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Le déférasirox pour la correction de la surcharge en fer chez les personnes atteintes de syndrome myélodysplasique

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Résumé scientifique

Contexte

La notion de syndrome myélodysplasique (SMD) recouvre un groupe hétérogène de pathologies des cellules souches hématopoïétiques. En raison de l'anémie symptomatique, la plupart des patients atteints ont besoin d'un traitement de soutien, notamment avec des répétées de globules rouges (érythrocytes). Cet apport, associé à une absorption accrue du fer, contribue à l'accumulation de fer, avec pour résultat une surcharge en fer secondaire et un risque de dysfonctionnement des organes et de perte d'espérance de vie. Puisque le corps humain n'a aucun moyen naturel d'éliminer l'excès de fer, un traitement de chélation du fer, c'est‐à‐dire un traitement pharmacologique de la surcharge en fer, est généralement recommandé. Cependant, il est difficile de savoir si le déférasirox, le chélateur du fer par voie orale le plus récent, apporte ou non à une amélioration pertinente.

Objectifs

Évaluer l'efficacité et l'innocuité du déférasirox par voie orale pour la correction de la surcharge en fer chez les personnes atteintes de syndrome myélodysplasique (SMD).

Stratégie de recherche documentaire

Nous avons effectué notre recherche dans les bases de données suivantes, jusqu'au 3 avril 2014 : MEDLINE, EMBASE, La Bibliothèque Cochrane, BIOSIS Previews, Web of Science, Derwent Drug File, et quatre registres d'essais : Current Controlled Trials (www.controlled‐trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), ICTRP (www.who.int./ictrp/en/), et le registre allemand des essais cliniques (www.drks.de).

Critères de sélection

Essais contrôlés randomisés (ECR) comparant le déférasirox à l'absence de traitement, à un placebo ou à un autre protocole de traitement chélateur du fer.

Recueil et analyse des données

Nous ne avons pas relevé d'essais admissibles pour l'inclusion dans cette revue.

Résultats principaux

Aucun essai ne répondait à nos critères d'inclusion. Toutefois, nous avons identifié trois essais en cours et un essai terminé (publié uniquement sous forme de résumé, et trop peu détaillé pour nous permettre de décider de son inclusion) comparant le déférasirox à la déféroxamine, à un placebo ou à l'absence de traitement.

Conclusions des auteurs

Nous avions prévu de rapporter les preuves fournies par les ECR évaluant l'efficacité du déférasirox par rapport au placebo, à l'absence de traitement ou à d'autres traitements chélateurs, comme la déféroxamine, chez les personnes atteintes de SMD. Cependant, nous ne avons pas relevé d'ECR terminés consacrés à cette question.

Nous avons trouvé trois ECR en cours et un autre complété (publié uniquement sous forme de résumé et trop peu détaillé) comparant le déférasirox avec la déféroxamine, un placebo ou l'absence de traitement, dont nous espérons que les données seront bientôt disponibles. Ces résultats seront importants pour informer les médecins et les patients sur les avantages et les inconvénients de cette option de traitement.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Résumé simplifié

Le déférasirox pour la correction de la surcharge en fer chez les personnes atteintes de syndrome myélodysplasique

Question de la revue

Nous avons cherché à examiner les preuves des effets du déférasirox (une option de traitement par voie orale) sur la réduction de la surcharge en fer chez les personnes atteintes d'un syndrome myélodysplasique (SMD), appellation qui regroupe différentes pathologies des cellules souches hématopoïétiques.

Contexte

Les transfusions répétées de globules rouges peuvent entraîner une surcharge en fer à secondaire (c'est‐à‐dire causée par les transfusions) cliniquement pertinente chez certains patients atteints d'un SMD, en particulier dans les groupes à faible risque, au cours de la maladie. Comme le corps humain n'a aucun moyen naturel d'éliminer l'excès de fer, des médicaments produisant cet effet peuvent être indiqués (traitement chélateur du fer), afin de les complications affectant certains organes. Depuis que le déférasirox, le chélateur du fer par voie orale le plus récent, est disponible, la chélation de fer est plus largement proposées aux personnes atteintes d'un SMD.

Nous avons voulu évaluer si l'administration de déférasirox est bénéfique pour les patients atteints d'un SMD.

