Deferoxamine and deferiprone

Deferiprone and deferoxamine have been compared in Lebanese patients, mainly with thalassemia major, of whom 17 used oral deferiprone, 75 mg/kg/day for 2 years, and 40 received subcutaneous deferoxamine 20-50 mg/kg/day on 5 days a week (6). Those who received deferoxamine had done so for 4-24 years and were followed for 2 years. Infusion site reactions occurred in 34 patients, including pain, tenderness, itching, burning, erythema, swelling, induration, and lipodystrophy. Five patients had disturbances of vision and hearing, three had growth retardation. Six patients had increased heart rates, four had dizziness, and one had leg cramps. 

Infection risk Reactivation of hepatitis B infection may have been caused by the combined use of deferiprone and deferoxamine [42 ]. 

A major review discussed 4113 recorded fatalities reported in 2012 during post-market sxuveillance of deferasirox, noting a mortality rate of 11.7% [IT ]. The author cites indiscriminate and uncontrollable use of deferasirox and recommends that deferiprone and deferoxamine, individually or in combination, be used in lieu of deferasirox. Subsequent commentaries in the same issue include a commentary from a scientist at Novartis (the manufacturer of deferasirox) challenging the credibility of the sources of data and a rebuttal by the article s author. 

In a retrospective review of 18 patients with beta-thalassaemia on regular transfusion, patients were treated with deferasirox (n = 9), deferoxamine (n=3), deferiprone (n=2) and combination deferiprone and deferoxamine (n=4) [35 ]. Twelve patients had renal tubular dysfunction all nine patients on deferasirox (20-30mg/kg/day) were among these. The cumulative increase in renal tubular dysfunction for those treated with deferasirox was 11% at 2months and approximately 90% at 6years. Withdrawal and dose reduction reversed the adverse effect, suggestive of Fanconi S5mdrome. 

Side effects Deferasirox (n = 105) Deferiprone (n = 29) Deferiprone and deferoxamine (n=30)... 

Pepe A, Meloni A, Rossi G, Cuccia L, D Ascola GD, Santodirocco M, et al. Cardiac and hepatic iron and ejection fraction in thalassemia major multicentre prospective comparison of combined deferiprone and deferoxamine therapy agairtst deferiprone or deferoxamine monotherapy. J Cardiovasc Magn Reson2013 15 l. 

In two patients with P-thalassemia in whom chelation with deferoxamine and deferiprone, alone and in combination, had been unsuccessful, daily alternating combination treatment with deferiprone and deferasirox orally maintained a low iron burden [25 ]. In one patient there was also a reduction in iron overload. In the other patient treatment was complicated by multiple hypersensitivity reactions, after subcutaneous deferoxamine had repeatedly led to systemic hypersensitivity reactions with a rash, fever, and pain, and the subsequent use of deferasirox was also complicated by a rash, which reappeared on two occasions after low-dose... 

Deferoxamine is the oldest of the chelation therapies, and is administered typically at 40mg/kg body weight, for 8-12 h, 4 days per week. However, some patients do not receive sufficient benefit from deferoxamine and develop cardiac iron overload and failure [S ]. More recently, orally bioavailable chelators, such as deferiprone and deferasirox, have become popular. However, the oral iron chelators have shown side effects that differ from those of deferoxamine. Deferiprone has proven to be more efficacious than deferasirox in several clinical trials, and is now routinely administered when deferoxamine treatment has failed. However, it is associated with agranulocytosis in about 1% of patients through an as yet undetermined mechanism and neutropenia more rarely. Deferiprone has been in use in Europe since 1999 but was not approved in the United States until 2011, due in part to a controversy over its safety [4 ]. 

A major theme in the 2012-2013 time period was comparisons of multidrug therapies against single-drug regimens. These are reviewed at the end of this section. An excellent review discusses the pros and cons of different iron chelation therapies together with associated side effects [1 ]. A major review comparing deferoxamine, deferiprone and deferasirox for the treatment of transfusion iron overload can also be foxmd [6 ]. 

TABLE 1 Comparison 23. METAL ANTAGONISTS of Three Commonly Prescribed Iron Chelators Deferoxamine, Deferiprone. and Deferasirox ... 

A Cochrane Database of Systematic Reviews meta-analysis of 22 trials including 2187 participants of deferoxamine mesylate for the treatment of iron overload in people with transfusion-dependent thalassaemias was performed [47 ]. Adverse events were recorded in 18 trials. Five trials reported a total of seven deaths, three in patients with defroxamine alone and two in patients who received deferoxamine and deferiprone. Seven trials reported cardiac function or liver fibrosis in end organ damage. The authors concluded that there is a need for adequately powered, high-quality trials comparing the overall clinical efficacy and long-term outcomes of deferiprone, deferasirox and deferoxamine. 

A controlled clinical trial on 26 patients with beta-tiialassaemia major compared combination therapy (deferiprone (n=12, 75 mg/kg/day three times per day) and deferoxamine (30-50mg/kg subcutaneously every other day)) with control monotherapy (deferoxamine (n = 14, 30-50 mg/kg/day subcufaneously for 6-12h/day, 5-6 day per week)) [56 ]. Side effects of combined fherapy included nausea (8.3%) and arfhropathy (8.3%), with a transient neutropenia... 

A group of 169 transfusion-dependent beta-thalassaemia patients (mean age 21.2) were treated with deferasirox alone (n = 105), deferiprone alone (n = 29) or both (n=30) [57 ]. Patients received at least one dose of deferiprone (40-75 mg/kg/day), deferasirox (10-40mg/kg/3-5 day per week) and combination therapy involving deferiprone (50-75 mg/kg/day) and deferoxamine (40-50 mg/kg 3-5 day per week). Table 2 illustrates the side effects observed with the treatments. The frequency of discontinuation was similar between the groups but the time to discontinuation was different deferiprone was stopped earlier than deferasirox and combination therapy (10.3, 23, and 28 months, respectively). 

