Oral iron chelators show promise compared with IV deferoxamine

Deferasirox and deferiprone efficiently eliminate iron and have fewer complications than the pump.

Issue: June 1, 2006

Three recent studies comparing oral iron chelators deferiprone (Ferriprox, Apotex) and deferasirox (Exjade, Novartis) with deferoxamine (Desferal, Novartis) suggest that the oral chelators clear iron more effectively and conveniently than the standard deferoxamine (DFO) infusion. Deferiprone therapy was also shown to offer greater cardiac protection in patients with thalassemia major.

Subcutaneous infusion of DFO is the standard for iron chelation, particularly as initial therapy for cardiac iron overload from blood transfusion. Deferoxamine is a large, positively charged lipophobic molecule that binds iron tightly, but may not effectively access and chelate intracellular iron. Its plasma half-life is short, so it is administered as a subcutaneous pump infusion overnight for five to seven nights a week. This method is particularly inconvenient for the patient, and compliance can be problematic.

The molecule of the iron chelator deferiprone is small, has no charge and can more efficiently penetrate membranes to access and remove intracellular chelatable iron from the tissues. With a moderate plasma half-life, it is administered orally three times a day.

Deferasirox has a plasma half-life of eight to 16 hours and remains in plasma at 24 hours, allowing once-daily dosing. Deferasirox also quickly accesses intracellular iron.

Deferiprone vs. DFO

One of three studies that appeared in a recent issue of Blood, Pennell et al compared deferiprone with DFO in patients with -thalassemia major and asymptomatic myocardial siderosis. Myocardial siderosis was identified by cardiac MRI of myocardial T2*, which is sensitive to iron in the tissues. High concentrations of iron inversely correlate with low T2* values, and are related to a greater risk of heart failure and death in thalassemia patients.

Sixty-one patients between 18 and 36 years old with homozygous -thalassemia major were selected from four transfusion centers in Italy and Greece, where they had been maintained on subcutaneous DFO. Patients’ myocardial T2* was abnormal (< 20 ms) and left ventricular ejection fraction was greater than 56%.

Patients were randomized into two groups. In the DFO group, 29 patients received 43 mg/kg for 5.7 days a week. Twenty-seven patients in the deferiprone group received 92 mg/kg per day. Compliance between the two groups was similar (deferiprone 94% ± 5.3%; DFO 93% ± 9.7%; P=.81). Change in myocardial T2* at six and 12 months was the primary outcome measure.

Improving myocardial iron

The change in myocardial T2* was significantly greater in the deferiprone group (P=.023). Myocardial T2* rose to 15.4 ms (P<.001) at six months and 16.5 ms (P<.001) at 12 months. In the DFO group, myocardial T2* rose to 14.4 ms (P=.003) and 15.0 ms (P<.001), at six and 12 months respectively. As for cardiac function, deferiprone showed a significant difference in reducing end-systolic volume (6.4 ± 6.8 mL vs. -0.6 ± 7.9 mL; P=.004).

“It … appears that deferiprone could reduce the risk of progression to iron-related cardiomyopathy by removing more cardiac iron than subcutaneous deferoxamine,” researchers said.

However, the clinical significance of mild improvements in T2* within the mildly abnormal range is not yet completely known, according to Ellis Neufeld, MD, PhD, an associate professor of pediatrics and associate chief of the division of hematology/oncology at Children’s Hospital, Boston.

Adverse events were mild to moderate, consisting of nausea, vomiting or abdominal pain, which usually occurred within the first few weeks of treatment and resolved quickly.

“This trial provides important further evidence that … deferiprone is probably better in vivo at improving myocardial iron than DFO (at the doses used),” Neufeld said in an accompanying editorial.

Interestingly, researchers suggested that splenectomized patients showed up to 20% greater T2* improvement than non-splenectomized patients. They determined that a greater white cell count and hemoglobin levels in the DFO-treated group resulted from this large number of splenectomized patients: 11 (34%) in the DFO arm compared with four patients (14%) in the deferiprone arm. A multivariate analysis of the effect on the myocardial T2* of baseline differences of splenectomy status found that splenectomy was significantly predictive (P=.0002) of T2* improvement. After controlling for baseline ferritin values and splenectomy status, the difference in T2* favoring deferiprone remained significant and would be expected to be greater with an equal number of splenectomized patients in each treatment arm, according to researchers.

Deferasirox vs. DFO

In a phase-3 randomized controlled trial, Cappellini et al measured hepatic iron in 586 patients with transfusion-dependent -thalassemia. Pediatric and adult patients with an elevated liver iron concentration value of 2 mg Fe/g dw or higher participated in the yearlong study. Most patients (97.4%) had previously received chelation therapy.

Dosing for both drugs was broken down into four levels determined by baseline liver iron concentration:

Group 1: <3 mg Fe/g dw or less (deferasirox: 15 patients at 5 mg/kg; DFO: 14 patients at 20 mg/kg-30 mg/kg)
Group 2: 3 mg Fe/g dw to 7 mg Fe/g dw (deferasirox: 78 patients at 10 mg/kg; DFO: 79 patients at 25 mg/kg-35 mg/kg)
Group 3: 7 mg Fe/g dw to 14 mg Fe/g dw (deferasirox: 84 patients at 20 mg/kg; DFO: 91 patients at 35 mg/kg-50 mg/kg)
Group 4: >14 mg Fe/g dw (deferasirox: 119 patients at 30 mg/kg; DFO: 108 patients at >50 mg/kg).

