| HOME | HELP | FEEDBACK | TABLE OF CONTENTS | ARCHIVE | SUBSCRIPTIONS |
|
|
|
||||||
|
||||||||
Iron Overload |
1 U.O. Ematologia e Centro Trapianti Cellule Staminali Emopietiche, Ospedale Oncologico Regionale "Armando Businco", Cagliari
2 Laboratorio di epidemiologia clinica, Fondazione IRCCS Policlinico S.Matteo, Pavia
3 Università Vita-Salute e IRCCS San Raffaele, Milano
4 Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena IRCCS, Università di Milano
5 U.O. di Ematologia, Università di Pavia e Fondazione IRCCS Policlinico S. Matteo, Pavia
6 Ospedale Regionale Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari
7 Centro Microcitemie, Divisione di Ematologia Pediatrica, Dipartimento di Scienze Pediatriche, Università di Torino
8 Istituto di Ematologia ed Oncologia Medica "Seràgnoli", Università di Bologna, Italy
Correspondence: Emanuele Angelucci, MD, Hematology Department and BMT Unit, Cancer Center "Armando Businco", viale Edward Jenner, 09121 Cagliari, Italy. E-mail: emnang{at}tin.it
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionDesign and MethodsResultsDiscussionReferences |
|---|
Key words: clinical practice guidelines, systematic review, thalassemia major, sickle cell anemia, deferoxamine, deferiprone, deferasirox.
|
Introduction |
|---|
|
TOPABSTRACTIntroductionDesign and MethodsResultsDiscussionReferences |
|---|
These developments have heralded a new era for iron chelation, with the expectation of reducing organ iron burden, improving function and, ultimately, survival. However, integrating scientific evidence of the appropriateness of these new health technologies may lead to conflicting conclusions being made. These may in turn result in variations in clinical practice, with related disease costs and patient outcome.
In order to offer patients the most appropriate treatment, the Italian Society of Hematology commissioned a project to produce recommendations for the use of new diagnostic technologies and iron chelators in thalassemia major and related disorders. Thalassemia in Italy is still a major health problem, and Italian hematologists caring for patients with thalassemia are largely involved in the development and appraisal of new diagnostic techniques and in clinical research on the effectiveness of new chelators.4–11 This has produced a group of acknowledged experts that have a comprehensive mastery of scientific and practical information that can give the most appropriate judgment.
Providing recommendations for management of iron overload in thalassemic syndromes today must involve decisions which are multifactorial in nature, and whose metrics are variable and difficult to define accurately. In an attempt to consider all the factors that may affect these decisions, analytical hierarchy process, a multiple-criteria decision-making technique,12,13 was applied in this study. The final aim of the project was to support the clinical practice of hematologists, transfusionists and internists who care for patients with thalassemia major and related disorders.
|
Design and Methods |
|---|
|
TOPABSTRACTIntroductionDesign and MethodsResultsDiscussionReferences |
|---|
Framing the domain of recommendations
During an initial meeting, the expert panel agreed on the aim of the project: to develop recommendations for the optimal treatment of iron overload in patients with thalassemia major. The expert panel agreed that the recommendations produced should be valid in the context of thalassemia major and related disorders, such as HbE/thalassemia, and sickle cell anemia.
The areas of major concern in the management of iron overload in thalassemia major and related disorders were selected by generating and rank-ordering clinical key-questions using the criterion of clinical relevance, i.e. impact on the management of patients and risk of inappropriateness, through iterative questionnaires (Delphi process).14 The five candidate key-questions that ranked highest formed the set of questions of the present guidelines.
Literature inquiry and evidence analysis
The advisory committee performed MEDLINE, EMBASE and Cochrane Databases searches of English-language literature using pertinent Medical Subject Headings (MeSH) and terms. The electronic databases were initially searched in April 2006 (period covered: from January 1990 through March 2006), and the search was updated in April 2007. Additionally, the proceedings of the latest annual meetings were searched for relevant unpublished evidence. Investigators and pharmaceutical companies identified as being active in the field were asked to provide unpublished data or studies.
