Iron chelation therapy in myelodysplastic syndromes: we need more evidence, not more guidelines

In the April issue of this journal, a consensus guideline was published by Bird et al.1 setting out their recommendations for iron chelation therapy (ICT) in myelodysplastic syndromes (MDS). There is evidence supporting the hypothesis that iron overload may play an important role in MDS which is worthy of further investigation but, in our view, this guideline presents a premature view of the field. Data from prospective, randomised studies are lacking, and there is limited consensus on this issue with other world experts.2,3 The current enthusiasm for ICT for MDS was ignited in September 2005 by the approval of the oral iron chelator deferasirox by the US Food and Drug Administration (FDA) Blood Products Advisory Committee. Deferasirox approval was given for ‘the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older’ based on data from patients with thalassaemia major. Specifically, the submission did not include any data showing efficacy or improved outcomes in patients with MDS; however, since then, we have seen the publication of at least eight guidelines recommending ICT for patients with low- or intermediate-1 risk MDS.4–11 In this editorial, we present a critical appraisal of the data upon which these and other guidelines are based and challenge several assumptions inherent in them. Advocates of ICT assume that transfusional iron overload in MDS and thalassaemia is fundamentally the same process. In thalassaemia, the process of iron deposition in the liver and heart starts at birth, and organ dysfunction begins after around 10 years. Transfusional siderosis and improvement in survival with ICT have been unequivocally demonstrated in thalassaemia. Non-invasive imaging techniques, such as T2* magnetic resonance imaging (MRI), allow measurement of cardiac iron and correlation with clinical and echocardiographic features of cardiac failure. Significant impairment of cardiac function has been observed when the T2* value is <20 ms and severe impairment occurs at values <10 ms. In contrast to thalassaemia, T2* values <20 ms are rarely observed in MDS even in the most heavily transfused patients.12–14 Other features of iron overload in congenital anaemia, such as liver cirrhosis, diabetes mellitus and endocrinopathies, are rarely evident in MDS. Transfusion dependence and iron overload (defined as serum ferritin >1000 mcg/mL) were independent poor prognostic markers in a cohort of de novo MDS patients reported by Malcovati et al.15 Iron overload could lead to organ damage and shorter survival as seen in thalassaemia, but it is also possible that transfusion dependence and hence transfusional iron overload simply reflects more severe underlying disease. In support of the latter are that cause of death in MDS is due mainly to leukaemic transformation or disease progression and infrequently due to either liver or cardiac impairments.16,17 The threshold of serum ferritin >1000 mcg/L given for starting ICT in the majority of guidelines is an arbitrary one and not based on data correlating it with organ dysfunction. A retrospective study of 126 patients with refractory anaemia with ringed sideroblasts, one of the most favourable subtypes of MDS, found no correlation between survival and either serum ferritin or number of units of red cells transfused.16 A study of children with transfusional iron overload found a poor correlation between serum ferritin >2500 ng/mL and T2* scores with sensitivity 54% and specificity 36% for cardiac siderosis.18 Similarly, studies of adult transfusion-dependent patients also did not find evidence of cardiac siderosis using T2* MRI or impaired left ventricular function on echocardiography even in heavily transfused MDS patients receiving up to 100 units and/or with serum ferritin level up to 6000 mcg/L.12–14 The International Prognostic Scoring System (IPSS) generates a prognostic model in MDS patients.19 The median survival of low- and intermediate-risk-1 MDS according to the IPSS is 5.7 and 3.5 years. Transfusion dependence is another independent indicator of poor risk, and together with the IPSS, has been used in the World Health Organisation prognostic scoring system.20 The median survival of even the lowest risk MDS is only around 5 years when transfusion dependence is present. In a single-institution retrospective review of another favourable risk group, patients with isolated deletion of the long arm of chromosome 5, 80% of patients were transfusion dependent at diagnosis.21 Overall, the median survival for transfusion-dependent patients was 52 months. Survival was not affected by serum ferritin, and no deaths were attributed to iron overload. A retrospective review of 273 deceased patients with lower-risk MDS at MD Anderson Cancer Centre reported median survival of 59 weeks.17 The cause of death was recorded as