Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Noninvasive assessment and risk factors of liver fibrosis in patients with thalassemia major using shear wave elastography.

OBJECTIVES: This study aimed to estimate the prevalence of liver fibrosis and assess the risk factors for developing significant liver fibrosis in patients with Thalassemia Major (TM). METHODS: All patients with TM over the age of 10 years were included in the study. RESULTS: A total of 94 eligible patients underwent 2-D SWE. The median age was 26.7 years. The median of the average 5-year serum ferritin (5yrSF) and liver iron concentration (LIC) assessed by MRI T2* were 1326 µg/L and 6.7 mg/g dw, respectively. Hepatitis C and hepatitis B core antibodies were positive in 38% and 1% of the patients respectively. The proportion of patients with significant fibrosis was 60%. Male gender increased the risk of significant fibrosis (Odds ratio of 0.4; p = .0373). Additionally, the 5yrSF (p = .00661), the LIC (p = .0225) and the lowest LIC of the previous 5 years (p = .0211) were significant. In the multivariable logistic regression model, only 5yrSF (p = .0035) and gender (p = .00984) remained significant. CONCLUSIONS: The risk of liver fibrosis is associated with iron overload and gender in patients with TM.

Assessment of left ventricular functions and myocardial iron load with tissue Doppler and speckle tracking echocardiography and T2* MRI in patients with ß-thalassemia major.

BACKGROUND: The purpose of this study is to determine early myocardial dysfunction in ß-thalassemia major (BTM) patients. Where the myocardial dysfunction cannot be detected by conventional echocardiography, it could be detected by tissue Doppler imaging (TDI) or speckle tracking echocardiography (STE). METHODS: In this study, we analyzed 60 individuals, 30 of whom were BTM patients and the other 30 of whom were the control group. T2* magnetic resonance imaging (MRI) was used to measure cardiac iron deposition. The myocardial functions were evaluated by conventional echocardiography, TDI and STE. RESULTS: When basal lateral left ventricular and basal septal wall TDI values were compared between the patient group and control group, only isovolumic contraction time values were significantly longer in the patients. The global circumferential strain was significantly lower in the patients. When evaluated as segmental, longitudinal strain values of basal inferoseptum and circumferential strain values of anteroseptum, anterior, and inferolateral segments were significantly lower in the patients. In the patients, global longitudinal and circumferential strains in the group who had pathological T2* values were significantly lower than the group who did not. In addition, circumferential strain values in anteroseptum, anterolateral, inferior, and inferoseptum segments were significantly lower in the patients with T2* values<20 ms than those with T2* values≥20 ms. CONCLUSION: Although T2* MRI is the most sensitive test detecting myocardial iron load, TDI and STE can be used for screening myocardial dysfunction. The abnormal strain values, especially circumferential, may be detected as the first finding of abnormal iron load and related to T2* values.

Tissue Doppler Imaging-derived Diastolic Function Assessment in Children With Sickle Cell Disease and Its Relation With Ferritin.

Diastolic dysfunction has been shown to occur earlier than systolic dysfunction in iron overload states in adult patients with sickle cell disease (SCD). Tissue Doppler imaging (TDI)-derived E/E' has emerged as a noninvasive marker of diastolic function. We sought to determine diastolic function in children with SCD and study its relation with iron overload. A retrospective review of medical records of 225 pediatric patients with SCD who received an echocardiogram between January 2008 and December 2012 was performed. Echocardiographic measures including M-mode, spectral Doppler, and TDI-derived E/E' were compared with previously published data in healthy children. The left ventricular end-diastolic and end-systolic dimensions were significantly higher in SCD (P<0.0001) and the shortening fraction was similar (P=0.66). E/E' ratio was significantly higher in SCD at the mitral annulus, septum, and tricuspid annulus. In 54% of subjects, the septal E/E' was >8, indicating elevated left ventricular filling pressure. However, there was no significant correlation between ferritin level and E/E' ratios. Pediatric patients with SCD have a high prevalence of elevated estimated left ventricular filling pressure, but this does not correlate with ferritin levels.