Two reviewers independently appraised and extracted details of selected articles that addressed the methods of measuring iron overload and the therapy of iron overload in thalassemia major, sickle cell anemia and congenital transfusion-dependent anemias using standardized extraction forms. For therapy studies, the following items were extracted: place of publication, study characteristics, population characteristics, detailed nature of intervention, comparator, concealment of allocation and outcomes. The study design was graded using the grading system elaborated by the Scottish Intercollegiate Guideline Network (SIGN), which grades at the top metanalyses and randomized clinical trials.15 For studies evaluating tests, the following items were extracted: prospective or retrospective design, inclusion of consecutive patients, time when the test was carried out, number of patients, gender, age, duration of therapy. For studies evaluating the prognostic value of tests, validity of selected articles was assessed according to whether the study group was well-defined, the population representative, the criteria of patient selection defined, adequate follow-up, and outcome definition. No grade of methodological quality was given since no score received general agreement. Narrative synthesis methods were then used to integrate findings into descriptive summaries.
Framing the decision model
For each of the defined key-questions, we framed the decision process needed to arrive at the final recommendation as an analytical hierarchy process. For each of the key questions, a set of candidate alternative decisions was proposed by the expert panel in a Delphi process.14 The appropriateness of candidate options was determined by comparing them according to criteria that were explicitly generated in order to make clear the expert’s judgments regarding which considerations are pertinent and their relative importance. Using a bottom-up approach, comparison of the options was made according to their ability to fulfill one of the selected criteria. This part of the process took place in consensus meetings using the nominal group technique, i.e. a face to face ordered group discussion process.16 Literature-derived evidence analysis was extensively used in this process to support the decision. If 80 percent or more of consensus about which of the two alternatives to select was reached, the selected alternative was subsequently submitted to pairwise comparisons with the next option of the group until every pair of options was evaluated. The final list of options formed the core of the recommendations. Recommendations on therapy were graded according to SIGN.15
|
Results |
|---|
|
TOPABSTRACTIntroductionDesign and MethodsResultsDiscussionReferences |
|---|
Since it was documented that LIC by biopsy and total body iron stores were highly correlated (R=0.98; p= 
0.001),17 liver biopsy was considered the gold standard for measurement of total body iron. Nine studies with more than 10 patients that analyzed the accuracy of SF were selected (Table 1).4,9,18–24 Strong linear correlation (R2=approximately 1.0), enabling precise quantitative estimation of body iron content, was demonstrated in one study20 but only in patients without a histological picture of liver hepatitis. There was good linear correlation (R2 >0.5) in four out of the remaining studies17,18,23,25 but in one of them, only in patients with lower iron burden.18 Quality limitation of the studies were sample size (only four studies had analyzed more than 100 patients), and directness (all of them analyzed a population of patients who had started iron chelation therapy and included patients with high iron burden).
|
|
In patients whose transfusional history is not known and iron burden may not be predicted by the transfusional iron intake, the criterion the expert panel selected for deciding which measurement was necessary before starting a new chelation therapy was the accuracy in revealing the total iron burden in patients who may have severe iron overload. In this decision, safety, availability and cost of the measurement were considered of minor importance. Evidence analysis on the correlation between SF, SQUID and MRI imaging and LIC by biopsy was reconsidered in this setting (Tables 1 and 2). The panel concluded that SF is not sufficient to demonstrate high body iron content accurately.
Recommendations
Patients with thalassemia major or related disorders in the early transfusional period, and with a known transfusional history, need to have serum ferritin levels determined 1–2 months apart in order to have a baseline value of iron load to use for initiating iron chelation therapy.
Patients over 5 years of age and with an unknown previous transfusion history and/or inappropriate chelation therapy should have both serum ferritin and liver iron concentrations determined in order to plan iron chelation therapy.