Principaux résultats

Nous avons effectué une recherche dans la littérature disponible jusqu'au 3 avril 2014. Nous n'avons pu inclure dans cette revue aucune donnée répondant à notre question. Cependant, nous avons trouvé trois essais en cours et un essai terminé portant sur le déférasirox chez les personnes porteuses d'un SMD à faible risque (SMD à risque faible et moyen ‐ niveau 1). L'essai terminé n'étant pas rapporté de manière suffisamment détaillée (résumé), nous avons été incapables de décider définitivement si nous pouvions l'inclure dans notre revue ou en tirer des conclusions. Une fois disponibles, ces résultats seront importants pour informer les médecins et les patients sur les avantages et les inconvénients comparatifs de cette option de traitement.

Authors' conclusions

Implications for practice

Based on the limited evidence from retrospective analyses and observational studies, some current clinical practice guidelines do recommend consideration of iron chelation therapy for low risk MDS. However, these recommendations can not be supported by high quality data from RCTs. Therefore, data from the ongoing or completed but not fully published trial are urgently needed to inform doctors whether widespread use of deferasirox outside clinical studies is warranted. The decision to use deferasirox for individual patients with MDS, while based on personal preferences, should be informed by the potential benefits and harms and the resource use incurred.

Implications for research

RCTs investigating the effectiveness of iron chelation therapy, in general and of deferasirox in particular, in people with MDS are urgently needed. Future RCTs should include (1) patient‐relevant outcomes and (2) investigate also long‐term benefits and adverse effects. Furthermore, the value of iron chelation therapy should be differentially investigated (3) for the various subtypes of MDS. If the value of iron chelation therapy is unambiguously established, (4) comparative trials defining the advantages and disadvantages of the various iron chelating regimens should follow.

Background

Description of the condition

The myelodysplastic syndrome (MDS) comprises a diverse group of haematopoietic stem cell disorders which are usually classified according to the World Health Organization (WHO) MDS classification (Harris 1999; Vardiman 2002). They are characterised by abnormal differentiation and maturation of blood cells, bone marrow failure and a genetic instability with an enhanced risk of transformation to leukaemia. The annual incidence reported in the literature is between 2.1 to 12.6 cases per 100,000 people per year (Aul 2001). Men aged over 70 years are mainly affected, with incidence rates reaching 50 cases per 100,000 people per year (Aul 2001).

People with MDS can be subdivided in prognostic groups according to the International Prognostic Scoring System (IPSS) taking into account bone marrow blast percentage, cytogenetic profile and the number of cytopenias (Greenberg 1997). For higher risk groups, drug treatment (e.g. with azacitidine), intensive chemotherapy or even haematopoetic stem cell transplantation (depending on disease‐ and patient‐related factors) is usually required. Recently, a new WHO classification‐based prognostic scoring system (WPSS) has been proposed (Malcovati 2007), classifying patients into five risk groups according to WHO subgroups, karyotype abnormalities according to IPSS and transfusion requirements.

Mainly for the risk groups designated low and intermediate‐1 (according to IPSS) only supportive therapy including red blood cell (RBC) transfusions for symptomatic anaemia might be indicated (NCCN Myelodysplastic Panel Members 2010). Regular RBC transfusions in combination with prolonged dyserythropoiesis and increased iron absorption contribute to the accumulation of iron resulting in secondary iron overload. This can ultimately lead to organ dysfunction affecting the liver, endocrine glands and the heart, resulting in reduced life expectancy (Malcovati 2005; Takatoku 2007). Since the human body has no natural means of getting rid of excess iron, iron chelation therapy, i.e. pharmacological treatment of iron overload, is usually recommended (List 2006; Valent 2008).

Description of the intervention

Deferoxamine (DFO, Desferal®), reviewed in detail in a Cochrane Review (Fisher 2013), has been the treatment of choice for iron overload for the last 40 years. Due to its long standing availability it is the only chelating agent for which profound effects on the long‐term survival of a large cohort of patients with thalassaemia have been shown (Zurlo 1989; Brittenham 1994; Gabutti 1996; Borgna‐Pignatti 2004). To be clinically effective DFO has to be administered as a subcutaneous infusion over eight to 12 hours, five to seven days per week. This regimen has been demonstrated to reduce the body iron load, prevent the onset of iron‐induced complications and even reverse some of the organ‐damage due to iron (Olivieri 1994). However, the arduous schedule of overnight subcutaneous infusions often leads to reduced compliance (Olivieri 1997; Cappellini 2005). Another problem concerns the toxicity of DFO, particularly at higher doses. Toxicities beside local skin reactions also include ophthalmologic (optic neuropathy, retinal pigmentation) and hearing problems (high frequency sensorineural hearing loss). Rare adverse effects like growth retardation, renal impairment (Koren 1991), anaphylactic reactions and pulmonary fibrosis (Freedman 1990) have been reported.

