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PRIORITY PRESS - 51st Annual Meeting of the American Society of Hematology

New Orleans, Louisiana / December 5-8, 2009

Five-year results from an extension of a major phase III clinical trial that established the efficacy of the oral iron chelator deferasirox in patients with beta thalassemia were presented concurrently with new evidence that this same iron chelator can improve survival in appropriately selected myelodysplastic disease (MDS) patients with iron overload. The evidence of outcome benefits with an oral agent comes at a time when there is increasing evidence that iron overload is often overlooked in at-risk populations, including those with MDS.

“Iron overload has been shown to be an independent, negative prognostic factor for survival and progression in MDS,” stated Dr. Mattias Schmid, University Hospital Ulm, Germany. The author of a study on deferasirox in MDS, Dr. Schmid told delegates, “We now have data from large studies showing that we can achieve sustained reductions in iron burden using an oral agent with very well-defined and manageable adverse effects.”

Long-term efficacy and safety data with deferasirox were also reported here at ASH. They were generated by five years of follow-up in patients with beta thalassemia, a hereditary condition associated with a lifelong risk of iron overload secondary to the need for regular blood transfusion. The follow-up is an extension of a one-year, controlled phase III trial in which patients were randomized to oral deferasirox or injectable deferoxamine. In that study, the two therapies produced similar dose-dependent effects on net body iron balance and liver iron concentration (LIC) levels. In the extension, patients who were initially randomized to deferasirox remained on this therapy, while those initially randomized to deferoxamine were crossed over.

Of the 555 patients in the extension, about 55% were initially treated with deferasirox and 45% were crossed over. There were incremental reductions over time for both LIC and serum ferritin measures with the reductions in the deferoxamine crossovers reaching statistical significance from the time of the switch. Reflecting good tolerability observed over follow-up, 73.4% of the crossovers remained on deferasirox for the full study period, which extends to five years. There was no progressive liver or renal dysfunction observed and side effects such as nausea, rash and abdominal pain dissipated over time. Indeed, rash, which was the most common side effect in the first year, was not observed in subsequent years.

EPIC: Post-hoc Analyses

Initial dose, however, does appear to be critical for optimal control in data generated last year by the EPIC (Evaluation of Patients with Iron Chelation) study and reinforced by a newly completed post-hoc subgroup analysis. In EPIC, the largest iron chelation study ever conducted, 937 beta thalassemia patients with a history of transfusional iron overload were evaluated with a range of doses to compare efficacy and safety. The study concluded that starting doses must be titrated according to the degree of iron burden. The new post-hoc analysis indicates that patients with a high iron burden can be controlled with deferasirox monotherapy at a dose of 30 mg/kg/day even when they were not previously controlled with a combination strategy. Moreover, a lower maintenance dose may be adequate once ferritin levels are brought under control.

“At a dose of at least 30 mg/kg/day for at least one year, deferasirox alone led to significant and clinically relevant reductions in serum ferritin irrespective of whether patients had received deferoxamine or deferiprone or a combination of these,” noted Dr. Ali Taher, American University, Beirut, Lebanon. “The safety profile was consistent with previously published data in patients with beta thalassemia major and confirms pooled data from other studies showing that doses of 30 mg/kg/day or greater are not associated with more adverse events or worsening of renal or liver function when compared with lower doses.”

In this post-hoc analysis, 129 patients from EPIC who were heavily iron-overloaded and received a deferasirox dose of at least 30 mg/kg/day over the one-year study were evaluated. All of the patients had a baseline serum ferritin level of >4500 ng/mL despite prior chelation therapy. In those on a prior monotherapy, the median decrease of serum ferritin was 1024 ng/mL (P<0.0001) at the end of one year. For those previously on a combination, the median decrease was 886 ng/mL (P=0.0078).

The reduction in these serum ferritin levels is particularly encouraging because deferasirox, as an oral agent, is far easier to administer. Although iron chelation is essential in patients with beta thalassemia receiving regular blood transfusions, oral therapies may have particular utility in populations with iron overload that have not been treated aggressively in the past. This includes a selected population of patients with MDS, particularly those in good performance status with a life expectancy of at least one year. The advantage of an oral agent might prompt more clinicians to intervene.

“When we recruited MDS patients for the EPIC study, almost half of patients were chelation-naive despite a heavy iron burden,” Dr. Schmid reported. Although the study was limited to the types of low-risk MDS patients who are expected to benefit from iron chelation, “The high rate of patients who had not been previously chelated suggests that iron overload is underestimated or at least undertreated.”

There were 341 MDS patients enrolled in the EPIC study. In the study population as a whole, individualized doses demonstrated that those with a relatively low baseline iron burden were adequately managed with doses of deferasirox 20 mg/kg/day or less, whereas those with the highest baseline serum ferritin levels required doses of 30 mg/kg/day or greater. Response rates in the two patient populations were similar whether or not patients had received previous chelation, as were the adverse events. The most common side effects were diarrhea (33%) and nausea (13%), but both were mild to moderate in nature for most patients.

Improving Overall Survival

In a second study, 93 patients with MDS undergoing long-term chelation therapy were matched with 93 controls by age at diagnosis, MDS type according to World Health Organization (WHO) classification and International Prognostic Scoring System (IPSS) level. Although both chelated patients and controls in this retrospective study had iron overload, the median serum ferritin level was 1954 ng/mL at baseline in the chelated group and 945 in the non-chelated group. Nevertheless, median survival time was greater in the chelated group (74 vs. 49 months, P=0.002). “Our data support the idea that iron chelation therapy results in improved overall survival in low-risk MDS patients, mainly by reducing the risk of non-leukemic death,” confirmed Dr. Frank Fox, Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany.

A third study evaluating deferasirox for iron chelation in MDS patients has two-year data on 83 low-risk patients. The mean dose in this study was 24.4 mg/kg/day. The serum ferritin level decreased from 3002 ng/mL to 2069 ng/mL over the two years. According to senior investigator Dr. Alan F. List, Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, Florida, “Deferasirox was generally well tolerated over the two years,” and the results appear to validate the efficacy and utility of an oral iron chelator in appropriately selected patients.

EPIC Cardiac Substudy

The efficacy of deferasirox against myocardial siderosis, demonstrated in the recently completed preplanned EPIC Cardiac Substudy, may explain the mortality reduction observed in MDS patients. In this substudy of 81 evaluable patients, magnetic resonance imaging was employed to evaluate cardiac iron load over time. Improvement was progressive over the full course of treatment with highly statistically reductions from baseline (P<0.001), paralleling observed reductions in hepatic and total body iron burden. The imaging improvements also paralleled improved cardiac dynamics. “The improvement in right ventricular function is best explained by improved left ventricular and right ventricular compliances associated with reduced cardiac iron,” noted Dr. Dudley J. Pennell, Royal Brompton Hospital, London, UK. He added that deferasirox at a median dose of 33.1 mg/kg/day was well tolerated with no evidence of progressive impairment of renal or liver function.

Summary

One potential advantage of the development of an effective and predictable oral iron chelator is its efficacy in populations beyond those that are regularly treated for iron toxicity, such as beta thalassemia, for which the indication is most well recognized. Not all patients with MDS are considered candidates for iron chelation, but for those who are, controlling iron overload has the potential to improve quality of life and may offer a survival benefit.