Galanello R, Kattamis A, Piga A, Fischer R, Leoni G, Ladis V et al. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron... 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

Table 1 Metal stability constants of deferiprone, deferoxamine, and diethylenetriaminepentaacetic acid (DTPA)...

Deferiprone has a concentration-dependent affinity for iron, with a higher binding constant than deferoxamine or diethylenetriaminepentaacetic acid (DTPA). However, it takes three molecules of deferiprone to bind one molecule of iron, whereas deferoxamine binds iron in a 1 1 ratio. For this reason, deferiprone must be present in very high concentrations, close to toxic concentrations, to be effective (2). Deferiprone dissociates from iron when its concentration in body fluids falls to the concentration achieved just a few hours after oral administration (3). Deferiprone is effective in excreting iron in iron storage diseases and aluminium in patients on hemodialysis (1). 

Taher A, Sheikh-Taha M, Koussa S, Inati A, Neeman R, Mourad F. Comparison between deferoxamine and deferiprone (LI) in iron-loaded thalassemia patients. Eur J Haematol 2001 67(1) 30. ... 

Skin In a prospective study in 78 patients with P-thalassemia aged 10 months to 37 years, skin disorders of any kind were observed in 65 (83%) pruritus and xerosis were the most common (Table 1) [3 ]. Adverse events can occur simultaneously xerosis, for example, was often associated with pruritus. Systemic medication was common in these patients 40 received deferoxamine by slow infusion over 8-12 hours, 5-7 days a week 25 received deferi-prone and 10 received deferasirox. Subcutaneous infusion of deferoxamine is a frequent cause of local reactions, reflected in this series by the occurrence of skin erythema or irritation in 10 patients. Xerosis was less common in those who received deferasirox than in those who received deferoxamine or deferiprone. Xerosis can occur because of iron storage and also in zinc deficiency. The high spontaneous prevalence of a variety of skin disorders in patients with p-thalassemia, as noted in this study, is of interest in the context of attributing skin events to the use of chelating agents. 

Infection risk Iron is an essential nutrient in many species, and iron overload increases the risk of infections. Deferoxamine is a natural siderophore, and its use is a susceptibility factor for infections with a variety of microbes, notably Yersinia enterocolitica and Mucorales infections, and increases their infectivity. On the other hand, iron chelators, by extracting iron, may also have cm anti-infectious action, which may be therapeutically beneficial, in particular in the treatment of malaria (deferiprone) [4 ] or mucormycosis (deferasirox) [5 ]. While the use of iron-chelating drugs is currently being further investigated, for the... 

With a further 2 years of follow-up, Telfer and colleagues have updated their previous study regarding the possible connection between the introduction of the combined use of deferoxamine by subcutaneous infusion and deferiprone (combination chelation therapy) and a reduction in the number of fatal events in patients with P-thalassemia [22 , 23 ]. Of 544 patients... 

In a cost-utility multiple appraisal of deferasirox, deferoxamine, and deferiprone, it was concluded that in the short term there is little clinical difference between any of the three chelators in terms of removing iron from the blood and the liver, and that deferasirox may be cost-effective compared with deferoxamine but not compared with deferiprone [15 ]. The authors emphasized that the primary focus for future research should be on the longterm benefits of chelation therapy, including adverse reactions and adherence. 

Hematologic In a 5-year randomized study in 213 patients with -thalassemia, deferiprone monotherapy 75 mg/kg/day was compared with deferiprone 75 mg/kg/day on 3 days/week alternating with deferoxamine 50 mg/kg/day on 3 days/week [335 ]. While neutropenia was equally frequent in the two groups (11 and 15 patients), there was agranulocytosis in three of the patients who received deferiprone monotherapy and none in the other group. This may be related to the... 

X 10 copies/ml, noimal baseline alanine aminotransferase). Deferiprone 50 mg/kg/day was added to deferoxamine 30 mgdtg on 3-S days/week and the alanine aminotransferase activity increased. Deferiprone was withdrawn and the enzyme activity fell Deferiprone was reintroduced and there was a new sustained rise in aminotransferase activity to about twice baseline. There were 139 x 10 copies/ml of HBV-DNA. Extensive testing did not identify autoantibodies. Deferiprone was withdrawn again and the HBV-DNA cleared partly within 8 weeks and alanine aminotransferase activity returned to normal. Later, deferiprone was reintroduced in the same dosage and there was no relapse of hepatitis after 24 months. 

Porter JB, Taher AT, Cappellini MD, Vichinsky EP. Ethical issues and risk/benefit assessment of iron chelation therapy advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox [Kontoghiorghes GJ, Hemoglobin 2008 32 (1-2) 1-15]. Hemoglobin 2008 32(6) 601-7. 

Combinations of these drugs are increasingly utilised so far, no synergies in side effects are evident. A major meta-analysis of 22 trials involving 2187 participants included eight deferoxamine to deferiprone comparisons, five deferoxamine to deferoxamine/deferiprone comparisons, two deferoxamine to deferasirox comparisons, and two comparisons of different routes of deferoxamine administration (bolus versus continuous infusion). The authors concluded that adverse events were less likely with deferoxamine than with deferiprone in one trial and less likely with deferoxamine than deferoxamine and deferiprone combination therapy in two trials [47 ]. 

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