Assessment of the relationship between fragmented QRS and cardiac iron overload in patients with beta-thalassemia major.

OBJECTIVE: Beta-thalassemia major (TM) is a genetic hemoglobin disorder causing chronic hemolytic anemia. Since cardiac insufficiency and arrhythmias are the primary causes of mortality in such patients, monitoring of cardiac iron load is important in management of the disorder. The purpose of this study was to investigate the importance of fragmented QRS (fQRS) and its relation to the cardiac T2* value for the evaluation of cardiac iron load in TM patients. METHODS: This retrospective study included 103 TM patients. The patients' T2* values, measured by cardiac MRI and 12-lead surface ECGs, were interpreted. The cardiac T2* values under 20 were considered as cardiac iron overload. The relationship between the cardiac T2* value and fQRS in ECG was investigated. RESULTS: The median age of the patients was 22.6 ± 6.6 years. All patients were on regular blood transfusions and iron chelators. The patients had no risk factors for coronary artery disease. In 50 (48%) patients fQRS was detected, and in 37 (74%) of these the T2* values were low. 86% of patients with cardiac involvement (37) had fQRS, but 22% of patients with non-involvement (13) had fQRS (p < 0.001). CONCLUSION: Since cardiac involvement is the primary cause of mortality in TM patients, the early diagnosis of cardiac dysfunction is of vital importance. The search for fQRS in the ECGs of these patients, particularly when cardiac T2* values cannot be determined and followed, is a non-expensive and easy-to-attain method for therapy management.

An assessment of iron overload in children treated for cancer and nonmalignant hematologic disorders.

UNLABELLED: Our goal was to assess the natural fate of iron overload (IO) following transfusions of packed red blood cells (PRBCs) in children treated for cancer and nonmalignant disorders according to the intensity level of their treatment. Sixty-six children were followed up from February 2010 to March 2013. The transfusion burden was compared between three treatment intensity groups assigned according to the Intensity of Treatment Rating Scale 3.0 (ITR-3). IO was assessed by serial measurements of serum ferritin (SF) (n= 66) and quantification of tissue iron by magnetic resonance imaging (MRI) (n=12). Of the children studied, 36 % (24/66) received moderately intensive treatment (level 2), 21 % (14/ 66) received very intensive treatment (level 3), and 42 % (28/ 66) received the most intensive treatment (level 4). The number of PRBC (p=0.016), the total transfused volume (p= 0.026), and transfused volume adjusted to body weight (p= 0.004) were significantly higher in the level 4 group. By the median follow-up time of 35.5 months (range 8­133), 21­ 29 % of patients (including level 2 and level 3 children) had SF >1,000 µg/l 1 year after cessation of transfusions. The slowest decrease of SF was observed in the level 4 group. Initial MRI examination demonstrated either mild or moderate IO in the liver and spleen. Repetitive MRI showed significant improvement in relaxation time between the initial and follow-up MRI performances in the liver (5.9 vs. 8.6 ms, p= 0.03) and the spleen (4.3 vs. 8.8 ms, p=0.03). CONCLUSION: IO diminished over time, but in the level 4 patients, it was detectable for years after cessation of transfusions.

Assessment of labile plasma iron in patients who undergo hematopoietic stem cell transplantation.

Body iron disorders have been reported after myeloablative conditioning in patients undergoing hematopoietic stem cell transplantation (HSCT). There is a concern that labile plasma iron (LPI), the redox-active form of iron, can be involved in the occurrence of toxicity and other complications commonly observed in the early post-HSCT period. In order to better understand the LPI kinetics and its determinants and implications, we undertook sequential LPI determinations before and after conditioning until engraftment in 25 auto-HSCT patients. Increased LPI was present in only 5 patients before starting conditioning. Shortly after conditioning, LPI levels were increased in 23 patients, with peak at day 0, returning to normal range upon engraftment in 21 patients. Overall, LPI levels correlated weakly with serum ferritin and more strongly with transferrin saturation; however, both parameters were apparently not applicable as surrogate markers for increased LPI. Although this was a small cohort, logistic regression suggested that baseline LPI levels could predict occurrence of grade III or IV toxicity. In conclusion, LPI kinetics is influenced by aplasia following conditioning and engraftment. Measuring LPI before starting conditioning can offer an opportunity to predict toxicity and, perhaps, the need for chelation therapy.

