A 75 year old male was brought to the hospital with breathlessness. On examination he had severe pallor, elevated jugular venous pressure, mild hepatomegaly and bilateral crepitations. The X-ray showed a consolidation.
He was anaemic for three years before presentation and was diagnosed to have a myelodysplastic syndrome (refractory cytopenia with multi-lineage dysplasia) with normal cytogenetics. He needed blood transfusions every four to five weeks. His transfusion requirement had increased over the last few months. He had taken about 20 units of blood.
He had a haemoglobin of 4.5g/dL a WBC count of 3700/mm3. The differential count showed 42% neutrophils, 40% lymphocytes, 3% eosinophils and 5% monocytes. The platelet count was 162,000/mm3. He had been treated with erythropoietin with filgrastim with no benefit and was now on transfusion therapy. He was transfused packed erythrocytes.
The serum ferritin was 1522ng/ml. Should the patient be prescribed iron chelation therapy?
Iron overload is a complication of multiple blood transfusions. Patients with thalassaemia major accumulate iron because of blood transfusion and increased absorption from the gut. Iron accumulation results in cirrhosis, heart failure, arthropathy, skin pigmentation and delayed puberty. Almost all children with thalassaemia major succumb to the consequences of iron accumulation by the end of second decade. Iron chelation by deferoxamine has allowed these patients to lead a near normal lifestyle. It needs to be given as a subcutaneous infusion lasting several hours a day. Two oral iron chelators, deferiprone and deferasirox are available. There are an increasing number of adults with transfusion dependent acquired anaemia who are at the risk of developing iron overload.
The issues to be considered before initiating chelation therapy in patients with myelodysplastic syndromes are:
- Are the principles of chelation in thalassaemia applicable to acquired anaemia?
- Is there evidence of deleterious effect of iron on the survival of MDS?
- Does evidence from clinical trials support iron chelation?
- What are the guidelines for use of iron chelators in MDS?
- Which of the iron chelators is suitable for use in MDS?
- Is there a role for chelation in other transfusion dependent anaemias?
Are the principles of chelation in thalassaemia applicable to acquired anaemia?
Myelodysplastic syndrome (MDS) is the commonest cause of acquired transfusion dependent anaemia. MDS is a group of haematological disorders characterised by cytopenias, ineffective erythropoiesis and a risk of transformation to leukaemia. It is classified into five risk categories depending on the type of MDS, presence or absence of bone marrow fibrosis, chromosomal changes present and transfusion requirements viz. very low, low, intermediate, high and very high risk. The survival in these groups is >10 years, >5 years, 4 years, 2 years and 1 year respectively. The higher the risk category higher is the risk of leukaemia. The incidence of MDS increases with age. Patients with thalassaemia major develop consequences of iron overload develop over a period of years. More than 80% of the patients of thalassaemia live for 10 years. The paradox in MDS patients is that those who need the most blood transfusions are not likely to live for long enough to develop consequences of iron overload.
Is there evidence of deleterious effect of iron on the survival of MDS?
Iron overload and transfusion dependency is associated with a shorter overall survival increased risk of leukaemic transformation in patients with MDS. Iron overload has been implicated in cardiac dysfunction, increased risk of leukaemic transformation, increased infections and increased mortality in patients who undergo stem cell transplantation. The most obvious cause of iron overload in patients with MDS would appear to be repeated blood transfusion. MDS is associated with ineffective erythropoiesis. Patients with anaemia associated with ineffective erythropoiesis like thalasssaemia and congenital dyserythropoietic anaemia develop iron absorption because of increased absorption from the gut. Iron overload may also in part represent a more aggressive disease characterised by more ineffective erythropoiesis. Decreased survival and iron overload may not have a cause and effect relationship.
Does evidence from clinical trials support iron chelation?
There are no randomized controlled trials to support the concept of chelation in MDS. Retrospective studies have shown benefits of chelation. In the absence of solid evidence one has to fall back on collective wisdom of experts in finding an answer to the question of chelation in MDS.
What are the guidelines for use of iron chelators in MDS?
Patients with high risk MDS do not survive long enough to develop complications of iron overload, Patients with low risk MDS are at a greater risk to develop complications of iron overload. The consensus among experts is that patients with low risk MDS should be give irons chelation is the serum ferritin is more than 1000ng/ml or the patient has received 20 units of blood.
Which of the iron chelators is suitable for use in MDS?
The three chelators appear to be equally effective in patients with thalassaemia. MDS patients are prone to infections and have cytopenias. Deferoxamine needs parenteral administration and is associated with increased risk of fungal infections. As these patients may be already thrombocytopenic and are prone to infections deferoxamine is not appropriate for MDS. Deferiprone is contraindicated in patients with neutropenia that may be present in many patients of MDS. Iron chelation may improve the haematopoiesis in some patients. For deferoxamine and deferiprone the effect correlates with degree or iron chelation. Deferasirox may have effects independent of iron chelation activity though this is no solid data to support this contention.
Is there a role for chelation in other transfusion dependent anaemias?
The concept of iron chelation evolved in thalassaemia major, which today is an established indication for chelation. Transfusion has been used in patients with sickle cell syndrome pre-operatively, to prevent acute chest syndrome and to prevent strokes. Patients with sickle cell disease may be relatively protected against damage by iron by ill understood mechanisms. SCD has a strong inflammatory component. Ferritin being an acute phase reactant may not reflect body iron accurately in patients with SCD. Chelation should be considered for adults who have transfused 20-30 units of blood, children who have transfusion induced load of 100mg/kg and/or hepatic iron concentration of 7-9mg/g (this corresponds better with a ferritin >3000ng/ml than the 1000ng/ml cut off used for thalassaemia and MDS). Chelation can reduce serum ferritin in overtransfused patients of other anaemias but the survival benefit of chelation is not clear.
This patients has a low risk myelodysplastic syndrome is a candidate for iron chelation preferable with deferasirox.