Oral preparations have been highly sought after for many years. In 1987, two studies showed that the orally active iron chelator deferiprone (1,2 dimethyl‐3‐hydroxypyrid‐4‐1, also known as L1, CP20, Ferriprox® or Kelfer) could achieve effective short‐term iron chelation (Kontoghiorghes 1987a; Kontoghiorghes 1987b). Doubts on the efficacy to reduce liver iron and prevent liver damage arose due to individuals with progression to overt liver fibrosis (Olivieri 1998), but the hypothesis of direct liver toxicity of deferiprone could not be confirmed (Wanless 2002; Wu 2006). In the meantime several studies have shown the efficacy of deferiprone for iron chelation (Ceci 2002; Maggio 2002) and in particular its benefit on cardiac iron and cardiac morbidity (Peng 2008). However, its use has remained limited due to its range of adverse effects (Hoffbrand 2003). These include gastrointestinal disturbances, arthropathy, neutropenia and agranulocytosis (Hoffbrand 1989). Recently, studies on combination therapy of deferoxamine and deferiprone have been performed (Kattamis 2003; Origa 2005; Farmaki 2006; Galanello 2006; Tanner 2007; Kolnagou 2008). A Cochrane Review on the effectiveness of deferiprone in people with thalassaemia has recently been published (Roberts 2007).

How the intervention might work

Deferasirox (4‐[3,5‐bis(2‐hydroxyphenyl)‐1H‐1,2,4‐triazol‐1‐yl]‐benzoic acid, also known as CGP 72670, ICL670 or Exjade®) is a new oral chelator available for routine use. The US Food and Drug Administration (FDA) (Food and Drug Administration (FDA) 2010) and the European Medicines Agency (EMA) (European Medicines Agency 2010) have approved it for the treatment of secondary iron overload. It is rapidly absorbed after administration and has a bioavailability of about 70%. Safety and tolerability was shown in a randomised dose escalation trial in 24 people with β‐thalassaemia (Nisbet‐Brown 2003). The elimination half‐life of eight to 16 hours allows a once daily administration after the tablets have been added to water or juice. Being a tridentate chelator, two molecules of deferasirox are needed to bind one molecule of iron. The excretion of the bound iron is mainly via faeces.

Adverse effects, known from the phase III study in people with thalassemia by Cappellini 2006 (n= 584 patients) and from experiences in people with thalassaemia, include gastrointestinal disturbances (nausea, stomach pain or diarrhoea) that are generally mild and a diffuse rash being more common at higher doses (Cappellini 2006). More rarely, fever, headache and cough have been encountered. The main adverse effect with the use of deferasirox seems to be a mild to moderate elevation of the creatinine level in about a third of patients. Elevations of liver enzyme levels have also been described with a lower incidence (5.6%) (Cappellini 2006). As with standard therapy (DFO), hearing loss and ocular disturbances including cataracts and retinal disorders have been reported with a lower incidence (< 1%).

Why it is important to do this review

Deferoxamine necessitates serious commitment on the user's side and deferiprone is only approved as second line therapy in some countries due to its adverse effects. Thus, much hope is being placed in the new oral chelator deferasirox, which apparently offers a promising line of treatment due to its iron chelation properties and safety and tolerability profile. Therefore, a systematic review of the effectiveness and safety of deferasirox according to Cochrane standards is urgently needed.

Objectives

To evaluate the effectiveness and safety of oral deferasirox for managing iron overload in people with MDS.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), of parallel group or cross‐over design, published or unpublished. To be eligible, either 80% of trial participants should have had MDS or data should have been available for the subgroup of participants with MDS.

Types of participants

People with diagnosis of MDS regardless of age, type of MDS and setting. To be eligible people were required to receive either more than two RBC concentrates per month or to have elevated ferritin levels of > 1000 ng/mL on at least two occasions.

Types of interventions

For oral deferasirox (all schedules and doses), we considered the following comparisons:

  1. deferasirox compared with no therapy or placebo

  2. deferasirox compared with another iron chelating treatment schedule (e.g. deferoxamine or deferiprone or any combination thereof).

