Clinical management of gastrointestinal disturbances in patients with myelodysplastic syndromes receiving iron chelation treatment with deferasirox.

Myelodysplastic syndromes are characterized by ineffective hematopoiesis resulting in peripheral cytopenias. The majority of patients is dependent on regular transfusions of packed red blood cells leading to a secondary iron overload which might result in organ damage. Therefore, sufficient iron chelation therapy in selected patients is mandatory. Deferasirox (DFX) is an orally administered iron chelator which has been highly efficient in the treatment of secondary iron overload. Most frequent side effects of DFX are gastrointestinal disturbances, which leads in some patients to low adherence to the therapy. An expert panel met in Lisbon in July 2010 to develop recommendations on prevention and management of GI disturbances based on existing data and personal experiences.

Response of iron overload to deferasirox in rare transfusion-dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias.

OBJECTIVES: It is widely assumed that, at matched transfusional iron-loading rates, responses to chelation therapy are similar, irrespective of the underlying condition. However, data are limited for rare transfusion-dependent anaemias, and it remains to be elucidated if response differs, depending on whether the anaemia has a primary haemolytic or production mechanism. METHODS: The efficacy and safety of deferasirox (Exjade®) in rare transfusion-dependent anaemias were evaluated over 1 yr, with change in serum ferritin as the primary efficacy endpoint. Initial deferasirox doses were 10-30 mg/kg/d, depending on transfusion requirements; 34 patients had production anaemias, and 23 had haemolytic anaemias. RESULTS: Patients with production anaemias or haemolytic anaemias had comparable transfusional iron-loading rates (0.31 vs. 0.30 mL red blood cells/kg/d), mean deferasirox dosing (19.3 vs. 19.0 mg/kg/d) and baseline median serum ferritin (2926 vs. 2682 ng/mL). Baseline labile plasma iron (LPI) levels correlated significantly with the transfusional iron-loading rates and with serum ferritin levels in both cohorts. Reductions in median serum ferritin levels were initially faster in the production than the haemolytic anaemias, but at 1 yr, similar significant reductions of 940 and 617 ng/mL were attained, respectively (-26.0% overall). Mean LPI decreased significantly in patients with production (P < 0.0001) and haemolytic (P = 0.037) anaemias after the first dose and was maintained at normal mean levels (< 0.4 µm) subsequently. The most common drug-related, investigator-assessed adverse events were diarrhoea (n = 16) and nausea (n = 12). CONCLUSIONS: At matched transfusional iron-loading rates, the responses of rare transfusion-dependent anaemias to deferasirox are similar at 1 yr, irrespective of the underlying pathogenic mechanism.

Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene.

Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload. We report the detection of a new mutation in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese family. The mutation lies in the 5'-UTR (untranslated region) of the gene and creates a new initiation codon in the context of a Kozak sequence. We found no trace of hepcidin protein in the patients' urine, suggesting that ribosomes select the mutant initiation codon for translation. The decrease of hepcidin production would thus lead to increased iron absorption, resulting in iron deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted in impressive clinical improvement.