Deferasirox for managing iron overload in patients with myelodysplastic syndrome
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the effectiveness and safety of oral deferasirox for managing iron overload in people with myelodysplastic syndrome.
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 characterized by abnormal differentiation and maturation of blood cells, bone marrow failure and a genetic instability with an enhanced risk of transformation to leukaemia. The crude annual incidence is reported in the literature between 2.1 to 12.6 cases per 100,000 people per year (Aul 2001). Among the mainly affected group of male people aged more than 70 years, incidence rates reach 50 cases per 100,000 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). Mainly for the risk groups designated low and intermediate‐1 supportive therapy including red blood cell (RBC) transfusions for symptomatic anaemia might be indicated (NCCN Myelodysplastic Panel Members 2008). 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). Since the human body has no natural means of getting rid of excess iron, iron chelation therapy is usually recommended (List 2006; Valent 2008).
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.
Description of the intervention
Deferoxamine (DFO, Desferal®), reviewed in detail in a Cochrane Review (Roberts 2005), 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 8‐12 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). The hypothesis of direct liver toxicity of deferiprone could not been confirmed though (Wanless 2002; Wu 2006). Several studies have shown in the meantime the efficacy of deferiprone for iron chelation (Ceci 2002; Maggio 2002) and in particular its benefit on cardiac iron and cardiac morbidity (Peng 2008). Use has still been quite limited though, 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. It is approved for the treatment of secondary iron overload by the US Food and Drug Administration (FDA) (Food and Drug Administration (FDA) 2008) and the European Medicines Agency (EMEA) (European Medicines Agency 2008). 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 people with β‐thalassaemia in 2003 (Nisbet‐Brown 2003). The elimination half‐life of 8 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 experiences in people with thalassaemia include gastrointestinal disturbances (nausea, stomach pain or diarrhea) that are generally mild and a diffuse rash being more common at higher doses (Cappellini 2006). More rarely, fever, headache and cough are 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 very low 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 myelodysplastic syndrome.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), published and unpublished, will be considered for this review.
Types of participants
People with diagnosis of myelodysplastic syndrome regardless of age, type of myelodysplastic syndrome and setting. To be eligible people are required to receive either more than 2 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), the following comparisons will be considered:
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deferasirox compared with no therapy or placebo;
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deferasirox compared with another iron chelating treatment schedule (e.g. deferoxamine or deferiprone or any combination thereof).
These comparisons constitute two separate groups and will be analysed separately.
Types of outcome measures
Primary outcomes
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Overall survival (measured at any point in time)
Secondary outcomes
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Reduced end‐organ damage due to iron deposition
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cardiac failure (necessitating medical treatment)
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endocrine disease (necessitating substitution therapy of hormones or treatment of diabetes)
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histological evidence of hepatic fibrosis
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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)
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Measures of iron overload
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serum ferritin (ng/ml)
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iron levels in biopsies of liver and other tissue (mg/g liver dry weight)
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tissue iron assessment by SQUID (superconducting quantum interference device) (mg/g liver wet weight)
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tissue iron assessment by MRI (magnetic resonance imaging) (ms)
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Measures of iron excretion (urine and faeces) over 24 hours (mg/kg/d)
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Any adverse events
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raised levels of creatinine or kidney failure (above upper normal limit or rise of more than 20% above baseline level)
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skin rash
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gastrointestinal disturbances
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neutropenia / agranulocytosis (ANC less than 1000/µl)
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raised levels of liver enzymes (above upper normal limit or raise of more than 20% above baseline level) or progression to liver fibrosis
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hearing loss
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eye problems (e.g. retinal toxicity)
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unanticipated adverse events as reported in the primary studies
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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 / application of iron chelator on 5 or more days per week)).
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Cost of intervention per year.