These comparisons constituted two separate groups and we planned to analyse them separately.

Types of outcome measures

We did not exclude studies on the basis of reported outcomes.

Primary outcomes

  1. Overall survival (measured at any point in time).

Secondary outcomes

  1. Reduced end‐organ damage due to iron deposition:

    1. cardiac failure (necessitating medical treatment)

    2. endocrine disease (necessitating substitution therapy of hormones or treatment of diabetes)

    3. histological evidence of hepatic fibrosis

    4. pathological surrogate markers of end‐organ damage (i.e. elevated liver enzymes, elevated fasting glucose or pathological oral glucose tolerance test (OGTT), pathological measures (e.g. ejection fraction) in echocardiography).

  2. Measures of iron overload:

    1. serum ferritin (ng/mL)

    2. iron levels in biopsies of liver and other tissue (mg/g liver dry weight)

    3. tissue iron assessment by SQUID (superconducting quantum interference device) (mg/g liver wet weight)

    4. tissue iron assessment by MRI (magnetic resonance imaging) (ms).

  3. Measures of iron excretion (urine and faeces) over 24 hours (mg/kg/day).

  4. Any adverse events:

    1. raised levels of creatinine or kidney failure (above upper normal limit or rise of more than 20% above baseline level)

    2. skin rash

    3. gastrointestinal disturbances

    4. neutropenia / agranulocytosis (ANC less than 1000/µL)

    5. raised levels of liver enzymes (above upper normal limit or raise of more than 20% above baseline level) or progression to liver fibrosis

    6. hearing loss

    7. eye problems (e.g. retinal toxicity)

    8. unanticipated adverse events as reported in the primary studies.

  5. Participant satisfaction (measured e.g. by questionnaire) and compliance with chelation treatment (measured by the number of people in each arm that show adequate level of adherence to treatment (intake or application of iron chelator on five or more days per week).

  6. Cost of intervention per year.

We planned to present data for the following time points: six months, 12 months, 24 months, 36 months, etc. Otherwise, we planned to present data for the latest time points available.

We did not anticipate that there would be any additional outcome measures. However, we planned to collect data from outcomes not defined a priori but which will arise from updated versions from the review, if we considered the outcome of clinical relevance.

Search methods for identification of studies

We did not apply any language restrictions.

Electronic searches

For this update, we searched the following databases for relevant trials:

Via Wiley Interscience: The Cochrane Library (Issue 4, 2014 for Cochrane Database of Systematic Reviews, Issue 3, 2014 for Cochrane Central Register of Controlled Trials, Issue 1, 2014 for Other Reviews (DARE), Technology Assessments and Economic Evaluations, Issue 3, 2012 for Methods Studies); via OvidSP: MEDLINE (1946 to March Week 4 2014), MEDLINE in Process and Other Non‐Indexed Citations (to April 2, 2014); via PubMed: MEDLINE subset "supplied by publisher" (to April 2, 2014); via DIMDI: EMBASE and EMBASE Alert (2010 to April 1, 2014); via Thomson Reuters: Web of Science (2010 to April 1, 2014), Biosis Previews (2010 to April 1, 2014); via DIMDI: Derwent Drug File (2010 to April 1, 2014). We performed the searches on 2nd and 3rd April 2014. We used an RCT filter MEDLINE, EMBASE, Biosis Previews, ISI Web of Science and Derwent Drug File searches; also, we limited the search to reports published between 2010 and 2014. For details of the search strategies see Appendix 1.

Since research into deferasirox treatment is ongoing, we searched the following four trial registries up to 16 April 2014 for all years available in all possible fields using the basic search function (using separately the following keyword terms: "deferasirox", "ICL670", "ICL 670" and "exjade"):

  1. Current Controlled Trials: www.controlled‐trials.com (all available registers were searched)

  2. ClinicalTrials.gov: www.clinicaltrials.gov

  3. ICTRP: www.who.int/ictrp/en/

  4. German Clinical Trial Register: www.drks.de

For the previous version of this review, we searched several databases and ongoing trials registers from 24 June 2010 up to 01 July 2010. Please see Appendix 2 for full details.

Searching other resources

In addition we searched the abstract books of two major haematology conferences from 2000 to 2013: the European Haematology Association conference and the American Society of Hematology conference.

We intended to screen reference lists of all identified papers to identify other potentially relevant citations.

We contacted selected experts in the field and the manufacturer of deferasirox (Novartis) to request information on unpublished studies that involved deferasirox.

