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PRIORITY PRESS - 15th Congress of the European Hematology Association

Barcelona, Spain / June 10-13, 2010

Myelodysplastic Syndrome

In myelodysplastic syndrome (MDS), ineffective hemopoiesis leads to peripheral cytopenias, among which anemia is the most frequent. “Many MDS patients eventually require regular red blood cell (RBC) transfusions,” Dr. Heather Leitch, Clinical Associate Professor of Medicine, University of British Columbia, Vancouver, told delegates here. Yet over time, dependence on RBC transfusions leads to iron overload which is toxic to a variety of organs, including the heart and the liver. In a study by Malcovati et al. (J Clin Oncol 2005;23:7594-603), overall and leukemia-free survival were significantly lower in MDS patients who were transfusion-dependent compared with transfusion- independent patients.

Other findings discussed here at the EHA have shown that iron burden significantly affects survival: the apparent threshold is a serum ferritin level in excess of 1000 µg/L, above which MDS patients have a 30% greater risk of death for every 500-µg/L increase in serum ferritin above this threshold. Guidelines recommend iron chelation be initiated in lower-risk MDS patients (an International Prognostic Scoring System [IPSS] rating of low and Int-1 risk) who are transfusion-dependent and who have a life expectancy of at least one year when serum ferritin levels exceed 1000 µg/L.

Treatment should also continue as needed to maintain serum ferritin under 1000 µg/L. In higher-risk MDS patients, current guidelines recommend chelation only for patients who are eligible for allogeneic stem-cell transplantation (SCT). In her own experience, Dr. Leitch demonstrated that iron chelation reduced mortality risk by 71% (HR=0.29) among lower-risk (low and Int-1) MDS patients compared to those who had no chelation (P=0.01).

The French investigators Le Groupe Français des Myélodysplasies also reported a median of 138 months from diagnosis to death in IPSS=low-risk MDS patients who were chelated compared with 70 months for the same low-risk patients who were not chelated. Results in IPSS=Int-1 patients in the same cohort followed the same pattern, although median time from diagnosis to death in this patient group was shorter at 115 months for the chelation group vs. 36 months for the non-chelated group.

Other interventions that may prevent or treat iron overload include phlebotomy, antioxidants and avoidance of glutathione-depleting agents such as acetaminophen.

Non-transferrin-Bound Iron

Iron overload also leads to non-transferrin-bound iron (NTBI) in the blood, which is likely to increase the risk of iron overload-related comorbidities as well. Labile plasma iron (LPI) is a directly chelatable form of NTBI, as pointed out by Dr. Norbert Gattermann, Professor of Internal Medicine, Heinrich Heine University, Düsseldorf, Germany. LPI levels are relatively high in MDS patients compared to other disease states at similar levels of transfusional iron load. Neither deferoxamine (DFO) nor deferiprone (DPO) is able to effectively chelate LPI because of their short plasma half-lives.

In contrast, deferasirox has demonstrated a long half-life. As documented in both the US03 as well as the EPIC study, deferasirox essentially normalized LPI in patients with elevated mean LPIs at baseline. As discussed by Dr. Wolf-Karsten Hofmann, Professor of Medicine, University Hospital, Mannheim, Germany, both DFO, which must be given subcutaneously, and DPO, which has to be taken three times a day, are associated with multiple side effects and are difficult for patients to take. As an oral preparation, deferasirox can be taken once a day and has fewer side effects, largely gastrointestinal (GI) in nature and rash.

In both US03 and EPIC, serum ferritin levels were consistently reduced over time with continuous daily dosing. In both studies, patients with a serum ferritin =1000 µg/L who had received >20 units of RBC transfusion were treated with a mean daily dose of approximately 20 mg/kg/day. At study entry, mean serum ferritin levels in the US03 study were 3397 µg/L while in the EPIC study, mean serum ferritin levels were 2729 µg/L.

At 12 months’ follow-up, mean serum ferritin levels had dropped to 2501 µg/L in the US03 study and to 1903 µg/L in the EPIC trial. At two years’ follow-up, data from the US03 trial demonstrated sustained efficacy of deferasirox with a mean reduction in serum ferritin of 1400 µg/L from baseline to 24 months. New findings from EPIC also showed that deferasirox was as effective in reducing serum ferritin levels in both chelation-naive as well as previously chelated patients.