It is not anticipated that there will be any additional outcome measures. However, data from outcomes not defined a priori but which have arisen from the review will be collected, if the outcome is considered to be of clinical relevance. We are aware of the problem of multiplicity in systematic reviews as discussed in Chapter 16.7.2 of the Cochrane Reviewer's Handbook (Higgins 2008) and by Bender (Bender 2001). We will bear this problem in mind while drawing conclusions. Once adequate multiple comparison procedures for use in systematic reviews will be suggested by the Cochrane Reviewer's Handbook we will apply these to the next version of our review.
Search methods for identification of studies
No language restriction will be applied.
Electronic searches
We will identify relevant trials by searching Medline (1950 to July 2008), EMBASE (1980 to July 2008), EBMR Evidence Based Medicine Reviews (1991 to July 2008), Biosis Previews (1969 to July 2008), ISI Web of Science (1945 to July 2008), Derwent Drug File (1983 to July 2008) and XTOXLINE (1965 to July 2008). The search strategy will include the following keyword terms (for details see Table 1; Table 2; Table 3; Table 4; Table 5):
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| .mp | = Abstract (AB), Subject Heading Word (HW), |
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| mp | = Abstract (AB), Device Manufacturer (DM), Drug Manufacturer Name (MF), |
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and<#6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| mp | = Abstract (AB), Accession Number (AN), Author (AU), Drug Trade Name (TN) |
| No. | Search |
| #1 | deferasirox* (Topic) |
| #2 | (ICL670* or "ICL 670*") (Topic) |
| #3 | (CGP72670* or "CGP 72670*") (Topic) |
| #4 | exjade* (Topic) |
| #5 | 2‐hydroxyphenyl (Topic) |
| #6 | triazol‐1‐yl (Topic) |
| #7 | "benzoic acid" (Topic) |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 OR #8 |
| No. | Search |
| #1 | deferasirox* (Topic) |
| #2 | (ICL670* or "ICL 670*") (Topic) |
| #3 | (CGP72670* or "CGP 72670*") (Topic) |
| #4 | exjade* (Topic) |
| #5 | 2‐hydroxyphenyl (Topic) |
| #6 | triazol‐1‐yl (Topic) |
| #7 | "benzoic acid" (Topic) |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 OR #8 |
deferasirox*
ICL670*
ICL 670*
CGP72670*
CGP 72670*
Exjade*
The chemical substance name "4‐(3,5‐bis(2‐hydroxyphenyl)‐(1,2,4)‐triazol‐1‐yl) benzoic acid" will be searched by splitting it up in searchable terms (2‐hydroxyphenyl, triazol‐1‐yl, benzoic acid) and combining those by AND.
Since deferasirox treatment is an intervention where there is a lot of ongoing research, the following three trial registries will be searched in all possible fields using the keyword terms as previously described.
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Current Controlled Trials Register: www.controlled‐trials.com
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ClinicalTrials.gov: www.clinicaltrials.gov
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ICTRP: www.who.int/ictrp/en/
Current trials will be listed and trigger the next update of this review if completed.
Searching other resources
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In addition abstract books of three major haematology conferences from 2000 on will be searched: the European Haematology Association conference, the American Society of Hematology conference, the British Society for Haematology Annual Scientific Meeting.
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Reference lists of all identified papers will be screened additionally to identify other potentially relevant citations.
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Contact will be made with the manufacturer of deferasirox (Novartis) as well as with selected experts in the field to request information on unpublished studies that involved deferasirox.
Data collection and analysis
Selection of studies
All title and abstracts of papers identified by the trial search strategy will be screened for relevance (JM). Only citations clearly irrelevant will be excluded at this stage. Full copies of all potentially relevant papers will be obtained. At this stage two authors (JM and DB) will independently screen the full papers, identify relevant studies and assess eligibility of studies for inclusion. Any disagreement on the eligibility will be resolved through discussion and consensus or if necessary through a third party (GA, CN). All irrelevant records will be excluded and details of the studies and the reasons for their exclusion will be recorded. Studies where important information is lacking (including foreign language studies awaiting translation) will be clearly categorised and reported as studies pending inclusion/exclusion decision.