Data collection and analysis

Selection of studies

One review author (JM and LS (update search)) screened all titles and abstracts of papers identified by the trial search strategy for relevance. We only excluded citations that were clearly irrelevant at this stage. We obtained full text copies of all potentially relevant papers and two review authors (JM, DB for previous version of review; LS, JM for current update) independently screened the full papers, identified relevant studies and assessed eligibility of studies for inclusion. We resolved any disagreement on eligibility through discussion and consensus or if necessary through referral to a third party (GA or CN). We excluded all irrelevant records and recorded details of the studies and the reasons for their exclusion. We planned to categorise studies that lacked important information (including foreign language studies awaiting translation) and report them as studies pending inclusion/exclusion decision for future updates.

Data extraction and management

This was not applicable as no trials met our inclusion criteria. For details on planned methods please see section "Differences between protocol and review".

Assessment of risk of bias in included studies

This was not applicable as no trials met our inclusion criteria.

Measures of treatment effect

This was not applicable as no trials met our inclusion criteria.

Unit of analysis issues

This was not applicable as no trials met our inclusion criteria.

Dealing with missing data

We contacted the original investigators of Castellano 2011 to request more detailed data regarding patient eligibility criteria. However, we were informed that data are not to be shared prior to publication.

Assessment of heterogeneity

This was not applicable as no trials met our inclusion criteria.

Assessment of reporting biases

We tried to minimise the likelihood of publication bias by using a comprehensive search strategy including the search of abstracts and contacting the manufacturer of deferasirox. However, we did not identify any trials for inclusion.

Data synthesis

This was not applicable as no trials met our inclusion criteria.

Subgroup analysis and investigation of heterogeneity

This was not applicable as no trials met our inclusion criteria.

Sensitivity analysis

This was not applicable as no trials met our inclusion criteria.

Results

Description of studies

Results of the search

Based on the searches for this review update (run in April 2014), we identified 546 unique citations (Figure 1). We included two additional abstracts after we contacted the authors of Castellano 2011. After we screened titles and abstracts of these citations we identified seven as potentially eligible. We excluded five citations after full text screening for the following reasons:


Study flow diagram (update search performed in April 2014),

Study flow diagram (update search performed in April 2014),

We identified 110 unique references to trials after searching the four trial registers (run on 02/03 April 2014). We found two ongoing (Novartis 2013; NCT02038816) and one completed RCTs (published as abstract only) (Castellano 2011) by this search, in addition to the ongoing trial already identified in the previous version of this review (TELESTO 2009). We categorised the Castellano 2011 trial as awaiting classification (since the two published abstracts do not provide enough detail to decide on definitive inclusion). A fifth study, which we identified through searching the registers (Pennell 2014, CORDELIA), was planned to also include people with MDS. However, as reported in Pennell 2014, CORDELIA, none of the four screened MDS patients fulfilled the other inclusion criteria of the trial.

Previous search

For the previous version of this review, we performed the literature search in August 2008, June 2009 and lastly between 24 and 30 June 2010. Altogether, we identified 2171 citations, including 1191 duplicates. After we screened titles and abstracts of the 980 unique citations, we excluded 686 citations. In total, we screened 294 full texts but we no RCTs met our inclusion criteria. Our reasons for exclusion were as follows:

  • included people with disease other than MDS

    • thalassaemia (N = 140)

    • sickle cell disease (N = 38)

    • other condition (N = 11)

  • review article or editorial/comment (N = 46)

  • intervention other than deferasirox (N = 1)

  • cost‐effectiveness analysis (N = 5)

  • non‐randomised data on people with MDS (N = 52) (see Characteristics of excluded studies)

  • ongoing study (N = 1) (see Characteristics of ongoing studies).

After we searched the three trial registers for the previous version of this review (last run on 30 June 2010) we identified 49 unique references to trials. However, we identified only one ongoing RCT including MDS patients (TELESTO 2009).

Included studies

In this version of the review, we could not include any data from completed trials.

Excluded studies

We excluded 25 studies, most of which were non‐randomised studies. For details please see Characteristics of excluded studies.

Risk of bias in included studies

We did not find any trials that were eligible for inclusion.

Effects of interventions

We did not find any eligible trials for inclusion in this review.

Discussion

Summary of main results

Through our comprehensive searches, we identified three ongoing and one completed trial. However, no data from any of these RCTs are currently available for inclusion in this review.

