Systematical (retro- and prospective) investigation of the long-term safety (toxicity assessment according to CTCAE v3.0) and efficacy of deferiprone either given alone or in combination with desferrioxamine

Patients with refractory anemias requiring regular blood transfusions accumulate iron at the rate of approximately 0.5 mg/kg/day, which may lead to serious organ toxicity, e.g. to the heart, liver and endocrine organs. The human body has no active mechanism for the excretion of excess iron. Therefore multiply transfused patients will develop a secondary hemosiderosis, if excess iron is not excreted by a chelating agent. Symptoms of iron-overload occur when body iron stores reach 10-20 g. At higher levels severe, even fatal complications, particularly cardiac failure, may develop.

Desferrioxamine (DFO, Desferal) is the established and commonly used iron-chelating drug, but is expensive and must be given by slow subcutaneous or intravenous infusion for 8-12 hours a day during 5-7 days weekly at a dosage of 40-50 mg/kg body weight/day. This often leads to failure of compliance of the patient and therefore to inefficient iron chelation. Further, some patients are hypersensitive to desferrioxamine and others suffer from toxicity, e.g. to the ears or eyes.

Deferiprone (L1; CP20; 1,2 dimethyl-3-hydroxypyrid-4-one) is an orally active iron chelator investigated in various clinical trials since 1987. Dosages of 75 - 100 mg/kg body weight/day of L1 have been considered effective to maintain stable iron balance (urinary iron excretion of 0.5 mg/kg/day) and to reduce serum ferritin levels between 6% and 25% within one year of treatment in iron-overloaded thalassemic patients. There exists long-term experience with patients who have received deferiprone continuously for more than 10 years so far. The main side effects encountered during a deferiprone therapy are arthropathy, gastrointestinal symptoms, headache, and mild zinc deficiency. These adverse reactions are usually reversed on reducing the dose or discontinuing the drug. Except for severe joint symptoms in few patients, most of the subjects in different clinical trials have been able to continue with L1 therapy for a long term. The most severe, but rare complication following administration of deferiprone is agranulocytosis or neutropenia.

A new treatment regimen combining deferiprone with desferrioxamine is currently being investigated in many countries. Preliminary data have demonstrated that the combined use of both drugs is highly active showing an additive or even synergistic effect (significant decrease of serum ferritin and hepatic iron content, increase of urinary iron excretion). This synergism could be explained by the different mode of action of the two drugs. It could be demonstrated that patients who were not sufficiently chelated with desferrioxamine or deferiprone, could achieve a negative iron balance with the combination treatment of both drugs. The combined regimen was generally well tolerated. It has been speculated that the individual toxicity profile of both drugs can be positively influenced by the simultaneous administration of L1 and DFO. The daily treatment with L1 tablets combined with at least twice a week administration of parenteral desferrioxamine is more patient-convenient and therefore may enhance the patient's compliance.

The primary aim of this study is to systematically investigate the long-term safety (toxicity assessment according to CTCAE v3.0) of deferiprone either given alone or in combination with desferrioxamine. Further, in patients agreeing to perform annual SQUID analysis of the liver, the annual change of liver iron concentration (LIC) will be examined for four years.

Inclusion Criteria:

• Iron overloaded male or female patients with primary or secondary hemochromatosis
• Age: 4 years and older
• Patients with desferrioxamine toxicity or allergy (e.g. visual or hearing defects, bone abnormalities, reactions at injection site)
• Patients unable or unwilling to comply satisfactorily with regular desferrioxamine administration on 5-7 days/week
• Combination treatment: patients not sufficiently chelated with desferrioxamine or deferiprone monotherapy
• Patients must be willing to undergo routine screening including medical history, physical examination and hematology, biochemistry and other laboratory tests
• Written informed consent

Exclusion Criteria:

• Children under 4 years of age
• Female and male of reproductive age, sexually active but not taking adequate contraceptive precaution
• Woman who are pregnant or breast-feeding
• Patients with HIV
• Patients with active hepatitis requiring treatment
• Patients with severe hepatic failure, cirrhosis
• Patients with neutropenia (neutrophils less than 1.5 exp9/l, MDS: less than 0.5 exp9/l)
• Patients with thrombocytopenia (platelets less than 100 exp9/l, MDS: less than 20 exp9/l)
• Patients with decompensated heart failure (LVEF less than 40% or patients under continuous cardiac medication)
• Patients with severe renal failure