Liver iron biopsy with iron measurement by atomic absorption spectroscopy remains the gold standard for the assessment of liver iron concentration. Evidence of the accuracy of non- invasive methods for assessment of liver iron concentration is sufficient to recommend MRI technology as a feasible alternative to liver biopsy. R2 sequences and individual local calibration are recommended. SQUID remains a method to be reserved for experimental use since there is no calibration homogeneity and liver iron concentration could be underestimated.
When to start iron chelation therapy
The panel identified as criterion for deciding the best time to start iron chelation that of avoiding a transfusional iron load that could produce end-organ damage. The literature revision was addressed to studies that compared the outcomes of chelation therapy which were started at different times.
There are no quantitative trials that prospectively compared the outcomes of the disease according to the patients’ age, transfusional load, or iron measurements at the start of chelation therapy. Four observational, retrospective outcome studies were analyzed.33–37 The panel concluded that there is good evidence of the relevance of age and SF values as indicators for deciding to start chelation therapy. However, evidence of the optimal thresholds values of such parameters is lacking. The panel therefore made its decision according to the principles of good clinical practice.
Recommendation
The panel judged that in children who have been regularly transfused, iron chelation should be started after they have received more than 10 units of blood, or with serum ferritin levels of over 1000 ng/mL. In patients with an unknown previous transfusional history or inappropriate chelation therapy, iron chelation should be started when liver iron content is over the normal range of the method used.
First-line therapy in regularly transfused patients
The criteria for selecting the iron chelating agent for prophylactic use in regularly transfused patients were long-term efficacy and safety of the chelator along with the expected compliance with therapy. Selected studies should have a comparative design, include participants showing little evidence of iron overload without end-organ damage, and, in principle, the tested drugs should be given from the beginning of chelation therapy. Therefore, this review arbitrarily excluded studies in which, when comparing drugs, the mean or median value of SF was greater than 2,000 ng/mL or LIC by biopsy greater than 7 mg Fe/g dry weight (d.w.). An additional exclusion criterion was an excessive hepatic or cardiac iron load as the reason for starting the comparative iron chelation.
Eight studies which compared DFP to DFO were selected10,32,37–43 (Table 3). Some of them did not meet the inclusion criterion of SF lower than 2,000 ng/mL. However, all of them met the criterion of LIC lower than 7 mg Fe/g d.w. No study included patients at the beginning of chelation therapy. Altogether, 231 evaluable patients received DFP or DFP plus DFO and 266 received DFO alone.
|
Compliance was significantly better in the DFP group than that in the DFO-treated group in one trial,37 but was similar in two other trials.10,32 The ability to compare data on compliance was limited by the different measurement methods used. Safety was an end-point of all but three trials.32,39,40 Safety review documented that 7 out of 167 (4.19%) patients treated with DFO interrupted the treatment because of side effects compared with 10 out of 155 (6.45%) treated with DFP or combined therapy. Neutropenia was reported in 1 out of 167 patients treated with DFO (0.59%) and 4 out of 152 with DFP or combined therapy (2.6%). Neither difference was statistically significant. One agranulocytosis was reported in DFP treated patients.37
Two randomized controlled studies comparing DFX to DFO and reporting separate results among patients with low iron burden were selected in this section.9,43 LIC modification was the main endpoint of the studies. In one study of thalassemic patients,9 those entering the trial with a LIC less than 7 mg Fe/g d.w., therefore taking low doses of DFX (5–10 mg/kg/d), resulted in an increase in LIC and SF in both arms. In the other study of sickle cell disease,43 patients entering the trial with a LIC less than 7 mg Fe/g d.w., showed a statistically significant reduction of LIC only with DFX in the dose cohort of 10 mg/kg/d. No significant changes in SF were observed. Adverse events resulted in drug discontinuation in 5.3% of patients on DFX and 3.2% of patients on DFO, but the difference was not statistically significant. Compliance was measured as an endpoint in sickle cell disease patients,43 indicating a high adherence to both treatment regimens. Satisfaction with treatment was separately reported in thalassemic patients.44 All patients receiving DFX were satisfied with treatment and found it to be more convenient than DFO.