Iron stores assessment in alcoholic liver disease.

BACKGROUND: The relation between alcoholic liver disease (ALD) and iron overload is well known. Liver biopsy is the gold standard for assessing iron stores. MRI is also validated for liver iron concentration (LIC) assessment. We aimed to assess the effect of active drinking in liver iron stores and the practicability of measuring LIC by MRI in ALD patients. MATERIALS AND METHODS: We measured LIC by MRI in 58 ALD patients. We divided patients into two groups - with and without active alcoholism - and we compared several variables between them. We evaluated MRI-LIC, liver iron stores grade, ferritin and necroinflammatory activity grade for significant correlations. RESULTS: Significant necroinflammation (40.0% vs. 4.3%), LIC (40.1 vs. 24.3 µmol/g), and ferritin (1259.7 vs. 568.7 pmol/L) were significantly higher in drinkers. LIC values had a strong association with iron stores grade (r s = 0.706). Ferritin correlated with LIC (r s = 0.615), iron stores grade (r s = 0.546), and necroinflammation (r s = 0.313). The odds ratio for elevated serum ferritin when actively drinking was 7.32. CONCLUSION: Active alcoholism is associated with increased ALD activity. It is also the key factor in iron overload. Scheuers' semiquantitative score with Perls' staining gives a fairly accurate picture of liver iron overload. Serum ferritin also shows a good correlation with LIC values and biopsy iron stores grade. As most patients present only with mild iron overload, serum ferritin measurement and semiquantitative evaluation of iron stores are adequate, considering MRI high cost. However, if MRI is required to evaluate liver structure, LIC assessment could be performed without added cost.

Effect of ambiguous hemochromatosis gene test results on physician utilization.

BACKGROUND: Genetic test results may be available to greater numbers of people through genetic screening projects and other means. The effects of widespread genetic testing and notification of genetic test results, particularly added costs through increased physician utilization, have not been clearly established. METHODS: A primary care-based cohort of 20,306 participants (Hemochromatosis and Iron Overload Study, Ontario site) were tested for the C282Y and H63D mutations of the HFE gene and for abnormal serum ferritin (SF) and transferrin saturation levels. The primary outcome variable was the total number of physician claims per patient after genetic test notification by mail. Multiple Poisson regression was used to adjust for age, sex, baseline SF, diagnoses of arthritis, diabetes, heart failure and impotence, self-rated health, and the number of claims during the 12 months before notification of results. The reference group had no HFE mutations (wild type) and normal transferrin saturation/SF values. RESULTS: Participants with an ambiguous hemochromatosis gene test and normal iron levels had statistically significantly higher average physician utilization of 3.0%. Participants with HFE mutations (excluding C282Y homozygotes) and elevated iron values showed a 6% increase in physician utilization. CONCLUSIONS: The health effects, if any, of increased utilization in heterozygotes or those with mild ferritin elevations are unknown but are unlikely to be large at the population level. Ambiguous genetic test results are associated with increased physician service use and should be considered when assessing the complete societal costs of widespread genetic testing.

Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias.

Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients.

Iron overload in thalassemia and related conditions: therapeutic goals and assessment of response to chelation therapies.

Transfusional iron loading inevitably results in hepatic iron accumulation, with variable extrahepatic distribution that is typically less pronounced in sickle cell disease than in thalassemia disorders. Iron chelation therapy has the goal of preventing iron-mediated tissue damage through controlling tissue iron levels, without incurring chelator-mediated toxicity. Historically, target levels for tissue iron control have been limited by the increased frequency of deferoxamine-mediated toxicity and low levels of iron loading. With newer chelation regimes, these limitations are less evident. The reporting of responses to chelation therapies has typically focused on average changes in serum ferritin in patient populations. This approach has three limitations. First, changes in serum ferritin may not reflect trends in iron balance equally in all patients or for all chelation regimens. Second, this provides no information about the proportion of patients likely respond. Third, this gives insufficient information about iron trends in tissues such as the heart. Monitoring of iron overload has advanced with the increasing use of MRI techniques to estimate iron balance (changes in liver iron concentration) and extrahepatic iron distribution (myocardial T2*). The term nonresponder has been increasingly used to describe individuals who fail to show a downward trend in one or more of these variables. Lack of a response of an individual may result from inadequate dosing, high transfusion requirement, poor treatment adherence, or unfavorable pharmacology of the chelation regime. This article scrutinizes evidence for response rates to deferoxamine, deferiprone (and combinations), and deferasirox.