At 12 months’ follow-up, the oral agent had reduced mean serum ferritin levels by approximately 35% in chelation-naive patients (n=165) and by 22% in the patients who had undergone previous chelation (n=176), for a 26% reduction in mean serum ferritin levels across the cohort from study entry. Further analysis of the EPIC data also showed that continuous treatment reduced liver enzyme levels, another benefit in MDS patients at risk for liver toxicity.

Importantly, as Dr. Hofmann told delegates, the dosage of deferasirox can be readily adjusted to iron intake. The recommended initial dose is 20 mg/kg/day but if transfusion requirements exceed 14 mL/kg/month (approximately 4 adult units of RBC), the therapeutic goal is reduction of body iron and the dose may be increased to 30 mg/kg/day.

If patients require approximately half that amount (7 mL/kg/month or approximately 2 adult units of RBC), the therapeutic goal should be maintenance of body iron and the dose of deferasirox should be reduced to 10 mg/kg/day. Deferasirox may be safely used in patients with a CrCl >60 mL/min but as Dr. Hofmann emphasized, it should be used with caution in patients with a CrCl of 40 to 60 mL/min, and the likelihood of patients experiencing adverse events is increased in those with levels <40 mL/min.

Beta-Thalassemia and Iron Chelation

Regular blood transfusions are required to treat chronic anemia in the setting of beta-thalassemia as well but experience indicates that growth and development can be adversely affected by intensive DFO therapy in children with beta-thalassemia. In a study presented here by Dr. Yesim Aydinok, Ege University Medical Faculty, Izmir, Turkey, and co-investigators, long-term treatment with deferasirox for up to five years effectively reduced serum ferritin to maintenance levels of approximately 1000 µg/mL in transfusion-dependent pediatric patients with beta-thalassemia. Moreover, growth and sexual development over the treatment interval progressed normally, suggesting that iron chelation with deferasirox abated the inhibitory effects of iron overload.

As observed by Pennell et al. iron-induced cardiomyopathy causes most deaths in transfused patients with beta-thalassemia major. In a cardiac substudy of the one-year EPIC trial, deferasirox was shown to remove cardiac iron in beta-thalassemia patients with all degrees of cardiac siderosis, as reflected by improved cardiac MRI T2 values at the end of one year. All patients enrolled in the extension study were previously chelated either with DFO monotherapy or DFO-DPO therapy. At two years, deferasirox significantly increased T2 values from 7.3 ms at baseline to 9.3 ms in patients with severe cardiac siderosis (T2<10 ms) and from 14.6 ms at baseline to 19.9 ms in patients with mild to moderate cardiac siderosis (10 to 20 ms) [both P<0.001]. Patients’ left ventricular ejection fraction was normal at the start of the study and remained stable throughout the two-year trial. Thus, deferasirox, given for up to two years at a dose of 30 to 40 mg/kg/day, allowed 57% of patients with mild to moderate cardiac iron overload to achieve normal cardiac T2 values and 43% of those with severe cardiac siderosis to achieve moderate to mild degrees of iron overload, regardless of the previous iron chelation therapy they had.

In a separate study of previously-chelated patients, Taher et al. found that on being switched to deferasirox, patients reported increased satisfaction in terms of side effects, acceptance and burden of iron chelaton therapy and adherence improved. Findings suggest that patient satisfaction with iron chelation therapy is important as it may lead to improved adherence and iron overload-associated outcomes.

Summary

Iron overload in transfusion-dependent patients has important clinical implications including significant organ toxicity. Iron chelation can help offset elevated morbidity and mortality from iron overload in both MDS and patients with beta-thalassemia, including cardiac iron overload. This has been reported in multiple studies: Leitch et al. (Clin Leuk 2008;2:205-11) demonstrated that iron chelation reduced mortality risk by 71% (HR=0.29) among low and intermediate-1 MDS patients compared to those who did not undergo chelation therapy (P=0.01); Le Groupe Français des Myélodysplasies (Leuk Res 2010;34:864-70) reported a median 138 months from diagnosis to death in IPSS=low-risk MDS patients who were chelated compared with 70 months for the same low-risk patients who were not. The availability of an effective, well-tolerated oral iron chelator has enhanced patient satisfaction with therapy and will likely improve subsequent adherence.