The panel agreed that the evidence on the efficacy of DFP or DFX oral chelators with respect to DFO standard therapy in the prophylaxis of iron overload was limited by the short-term evaluation. There is no strong evidence that DFP alone or in combination with DFO is superior to DFO alone in removing iron from the body, as measured by SF or from the liver. Evidence that DFP is superior to DFO alone in preventing iron accumulation in the heart came from studies whose efficacy measurement was directed towards the removal of small amounts of iron from the heart and not towards the prophylactic use of therapy. Evidence points to ineffectiveness of DFX in removing iron from the liver when compared with DFO in patients with limited iron overload when used at the tested doses. Evidence in sickle cell anemia, however, pointed to better iron removal from the liver in patients with at least 3 mg Fe/g d.w. and with doses of at least 10 mg/kg. For all these reasons, existing evidence was judged insufficient to support the prophylactic use of new oral chelators in transfusional iron overload of thalassemia major or related disorders.
Recommendation
Children who start iron chelation therapy before 6 years of age, when the body iron burden is always modest, and in whom the goal of chelation therapy is the prophylactic maintenance of iron balance, should receive iron chelation with deferoxamine (level D). The better compliance of oral compounds make these new drugs attractive. The option of oral chelators in first line therapy should, for the moment, be considered investigational and should only be performed within clinical trials or registries.
Monitoring iron chelation
Monitoring patients during chelation therapy is aimed at avoiding both excessive iron deposition and excessive iron depletion, and allows the efficacy of therapy and the compliance to the chelator to be evaluated. The criterion the panel selected to use for deciding which is the best measurement for monitoring iron load during iron chelation therapy was the prognostic value of the test.
Studies including any sort of analysis of prognostic factors were selected. The prognostic value of SF was evaluated in six retrospective studies.33–36,45,46 Hypogonadism, short stature, cardiac disease-free survival and death were the measured outcomes. For all the studies, study groups were judged well-defined, and the number of patients and the follow-up sufficient. However, the studies were judged to be limited by their different thresholds for SF value, and lack of a common definition of cardiac outcomes. The prognostic value of LIC by biopsy was evaluated in one retrospective analytical study45 in which cardiac disease-free survival was significantly associated with initial LIC.
Monitoring cardiac function was shown to have prognostic value on symptomatic cardiac disease and death in three retrospective analytical studies,35,47,48 while in another study it was not.49 The validity of the studies was judged to be good for the number of patients and for the follow-up, but poor for the definition of cardiac outcomes. Two retrospective studies evaluated the prognostic value of measures able to monitor myocardial iron loading,50,51 reporting that subjects with a low myocardial T2* were at risk of symptomatic heart failure and ventricular arrhythmias.
Recommendations
Patients undergoing iron chelation should receive periodic monitoring of serum ferritin. With a trend of increasing serum ferritin or decreasing serum ferritin below 1,000 ng/mL, liver iron content should be assessed in order to avoid under- or over-treatment.
Patients who have received determination of liver iron content before starting chelation therapy should repeat liver iron content every year during chelation therapy.
In patients with a poor chelation history or in which liver iron content documents non-optimal chelation therapy, T2* MRI heart iron content should be monitored every year.