Overall completeness and applicability of evidence

This was not applicable as we did not include any trials in this review.

Quality of the evidence

This was not applicable.

Potential biases in the review process

We conducted a very comprehensive search including searches of several study registers. This led to the identification of three ongoing and one completed RCTs. However, despite correspondence with trial authors, we were unable to decide on definite inclusion of the completed RCTs, nor include any data in this current review version.

Agreements and disagreements with other studies or reviews

People with MDS potentially constitute the largest group of patients at risk of iron overload. However, the impact of iron chelation therapy in people with MDS has not been investigated as extensively as in other transfusion‐dependent anaemias such as thalassaemia (Roberts 2007; Cianciulli 2008; Porter 2009; Fisher 2013). In theory, the biological rationale behind treating iron overload in patients with other anaemias should also apply to people with MDS. Thus, clinical practice guidelines do suggest consideration of iron chelation therapy for certain subgroups of MDS patients (Bennett 2008; Gattermann 2008; Greenberg 2011; Malcovati 2013). With the emergence of deferasirox, which avoids the cumbersome application mode of deferoxamine, iron chelation therapy has been offered more widely to MDS patients. However, data from thalassaemia patients is not likely to be directly transferred to people with MDS considering that people with MDS are older and suffer from a different disease entity. For example, people with MDS are potentially more prone to iron‐related organ dysfunction and certain adverse effects. Furthermore, reduced life‐expectancy in people with MDS compared to people with other anaemias could render the beneficial effects of iron chelation therapy clinically less relevant since such patients may not survive long enough to accumulate iron to toxic levels.

The negative impacts of iron overload and the benefits of iron chelation therapy for people with MDS are nevertheless suggested by recent retrospective survey data (Takatoku 2007) and observational studies (Rose 2007; Leitch 2008), although not all studies could confirm beneficial effects of iron chelation therapy (Chee 2008). More specifically, several retrospective analyses and observational studies suggest a benefit with regard to certain outcomes in patients with MDS from deferasirox (see the Excluded studies section; also Porter 2004; List 2006, US3 study; Gattermann 2007, EPIC; List 2012; Cermak 2013). Additionally, several narrative reviews of deferasirox have been published over recent years (Shah 2012; Adams 2013; Breccia 2013). However, the impact of iron chelation therapy (either with deferasirox or any other iron chelator) on long‐term outcomes or patient‐relevant outcomes such as organ dysfunction or mortality has not been evaluated in rigorous RCTs (Leitch 2009b). Indeed, we found no RCTs published to date that studied the impact of iron chelation with deferasirox for patients with MDS.

Since iron chelation therapy has such a positive impact on survival in thalassaemia patients and is increasingly being offered to people with MDS, further evaluation of the effects of iron overload and chelation therapy in patients with MDS is urgently required in order for clinical practice guidelines based on high quality evidence to be formulated. In particular, the profile of adverse effects urgently needs to be established to allow adequate balancing of the benefits and potential harms of iron chelation therapy for people with MDS. Adverse events may differ compared to people with thalassaemia; an RCT conducted with acute myeloid leukaemia patients points to poor tolerability and excess gastrointestinal and infectious toxicity (Kennedy 2013). Furthermore, the generation of further data supporting the application of this intervention instead of no intervention or other iron chelating regimens seems to be even more important considering the costs implied by a continuous therapy with deferasirox (Delea 2005; Karnon 2007a; Karnon 2007b; Bozkaya 2008).

To address some of the uncertainties in the evidence base, three prospective RCTs are currently enrolling patients (TELESTO 2009; Novartis 2013; NCT02038816), while one has already completed patient recruitment and is awaiting publication (Castellano 2011). Castellano 2011 has already presented findings as an abstract at two conferences. Castellano et al. reported statistically significant decreases in serum ferritin for both groups over time, but comparative analyses between groups are not provided. Also, these abstracts did not provide sufficient information on patient eligibility criteria in order to be included in the current version of this review.

These trials should improve the evidence base and possibly lead to clearer indications being established for iron chelation therapy in MDS patients. If the effectiveness of deferasirox in MDS is confirmed in the future, further comparisons with other iron chelation regimens, such as deferiprone, will be worthwhile since the profile of adverse effects, in particular, varies between different chelating agents.

Study flow diagram (update search performed in April 2014),
Figures and Tables -
Figure 1

Study flow diagram (update search performed in April 2014),