads to persistent iron elevations. Mediated by compounds such as hydroxyl radicals that are formed in the presence of free iron, the damage from excess iron to such organs as the liver and the heart is well documented. Diseases, including cancers, that produce chronic anemia requiring blood transfusions, place patients at risk for complications of iron overload even after patients recover. Iron chelation reduces iron levels, and new data with an oral iron chelator, deferasirox, show it prevents iron-related complications in patients with ß-thalassemia.

Improvement in Ishak Fibrosis Staging

Of patients treated for at least 3 years with deferasirox, “approximately 80% experienced either stabilization or improvement in their Ishak fibrosis staging,” reported Prof. Yves Deugnier, Liver Disease Unit, University Hospital Pontchaillou, INSERM, Rennes, France. Referring to one of the most commonly used methods to score liver fibrosis, Prof. Deugnier reported that this is a compelling demonstration that iron chelation can stabilize or reverse liver fibrosis due to iron overload.

The evidence was generated from 219 ß-thalassemia patients who received deferasirox for at least 3 years. All had initially participated in controlled trials with this oral iron chelation agent. Over the long-term follow-up, patients were evaluated for change in Ishak fibrosis staging. Serum ferritin and ALT were also assessed periodically as was liver concentration control as assessed by biopsy. It is notable that although 76 patients (34%) did not meet the predefined levels of iron control, which were based on baseline levels (e.g. at least a 3 mg reduction in Fe/g dw for those with a level of at least 10 Fe/g dw), the improvement in Ishak staging was independent of these study definitions.

“The improvement or stabilization in liver fibrosis was observed in patients who met the liver iron concentration success criteria and in those who did not, suggesting that the observed effects are independent of the degree of chelation effect,” Prof. Deugnier told delegates. Although he did note that the reductions in elevated liver enzymes were statistically significant only in those who met the criteria for treatment success, he characterized the overall improvement in liver fibrosis on long-term deferasirox treatment “striking compared with other reports in the literature.” Impressed by this degree of protection, Prof. Deugnier called for studies to look for the same protection in other vulnerable organs.

MRI Study

In fact, some data are already available from other organs. In a magnetic resonance imaging (MRI) study to evaluate the effect of oral chelation on iron in the heart, the data correlated reductions in iron levels with a reduction in clinical risks. In this study, 71 ß-thalassemia patients with myocardial siderosis followed for at least 3 years on deferasirox 30 to 40 mg/kg/day were evaluated with MRI T2 images of the heart using a blinded review process. Of those with mild-to-moderate myocardial iron levels at baseline, 68% normalized by the end of 3 years on T2 imaging. Of those with severe myocardial iron loading, 50% improved to the mild-to-moderate range.

“This is the first prospective study to report 3-year follow-up on cardiac iron removal for an iron chelator and adds to recently published findings from a 2-year study of deferasirox in cardiac iron overload,” stated Dr. Dudley J. Pennell, CMR Unit, Royal Brompton Hospital, London, UK. Referring to a study by Wood et al. (Am J Hematol 2010;85:818-9), Dr. Pennell reported that cardiac function, as assessed by left ventricular ejection fraction (LVEF), remained normal over the period of treatment. According to Dr. Pennell, the reduction in iron loading among patients with severe levels at baseline was “associated with a much lower risk of heart failure.” This was achieved with no significant decline in renal function.

Five-year Efficacy and Tolerability Findings in Patients with Sickle Cell Anemia

In one of the longest prospective studies with iron chelation, 5-year outcome in patients with sickle cell disease demonstrated persistent control of iron levels with reassuring safety. Indeed, among patients remaining on treatment, median iron loads remained significantly reduced from baseline, while the tolerability actually improved as the frequency of the many side effects, such as gastrointestinal symptoms, diminished. “This is the first study to report that deferasirox can significantly decrease serum ferritin levels over the long term in sickle cell disease patients with a manageable safety profile,” confirmed Dr. Elliott Vichinsky, Children’s Hospital and Research Center, Oakland, California. All of the patients in this study had initially participated in a controlled trial and were then followed on treatment long-term. Of the 185 patients included in this analysis, 132 were randomized initially to deferasirox and 53 crossed over to deferasirox after the controlled study was completed. Median serum ferritin levels in patients who remained on treatment for at least 4 years decreased significantly (median absolute change of 591 ng/mL; P=0.027), but the study may be even more important for demonstrating long-term safety.

While it has been suggested before that iron chelators might have an adverse effect on renal function, median creatinine clearance remained in the normal range without any evidence of progressive impairment. The most common side effects associated with deferasirox were gastrointestinal, especially nausea (14.6%) and diarrhea (10.8%), but these were largely confined to the first months of therapy. There were few significant side effects in patients after the first year of therapy. In this study, which included a sizeable proportion of children who were pre-adolescent at the start of treatment, no differences in growth or sexual development could be detected relative to population norms.

However, Dr. Vichinsky did stress that dose titrations are needed to achieve target reductions in serum ferritin. Although there was a range in the doses needed, the data from this study suggest that the minimum daily dose appears to be >20 mg/kg. In a subgroup evaluated for adverse events before and after dose adjustments, uptitrations were generally well tolerated.

EPIC Post-hoc Analysis in Myelodysplastic Syndrome

While the safety of iron chelation is reassuring, the most exciting new data regarding this treatment is the evidence that it may have a favourable effect on hematopoiesis in patients with hematological malignancies. In a post-hoc analysis of the EPIC (Evaluation of Patients with Iron Chelation) study conducted in 341 patients with myelodysplastic syndrome (MDS), the iron reductions achieved with deferasirox chelation were found to correlate with improved erythroid, platelet and neutrophil response. Specifically, while 22.6% of patients had erythroid and 14% had platelet and neutrophil responses, the hematologic responses were associated with larger decreases in serum ferritin even though baseline levels among responders and non-responders were comparable.

While these findings are consistent with previous case reports, “this is the first large analysis from a study of iron-overloaded MDS patients to show that treatment with an oral chelator improves hematologic parameters along with reducing iron,” reported Dr. Norbert Gattermann, Hematology Clinic, Heinrich-Heine-Universität, Düsseldorf, Germany. He speculated that although simply reducing iron overload might be sufficient to improve hematopoiesis, other more indirect effects, such as a decrease in oxidative stress, might also play a role.

Summary

The importance of monitoring for transfusional iron overload has long been recognized in ß-thalassemia patients, but the risk of end-organ damage and the evidence that iron chelation can reduce this risk encourages aggressive management of excess iron in all patients who are transfusion-dependent. In a retrospective study of the medical records of any patient receiving transfusions, led by Dr. Leslie A. Ray, H. Lee Moffitt Cancer Center, Tampa, Florida, the 73 patients monitored for iron overload had a significantly longer survival than the 90 patients who were not (16.1 vs. 2.3 months; P<0.0001). Such data are part of a growing body of evidence demonstrating that identifying and treating iron overload improves outcomes. In conjunction with the safety of iron chelation and the evidence that therapy may favourably affect some types of underlying pathology, control of iron overload appears to have an important potential role in improving outcome.