Switching to an alternative iron chelation therapy in patients uncompliant, intolerant, or refractory to DFO therapy
The criteria identified by the panel for switching to an alternative chelation therapy differed according to the clinical context. In patients with evidence of non-compliance to DFO or with severe adverse effects which preclude DFO continuation, but without evidence of severe iron overload, the panel decided that the criteria for selecting between alternative therapeutic approaches should be long-term efficacy, safety and compliance. The decision options were restricted between the two oral chelators DFP and DFX, and studies with a comparative design including patients showing little evidence of iron overload were analyzed (Table 3). No study directly compared the two oral iron chelators, therefore evidence for efficacy was taken indirectly from studies comparing the new oral chelators with DFO. Similarly, compliance and safety were first analyzed from these trials (as reported in the section on prophylactic chelation treatment). However, since safety was a highly influential criterion for the decision, the panel also considered studies without a comparative design but which evaluated the safety of oral iron chelators. Three cohort studies using the standard dose of 75 mg/day were analyzed for DFP including a total of 738 patients.52–54 Post-marketing unpublished reports were taken into consideration for DFX (data on file kindly provided by Novartis). For DFP, the incidence of agranulocytosis and of severe neutropenia was of 0.5% and 4% respectively. There were reports of DFX recipients with hematologic disorders associated with marrow failure who developed neutropenia and thrombocytopenia, but the relationship between DFX with these events is uncertain. Long-term toxicity studies have now clarified that a serum creatinine increase from baseline is common during DFX therapy, but that this alteration never evolved into a true renal damage. Based on these safety considerations, the expert panel argued against the use of DFP as second-line therapy in patients without severe iron overload. For patients who develop severe iron overload during DFO therapy, the panel first provided a definition of how severe iron overload should be before a change in DFO iron chelation therapy is required. Since the panel identified SF, LIC and heart T2* MRI as monitoring procedures, the literature revision was addressed to studies that compared the prognosis of patients at different values of these tests.33–36,45–49 Only non-prospective studies, with an uncontrolled or unblinded design, and in which the cut-off values of the test were determined without test performance analysis, were available. The panel reconciled the discrepant results according to principles of good practice.
The panel agreed that the major criterion for selecting the therapy in patients who failed DFO standard therapy were the short- and long-term efficacy of iron removal of the alternative strategy. Compliance and safety were not considered to be important since iron chelation in this setting is a life-saving intervention. Literature reports two different approaches to an alternative chelation therapy. The first modality is DFO dose intensification.55 The second modality is changing DFO with DFP or DFX or adding DFP to DFO. These different modalities were the selected options the panel submitted for comparison in the decision model.
Analysis of evidence first considered studies with a comparative design including participants in which the comparative strategies were started after documentation of excessive iron burden, or end-organ damage due to previous chelation failure. No such studies included intensive DFO therapy. Eight studies comparing DFP to DFO were analyzed (Table 4).5,8,56–61 Altogether, 563 evaluable patients received DFO and 370 DFP or DFP plus DFO. The maximum observation time was nine years.8 Two studies evaluated survival as an outcome.5,8 In the first, time-to-event analysis noted 52 cardiac events, including 10 deaths, in patients while on DFO and no events while on DFP.8 In the other study,5 none of the 54 patients treated with DFP died, while 4 out of the 75 patients treated with DFO died during the study period. Cardiac events were the outcome of two studies.5,8 More cardiac events occurred while on DFO, and the analysis of cardiac disease free survival over the 5-year period was significantly more favorable in the DFP group.8 LIC was measured at baseline and at the end of the trial in one study,60 and SF in six,8,57–61 There was no significant difference in pre- and post-study LIC between patients using combined therapy and patients using DFO alone.61 Patients receiving DFP, or DFP with DFO, showed a reduction in SF over time greater than patients who received DFO alone in two trials.57,58
|
Changes in cardiac T2* MRI and LVEF due to DFO or DFX were reported in abstract form.62 In a total of 23 patients treated with DFX, myocardial T2* improved significantly, while there was no significant change in LVEF before or after treatment over the same period. Patients treated with DFO also showed a small non-significant increase in myocardial T2*.
The panel concluded that in patients with high iron burden due to DFO failure, there is evidence that DFP in combination with DFO is able to reduce body iron burden more than DFO at standard dose, and that DFP is able to remove iron from the heart and to reduce cardiac events, including mortality, over a long period more efficiently than DFO. Even though evidence was provided by studies with a non-prospective design, time and selection biases were appropriately analyzed and excluded. By contrast, the studies with DFX provided evidence that the amount of iron removal achieved from DFX at doses of 20–30 mg/kg does not differ from that with DFO at standard doses. Furthermore, evidence of the ability of DFX to remove iron from the heart is based on a small number of patients.63 No study evaluated mortality as an outcome.
