Haematological improvement as a beneficial effect during deferasirox treatment in transfusion-dependent patients with myelodysplastic syndrome.

Abstract

Dear Sir, We read with great interest the review by Poggiali et al.1 on iron chelation therapy and in particular the fact that deferasirox can induce an haematological improvement in transfusion-dependent patients with myelodysplastic syndrome (MDS). As stated in the review, iron overload is an established and well-known prognostic factor that strongly affects survival in heavily transfused patients with MDS. If untreated, iron overload may cause damage to the liver, heart, pancreas, brain, joints and endocrine tissues, thus increasing morbidity and the risk of early death1. Moreover, iron overload increases the risk of bacterial and fungal infections, while iron chelation therapy lowers this risk in patients with MDS. Organ complications developing in transfusion-dependent patients with MDS may derive not only from the direct toxicity of parenchymal iron, but also from chronic exposure to non-transferrin-bound iron (NTBI) that accumulates after the capacity for iron storage has been saturated. Labile plasma iron represents the most toxic fraction of NTBI which is both redox active and chelatable and, over time, sustained levels of labile plasma iron may compromise organ function and overall survival. Labile plasma iron is taken up into cells leading to an increased labile iron pool with rapid creation of reactive oxygen species1. The iron pool has, therefore, been regarded as one of the main regulators of the production of reactive oxygen species in cells. Oxidative stress leads to oxidation of proteins, lipids and DNA, as well as suppression of the self-renewal of the haematopoietic stem cells, a decrease in the number of these cells and increased apoptosis and organ damage1. Deferasirox has been demonstrated to decrease NTBI, to maintain or reduce body iron (as assessed by serum ferritin) and to have a good tolerability profile with no severe adverse effects in pre-treated or therapy-naive MDS patients1. The currently indicated dose of the drug is 20 mg/kg and gastrointestinal events (nausea, vomiting, diarrhoea), skin rashes and renal impairment are indicated as potential side effects of the drug. Given its possible renal effects, deferasirox is contraindicated in patients with a low creatinine clearance (less than 40 mL/min)1. Several published case reports and small studies have reported improvement in haematological parameters and transfusion requirements during deferasirox treatment, although the exact mechanism of the haematological response to iron chelators is unknown and the relationship between deferasirox and erythroid improvement has not yet been clarified2. It has been hypothesised that deferasirox acts not only at the plasma level by reducing the high levels of labile plasma iron but also in the bone marrow through a direct and protracted effect on the neoplastic clone and on the microenvironment. In 2010, we described the case of a heavily transfused patient with low-risk MDS who, after 6 months of deferasirox treatment, had a substantial increase of haemoglobin concentration up to 10 g/dL, which was lost due to a concomitant infection and discontinuation of iron chelation. The response was then regained following resolution of the infective episode and the recommencement of deferasirox3. More recently, in a report on our consecutive series of patients treated with the drug, we described four additional patients (three with refractory anaemia and one with refractory anaemia with excess blasts type 1) who had a reduction of transfusion requirements (from a median of 5 units/month to 1 unit/month) according to 2006 International Working Group criteria, with a mean increase in haemoglobin concentration of 2 g/dL (P =0.02), from 8.5 to 10.5 g/dL4. Gatterman et al.5 reported a post-hoc analysis of haematological response to deferasirox in a cohort of 247 iron-overloaded patients with MDS enrolled in the EPIC trial. Erythroid, platelet and neutrophil responses were observed in 21.5% (53/247), 13.0% (13/100) and 22.0% (11/50) of the patients after a median of 109, 169 and 226 days, respectively. Of the patients with an erythroid response, 28 (11.3%) had only a transfusion response and 22 (8.9%) had only a haemoglobin response. Three patients (1.2%) had both transfusion and haemoglobin responses. The overall median time to transfusion response was 100 days. The overall median time to haemoglobin response was 113 days. The mechanisms underlying the haematological improvement induced by deferasirox remain unknown: as compared to other iron chelators, deferasirox is a potent NF-kB inhibitor and is able to increase glutathione (GSH) in red blood cells thus protecting them from oxidative insults1–2. In conclusion, there are several pieces of evidence supporting a role of oxidative stress as a possible cause of bone marrow dysfunction in MDS and deferasirox treatment may, in some instances, reduce this phenomenon. Further prospective studies are needed to confirm the role of this drug and to define its mechanisms of action better.