Success was defined as maintenance or improvement in hepatic iron content depending on baseline levels. The study’s primary objective, establishing that deferasirox was equivalent or better than DFO across all dosing categories, was not met. Researchers said that disproportionately low dosing with deferasirox at 5 and 10 mg/kg/d could have been too low to overcome ongoing iron loading through transfusion. However, success rates were similar in patients with liver iron concentrations greater than 7 mg Fe/g dw who received deferasirox and DFO (60% vs. 59%, respectively).

Once-daily dosing of 20 mg/kg DFO provided maintenance of liver iron concentration, stable serum ferritin levels and neutral iron balance. At 30 mg/kg once daily, patients experienced significantly reduced liver iron concentrations, decreased serum ferritin levels and negative iron balance.

Suspected side effects from deferasirox included abdominal pain and other mild-to-moderate gastrointestinal symptoms (15.2% of patients), as well as skin rash (10.8% of patients). Deferasirox presented no cardiac safety concerns.

Researchers noted that deferasirox efficacy in achieving iron balance would most likely be greater in patients receiving less than 0.5 mg/kg/day transfused iron.

DFO vs. deferiprone

A retrospective cohort study by Borgna-Pignatti et al suggested that deferiprone therapy may offer considerably greater cardiac protection than DFO in patients with -thalassemia major.

Included in the nine-year analysis were Italian patients who were born between 1970 and 1993 and who were alive at study entry in 1995. Patients had no cardiac events or heart disease and had not undergone bone marrow transplant.

Of 516 patients, 359 (70%) were treated only with DFO at 30 mg/kg to 50 mg/kg/day, five to six times a week, whereas, 157 patients (30%) who had started treatment on DFO switched during the study to deferiprone. Patients received 75 mg/kg deferiprone in three equal daily doses.

Treatment with deferiprone lasted a median 4.3 years. The median duration of treatment with DFO since January 1995 before switching to deferiprone was two years.

Researchers analyzed the data using time-to-event analysis. They defined a cardiac event as cardiac failure or arrhythmia requiring anti-arrhythmic or inotropic drugs. During the observation period, no patient experienced a cardiac event while being treated with deferiprone. In patients receiving DFO, 52 cardiac events occurred, 10 of which resulted in death. Five of the 42 surviving patients died of cardiac failure or arrhythmia within four to 47 months of the first cardiac event.

Six events occurred in patients who had been previously treated with deferiprone, but were receiving DFO at the time of the event. In these patients, the elapsed time between stopping deferiprone treatment and the occurrence of the cardiac event ranged from about two years to five years. Mean ferritin levels in both groups did not change significantly.

Deferiprone adverse events

Forty-six patients (31%) receiving deferiprone discontinued it because of possible adverse events, primarily increased ferritin levels or liver iron concentration (21 patients); arthropathy or arthralgia (10 patients), and neutropenia (8 patients). Sixteen patients (10%) discontinued deferiprone for reasons other than adverse events.

Researchers suggested that because it is a smaller molecule and more lipophilic than DFO, deferiprone may access intracellular chelatable iron more efficiently. Although they could not analyze patient compliance because of the observational nature of the study, researchers suggested that oral dosing resulted in greater compliance. However, given the lack of change in ferritin levels in the two groups, it is uncertain that greater compliance is the mechanism for cardiac protection.

Caterina Borgna-Pignatti, MD, from the pediatric clinic at the University of Ferrara, Italy, told Hem/Onc Today that her study team was surprised by the extent of data in the literature suggesting that deferiprone offered greater cardiac protection than DFO.

“The result is dramatic and unexpected,” said Neufeld. “This stunning finding, coupled with similar but less rigorous data from other sites, is hard to ignore. However, he also suggested that because the study was not only retrospective, but also unmatched, possible uncontrolled study bias may have contributed to the results.

These novel oral chelators represent an important strategy for treating cardiac disease from myocardial iron overload, the leading cause of death for young people with thalassemia major. Although questions remain about proper dosing and other issues, “we are clearly in a new era where alternatives to the tried and proved deferoxamine are available,” said Ralph Green, MD, PhD, FRCPath, chair of the department of pathology and laboratory medicine at the University of California, Davis Medical Center. “Issues like efficacy, safety, convenience and cost will drive the future choice of iron chelator regimens for treatment and prevention of life-threatening transfusion iron overload.” – by Carey Cowles

For more information:

Borgna-Pignatti C, Cappellini MD, DeStefano P, et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood. 2006;107:3733-3737.

Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with -thalassemia. Blood. 2006;107:3455-3462.

Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood. 2006;107:3436-3441.

Pennell D, Berdoukas MK, Ladis V, et al. Randomized controlled trial of deferiprone or deferoxamine in -thalassemia major patients with asymptomatic myocardial siderosis. Blood. 2006;107:3738-3744.