Even in the absence of direct and comparative evidence of the efficacy of intensive chelation therapy with DFO, the panel decided to provide recommendations on its use based on consensus statements.
Recommendations
For patients with evidence of non-compliance to deferoxamine, or with severe adverse effects from deferoxamine which preclude its use, but without existing or pending severe iron overload, an oral iron chelator should be used as an alternative to deferoxamine therapy (level D). The lack of studies comparing deferiprone with deferasirox in thalassemia major or related disorders did not allow the panel to recommend one of them on the basis of scientific evidence on long-term efficacy. The panel felt justified in recommending deferasirox as the alternative therapy to deferoxamine on the basis of its better safety profile compared with deferiprone (level D). Deferiprone should be considered in the case of resistance or intolerance to deferasirox (level D).
Patients who develop severe iron overload (serum ferritin higher than 3,000 ng/mL maintained for three months at least, liver iron content higher than 15 mg/g d.w., or heart T2* <12 msec) or overt iron-related cardiomyopathy (left ventricular ejection fraction <55%, arrhythmias, cardiac failure) should receive "intensive" or "combined" iron chelation therapy. The panel judged that the first choice for combined therapy is deferoxamine associated with deferiprone (level B).
Patients who develop life-threatening cardiomyopathy should receive continuous intensive or combined chelation therapy.
|
Discussion |
|---|
|
TOPABSTRACTIntroductionDesign and MethodsResultsDiscussionReferences |
|---|
The results of this project cannot be compared with others obtained with similar evidence- and consensus-based methodology. The systematic reviews of literature and guidelines on iron chelators produced over recent years are now out of date.63–66 By using SIGN grading system for therapeutic recommendations, no level A sentence was issued in our document. A B level was attributed to the recommendation on using combined therapy with DFO and DFP in patients who develop severe iron overload or overt iron-related cardiomyopathy. Most of the recommendations were made by the consensus of the experts (level D), testifying for the absence of sufficient scientific evidence. Indeed, most of the trials considered in the systematic review had design, directness and concealment failures. This also applies to the most critical decision on the choice of first-line, prophylactic iron chelation in patients who start therapy or who switch standard therapy. Even though on November 2005 the FDA granted DFX accelerated approval for the treatment of chronic iron overload due to blood transfusions in patients over two years of age, and similar approval was granted by the EMEA in Europe in 2007, the present guidelines do not recommend DFX to be used instead of DFO in first-line therapy. The panel judged that the evidence on long-term efficacy and safety of DFX was not sufficient to allow approval of its use as first-line therapy in practice. The use of the drug in registries or clinical trials seemed a more cautious recommendation.
The treatment policy of these guidelines is provisional. An early update of the present guidelines in accordance with incoming evidence-based information should be expected and encouraged.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
All authors were part of the expert panel and contributed equally to the research, data collection, analysis and interpretation, statistical analysis, and drafting the manuscript. GB and ST designed the project and obtained funding. GB and MM conducted the systematic literature review. Authors are listed in alphabetic order. The Italian Society of Hematology (SIE) received an unrestricted educational grant from Novartis Pharma for literature search, consensus conferences and secretarial personnel for this project. EA received honoraria as part of the speaker bureau from Novartis Pharma GB; no information to disclose. CC no information to disclose; MDC received honoraria as part of the speaker bureau from Novartis Pharma; MC no information to disclose; RG has been supported in part by research funding and received honoraria as a speaker from Novartis Pharma and Apotex. MM no information to disclose. AP has been supported in part by research funding and received honoraria as part of the speaker bureau from Novartis Pharma, Apotex and Genzyme. ST is recipient of an unrestricted educational grant from Novartis.
Received for publication October 22, 2007. Revision received January 3, 2008. Accepted for publication January 8, 2008.
|
References |
|---|
|
TOPABSTRACTIntroductionDesign and MethodsResultsDiscussionReferences |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | TABLE OF CONTENTS | ARCHIVE | SUBSCRIPTIONS |