Data extraction and management
Aside from details relating to the quality of the included studies, two groups of data will be extracted.
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Study characteristics ‐ place of publication, date of publication, population characteristics, setting, detailed nature of intervention, detailed nature of comparator and detailed nature of outcomes. A key purpose of this data will be to define unexpected clinical heterogeneity in included studies independently from analysis of results.
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Results of included studies with respect to each of the main outcomes indicated in the review question. Reasons why an included study does not contribute data on a particular outcome will be carefully recorded and the possibility of selective reporting of results on particular outcomes considered.
Data extraction will be undertaken by two authors independently (JM, DB). Data will be extracted with a data extraction form developed by the authors. Missing data will be requested from the original investigators. Disagreements will be resolved by consensus between the reviewers. Once disagreements have been resolved, the data extracted will be recorded onto the final data extraction form. One reviewer (JM) will transcribe these into RevMan 5 (Review Manager 5, 2008). Another reviewer (DB) will verify all data entry for discrepancies.
Assessment of risk of bias in included studies
Two review authors (JM, DB) will assess every trial using a simple form and will follow the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.0 (Higgins 2008).
We will assess the following domains as 'Yes' (i.e. low risk of bias), 'Unclear' (uncertain risk of bias) or 'No' (i.e. high risk of bias):
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Sequence generation
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Allocation concealment
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Blinding (of participants, personnel and outcome assessors)
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Incomplete outcome data
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Selective outcome reporting
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Other sources of bias
The assessments will be compared and any inconsistencies between the review authors in the interpretation of inclusion criteria and their significance to the selected trials will be discussed and resolved with a third author (GA). No study will be automatically excluded as a result of a rating of 'Unclear' or 'No'. The evaluation of the risk of bias in included studies will be presented in tabular form in the 'Results' section of the review.
Measures of treatment effect
Extracted data will be analysed using the most up‐to‐date version of RevMan available at the time of analysis (Review Manager 2008).
Ideally, we plan to extract hazard ratios with their 95% confidence intervals for the time‐to‐event data mortality and end‐organ damage (s. below). If hazard ratios are not given, we will use indirect estimation methods described by Parmar (Parmar 1998) and Williamson (Williamson 2002) to calculate them.
If we will neither be able to extract these data from the study reports nor will be able to receive the necessary information from the primary investigators, we will, as an alternative, use the proportions of participants with the respective outcomes measured at three months, six months, then six monthly intervals (i.e. twelve months, eighteen months and so on) to be able to calculate relative risks. If outcome data are recorded at other time periods, then consideration will be given to examining these as well.
For binary outcomes results will be expressed as relative risk (RR) with 95% confidence interval as measure of uncertainty. Continuous outcomes will be expressed as weighted mean difference (WMD) with 95% confidence intervals as measure of uncertainty.
Unit of analysis issues
When conducting a meta‐analysis combining results from cross‐over studies we plan to use the methods recommended by Elbourne (Elbourne 2002). For combining parallel and cross‐over trials, methods described by Curtin will be used (Curtin 2002a; Curtin 2002b; Curtin 2002c).
For some outcomes, a possible perception of the comparison might be whether deferasirox is equivalent to standard treatment with deferoxamine. Therefore, as secondary analysis we might consider per‐protocol analysis, as is often used for equivalence studies, for our primary outcome as well as for the groups one to five of our secondary outcomes.
For time‐to‐event data, we would consider a relative difference in hazard ratios of less than 10% equivalent. For relative risks, we would define non‐inferiority as a relative risk difference of less than 10% in treatment failures compared to standard therapy. For the continuous outcomes of "measures of iron overload and iron excretion" as well as "costs" we would also consider a relative difference of 10% as equivalent. Resulting confidence intervals will be discussed with respect to methods suggested by Witte (Witte 2004).