disease related in 84%. These data do not support the general recommendation to consider ICT in low and intermediate-1 risk patients. The Australian guideline recommends considering ICT in high-risk MDS patients who have responded to azacitidine. In the pivotal trial by Fenaux et al., the overall survival in high-risk patients was 24 months, and the time to leukaemic transformation was 17.8 months.22 There are no data to support the institution of ICT in this group of patients. Two of the most frequently cited examples of clinical benefit from ICT come from a retrospective case series and a non-randomised prospective study. A retrospective review of 178 patients with MDS in Canada reported a reduction in serum ferritin and a statistically significant improvement in overall survival (OS) in 18 patients treated with desferrioxamine for a median of 15 months.23 The results are open to selection bias of favourable patients to the ICT group. In a subsequently reported subgroup analysis, the 18 chelated patients again showed better survival than matched control patients, but the control patients were significantly older, and no deaths in their group could be linked with iron overload.24 Rose et al. analysed, by multivariate analysis, survival and cause of death in 97 low- or intermediate-1 risk transfusion-dependent patients.25 Patients receiving ICT were younger with lower IPSS. Median OS was 124 months and 53 months in ICT and non-ICT groups respectively. Caution is again required because ICT patients were selected by the treating physician, and cause of death did not differ significantly between the two groups. Two large prospective phase-2 studies of ICT have recently reported improvements in surrogate end-points of serum ferritin and liver iron concentration in MDS patients,26,27 but one might question the benefit of fairly modest reductions in serum ferritin, bearing in mind the discontinuation rate of 49% in the Evaluation of Patients' Iron Chelation with Exjade (EPIC) trial and adverse events (vide infra). A prospective, randomised, placebo-controlled trial of deferasirox in transfusion-dependent low- or intermediate-1 risk MDS (TELESTO) is underway and aims to follow 630 patients for 5 years, but data collection is not scheduled to be complete until January 2016.28 Despite the lack of data showing benefit for ICT, it may now be difficult to recruit patients to this placebo-controlled trial given that deferasirox is available off-study in many countries. If ICT was cheap and safe, there would be few reasons not to use it in all patients with MDS, even those with high-risk disease. In contrast to studies of congenital anaemia, the discontinuation rate in MDS patients has been high, in part due to drug-related adverse events, and elevated serum creatinine is common.26,27 This contrasts with studies of thalassaemia in which self-reported compliance with both deferasirox and desferrioxamine is high (97% and 92% respectively).29 In February 2010, the FDA issued a warning to health professionals regarding the possible association with renal impairment, hepatic impairment and gastrointestinal haemorrhage.30 It is difficult to assign causality to adverse reactions in the elderly MDS population, but potential adverse effects need to be weighed against the evidence of benefit. In 2009 in the United States, the cost of deferasirox was reported to be US$60 000 per year, exceeding the median annual household income.2 The Australian Pharmaceutical Benefits Scheme reimbursement for deferasirox at 20 mg/kg/day for an 80 kg adult is approximately AU$15 000 per year,31 and the drug cost in New Zealand where it is not subsidised, is around NZ$40 000.32 The cost–benefit for deferasirox calculated by the Australian Pharmaceutical Benefits Advisory Committee in July 2006, estimated to be AU$36 420 per quality-adjusted life year gained, was derived from trial data submitted to the FDA showing improvements in survival in thalassaemia. As discussed earlier, similar cost–benefit has not been shown in MDS. Deferasirox is an effective, well tolerated, orally active iron chelator, and for patients with thalassaemia, it has greatly improved quality of life. The case for ICT in MDS is more complicated and worthy of further investigation. The finding that labile plasma iron is completely removed by deferasirox and improvement in cardiac function may occur before any reduction in siderosis is intriguing. It is also possible that iron chelators may have additional benefit in MDS (e.g. infection) independent of their ability to reduce iron burden. It is acknowledged that trial design of ICT is problematic, given the many confounding factors in MDS, but ultimately, evidence of benefit must come from demonstrating improved outcomes in quality randomised, prospective trials in patients representative of the general MDS population.

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