Cost effectiveness of deferasirox compared to desferrioxamine in the treatment of iron overload in lower-risk, transfusion-dependent myelodysplastic syndrome patients.

OBJECTIVE: The study evaluated the cost effectiveness of deferasirox (Exjade * ) compared to non-proprietary desferrioxamine (DFO) for the control of transfusional iron overload in lower risk myelodysplastic syndromes (MDS) patients. A UK National Health Service perspective was adopted. METHODS: Recent clinical evidence has demonstrated the efficacy and safety of deferasirox in transfusion-dependent MDS patients with elevated serum ferritin levels. An economic model was used to extrapolate the clinical benefits of iron chelation therapy (ICT) in a cohort of lower risk MDS patients. Costs for drug acquisition, drug administration and monitoring, and quality of life (utility) outcomes associated with mode of drug administration were derived from a variety of sources. The incremental cost per QALY gained for deferasirox was estimated. Costs and outcomes were discounted at 3.5% in line with UK standards. RESULTS: The base-case cost effectiveness of deferasirox versus DFO was estimated to be £20,822 per QALY gained, the key driver being the additional quality of life benefits associated with a simpler mode of administration for deferasirox. A mean survival benefit for both forms of ICT of 4.5 years was estimated. The results were sensitive to drug dose, days of DFO administration, and patient weight. CONCLUSIONS: In the UK, a cost per QALY below £20,000-30,000 is considered cost effective. Hence, the results from this economic analysis suggest deferasirox is cost effective in lower risk, transfusion-dependent, MDS patients. Limitations with the analysis include a lack of comparative randomised controlled trial evidence, in particular to differentiate survival and clinical outcomes for deferasirox and DFO.

Prospective assessment of effects on iron-overload parameters of deferasirox therapy in patients with myelodysplastic syndromes.

We report the first prospective study evaluating the effects of deferasirox on liver iron concentration (LIC), labile plasma iron (LPI) and pharmacokinetics (PK) along with serum ferritin values in patients with IPSS Low- and Intermediate-1 risk myelodysplastic syndromes (MDS) and evidence of iron overload. Twenty-four heavily transfused MDS patients were enrolled in a planned 52 weeks of therapy. PK studies showed dose-proportional total drug exposure. Data demonstrated that deferasirox was well tolerated and effectively reduced LIC, LPI and serum ferritin in the iron-overloaded patients with MDS who completed 24 and 52 weeks of therapy despite ongoing receipt of red blood cell transfusions.

Iron chelation therapy: clinical effectiveness, economic burden and quality of life in patients with iron overload.

INTRODUCTION: This study of UK patients examines clinical, health-related quality of life (HRQOL) and economic outcomes associated with iron chelation therapy (ICT). Desferrioxamine (DFO) (Desferal; Novartis, Switzerland) and Deferiprone (Ferriprox; Apotex, Canada) are ICTs used to treat iron overload. DFO requires 8-to 12-hour infusions a minimum of five times per week. Deferiprone is administered in an oral daily regimen. Although pharmacologically efficacious, clinical effectiveness of ICT within the real-world setting is yet to be fully elucidated. METHODS: A naturalistic cohort study of 60 patients (beta-thalassaemia, n=40; sickle cell disease, n=14; myelodysplastic syndromes, n=6; 63% female) receiving ICT in four UK treatment centres was conducted. Serum ferritin level data were abstracted from medical charts. Compliance, HRQOL, satisfaction and resource utilisation data were collected from interviews. Maximum ICT costs were estimated using the resource utilisation data associated with DFO. RESULTS: Mean serum ferritin levels, generally, remained elevated despite ICT. Compliance was suboptimal and HRQOL scores were lower than population norms. The total estimated mean weighted annual per-patient cost of DFO treatment was approximately pound19,000. DFO-related equipment, DFO drug, and home healthcare were estimated to account for 43%, 19% and 24% of costs, respectively. Other more minor components of total annual costs were for in-patient infusions, ICT home delivery services and monitoring costs. CONCLUSION: Generally, patients are not achieving target serum ferritin thresholds despite chronic treatment for iron overload. ICT appears to negatively impact HRQOL; compliance with ICT is poor; and, in the case of DFO, treatment costs well exceed the cost of DFO alone. These results suggest that current ICT in the real-world setting is suboptimal with respect to various clinical, HRQOL and economic outcomes.