In principle it is conceivable that the found evidence is suitable for indirect comparisons or multiple‐treatments meta‐analysis. If so, we will consider to apply these concepts according to methods discussed by Glenny (Glenny 2005) and Salanti (Salanti 2008), respectively, as suggested by the the Cochrane Reviewer's Handbook (Higgins 2008), once they are supported by RevMan.
Dealing with missing data
Missing data will be requested from the original investigators.
Assessment of heterogeneity
Clinical heterogeneity will be assessed by examining differences between groups as detailed below. Statistical heterogeneity in the results of trials will be assessed using the I2 test (Higgins 2002; Higgins 2003). If we find marked clinical or statistical heterogeneity (I2 more than 50%) (Deeks 2008), further reasons for this heterogeneity except those mentioned in the paragraph on subgroup analysis will be explored.
Assessment of reporting biases
Great effort will be made to identify unpublished trials and minimise the impact of possible publication bias by using a comprehensive search strategy and contacting the manufacturer of deferasirox. Funnel plots will not be used to assess publication bias, since asymmetry is difficult to detect with a small number of studies (i.e. less than 10) as we expect to identify for this systematic review. If, in future versions of this review, more than 10 studies will be included, funnel plots will be used to graphically assess the likelihood of publication bias. Care will be taken in translating the results of the included studies into recommendations for action by involving all reviewers in drawing conclusions.
Data synthesis
If appropriate, meta‐analyses of pooled data from all contributing trials will be conducted using a fixed‐effects model for the primary analysis. However, if we find marked clinical or statistical heterogeneity (I2 more than 50%) we will also use a random‐effects model. Results from both models will be reported.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses are planned for the different prognostic subtypes of myelodysplastic syndrome according to the International Prognostic Scoring System (IPSS) (Greenberg 1997) as well as to the morphological MDS subtypes according to the WHO classification (Harris 1999; Vardiman 2002). Clinical heterogeneity will be assessed by examining differences due to baseline measures of iron overload, dose of intervention, concomitant use of growth factors (erythropoetin, G‐CSF) and age. In addition, heterogeneity will be assessed regarding study characteristics as described in the paragraph on "data extraction and management".
Sensitivity analysis
Sensitivity analysis will be performed based on methodological quality and publication status (unpublished and published studies).
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| .mp | = Abstract (AB), Subject Heading Word (HW), |
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| mp | = Abstract (AB), Device Manufacturer (DM), Drug Manufacturer Name (MF), |
| No. | Search |
| #1 | deferasirox*.mp |
| #2 | (ICL670* or ICL 670*).mp |
| #3 | (CGP72670* or CGP 72670*).mp |
| #4 | exjade*.mp |
| #5 | 2‐hydroxyphenyl.mp |
| #6 | triazol‐1‐yl.mp |
| #7 | benzoic acid.mp |
| #8 | #5 and<#6 and #7 |
| #9 | #1 or #2 or #3 or #4 or #8 |
| mp | = Abstract (AB), Accession Number (AN), Author (AU), Drug Trade Name (TN) |
| No. | Search |
| #1 | deferasirox* (Topic) |
| #2 | (ICL670* or "ICL 670*") (Topic) |
| #3 | (CGP72670* or "CGP 72670*") (Topic) |
| #4 | exjade* (Topic) |
| #5 | 2‐hydroxyphenyl (Topic) |
| #6 | triazol‐1‐yl (Topic) |
| #7 | "benzoic acid" (Topic) |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 OR #8 |
| No. | Search |
| #1 | deferasirox* (Topic) |
| #2 | (ICL670* or "ICL 670*") (Topic) |
| #3 | (CGP72670* or "CGP 72670*") (Topic) |
| #4 | exjade* (Topic) |
| #5 | 2‐hydroxyphenyl (Topic) |
| #6 | triazol‐1‐yl (Topic) |
| #7 | "benzoic acid" (Topic) |
| #8 | #5 and #6 and #7 |
| #9 | #1 or #2 or #3 or #4 OR #8 |