Evaluation of at-home phlebotomy for iron overload: feasibility and satisfaction of patients and healthcare workers.

OBJECTIVE: This study aimed to evaluate at-home phlebotomy and the satisfaction of iron-overload patients and healthcare workers with the procedure. METHODS: Forty-two patients underwent at-home phlebotomy between 2003 and 2006. The phlebotomy was performed by the patient's nurse, who was trained by the private healthcare firm that also took charge of the disposal of the blood products. Data concerning these phlebotomies were collected via telephone interviews with all 42 patients, as well as 35 nurses and 40 primary-care physicians. The Limousin Regional Health Observatory processed the data collection. RESULTS: Ninety percent (38/42) of the patients, 80% (28/35) of the nurses and 67% (27/40) of the primary-care physicians responded. For 80% of the patients, phlebotomy volume and frequency were as prescribed. Patients chose home phlebotomy for personal reasons, or because of the limited availability of French Blood Establishment facilities (68%), or in response to being offered it by their hospital physician (32%). For 81.6% of the patients, at-home phlebotomy was more satisfactory than phlebotomy in hospital or at the French Blood Establishment and, for 84%, the constraints required were fully acceptable. The nurses considered that these homecare procedures were within their area of responsibility (100%), but felt that the remuneration was insufficient (65%). Ninety-six percent of the primary-care physicians said they were correctly informed, but only 40% felt that they were truly committed to the procedure. CONCLUSION: At-home phlebotomy is feasible, less costly than institutional phlebotomy and improves patient comfort.

The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic.

BACKGROUND: The gene that causes most cases of hereditary hemochromatosis is designated HFE. Three mutations exist at this locus at a relatively high gene frequency. OBJECTIVE: To determine the gene frequency of the three HFE mutations and to relate genotypes to various clinical and laboratory variables. DESIGN: Observational study. SETTING: Health appraisal clinic. PATIENTS: 10,198 adults who registered for health appraisal and consented to DNA examination for hemochromatosis. Consenting patients were slightly older and had attained a slightly higher educational level than nonconsenting patients. MEASUREMENTS: Extensive medical history and laboratory tests, including complete blood count, transferrin saturation, and other chemistries; serum ferritin levels; and HFE genotype. RESULTS: In white participants, the gene frequencies were 0.063 for the C282Y mutation, 0.152 for the H63D mutation, and 0.016 for the S65C mutation. Gene frequencies were lower in other ethnic groups. In participants with HFE mutations, the average serum transferrin saturation and ferritin levels were slightly increased, as were mean hemoglobin levels and mean corpuscular volume. A transferrin saturation of 50% had a sensitivity of only 0.52 (95% CI, 0.345 to 0.686) and a specificity of 0.908 (CI, 0.902 to 0.914) for detection of homozygosity. A ferritin level of 200 microg/L in women and 250 microg/L in men had a sensitivity of 0.70 (CI, 0.540 to 0.854) and a specificity of 0.803 (CI, 0.796 to 0.811). The prevalence of iron deficiency anemia was lower in women who carried HFE mutations. CONCLUSIONS: Screening for transferrin saturation and ferritin levels does not detect all homozygotes for the major hemochromatosis mutation. Heterozygotes for HFE mutations had a lower prevalence of iron deficiency anemia.