Subject(s)
Cardiomyopathies/diagnostic imaging , Iron Overload/diagnostic imaging , Magnetic Resonance Imaging, Cine , beta-Thalassemia/complications , Adolescent , Age Factors , Cardiomyopathies/etiology , Cardiomyopathies/physiopathology , Child , Deferiprone/therapeutic use , Deferoxamine/therapeutic use , Female , Fibrosis , Humans , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron Overload/etiology , Male , Myocardium/pathology , Predictive Value of Tests , Prospective Studies , Ventricular Function, Left , Ventricular Function, Right , Ventricular Remodeling , beta-Thalassemia/diagnosis , beta-Thalassemia/therapyABSTRACT
Beta thalassemia major (ß-TM) displays a great deal of phenotypic heterogeneity, not fully investigated in terms of cause-effect. We aimed to detect if different genotypic groups could be related to different levels of cardiac impairment, evaluated by cardiovascular magnetic resonance (CMR). We considered 671 ß-TM patients (age 30.1â¯years, 52.9% females) consecutively enrolled in the Myocardial Iron Overload (MIO) in Thalassemia network. MIO was assessed by T2* technique. Biventricular function was quantified by cine images. Myocardial fibrosis was evaluated by late gadolinium enhancement (LGE) technique. Three groups of patients were identified: heterozygotes ß+/ß° (Nâ¯=â¯279), homozygotes ßâ¯+â¯(Nâ¯=â¯154), homozygotes ß° (Nâ¯=â¯238). Transfusional needs resulted significantly lower in homozygous ßâ¯+â¯TM patients when compared to the other groups. The homozygous ßâ¯+â¯group versus the heterozygous and homozygous ß° groups showed higher global heart T2* values (Pâ¯<â¯0.0001) and a lower number of patients with a global heart T2* value<20â¯ms (Pâ¯<â¯0.001). The homozygotes ßâ¯+â¯showed a lower number of patients with a pathological left ventricular ejection fraction (LVEF) than the other two groups (Pâ¯<â¯0.05). The ß+/ßâ¯+â¯TM patients showed less MIO and a concordant better systolic heart function. These data support the knowledge of different genotypic groups in the management of ß-TM patients.
Subject(s)
Genotype , Heart Diseases/diagnosis , Heart Diseases/etiology , Magnetic Resonance Imaging , beta-Globins/genetics , beta-Thalassemia/complications , beta-Thalassemia/genetics , Adult , Alleles , Biomarkers , Blood Transfusion , Erythrocyte Indices , Female , Heart Function Tests , Humans , Iron Overload/complications , Iron Overload/diagnosis , Iron Overload/etiology , Iron Overload/therapy , Magnetic Resonance Imaging/methods , Male , Middle Aged , Young Adult , beta-Thalassemia/diagnosis , beta-Thalassemia/therapyABSTRACT
Aims: Cardiovascular magnetic resonance (CMR) has dramatically changed the clinical practice in thalassemia major (TM), lowering cardiac complications. We prospectively reassessed the predictive value of CMR parameters for heart failure (HF) and arrhythmias in TM. Methods and results: We considered 481 white TM patients (29.48 ± 8.93 years, 263 females) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. Mean follow-up was 57.91 ± 18.23 months. After the first CMR scan 69.6% of the patients changed chelation regimen. We recorded 18 episodes of HF. In the multivariate analysis the independent predictive factors were myocardial fibrosis (HR = 10.94, 95% CI = 3.28-36.43, P < 0.0001), homogeneous MIO (compared with no MIO) (HR = 5.56, 95% CI = 1.37-22.51, P = 0.016), ventricular dysfunction (HR = 4.33, 95% CI = 1.39-13.43, P = 0.011). Arrhythmias occurred in 16 patients. Among the CMR parameters only the atrial dilation was identified as univariate prognosticator (HR = 4.26 95% CI=1.54-11.75, P = 0.005). Conclusions: CMR guided the change of chelation therapy in nearly 70% of patients, leading to a lower risk of iron-mediated HF and of arrhythmias than previously reported. Homogeneous MIO remained a risk factor for HF but also myocardial fibrosis and ventricular dysfunction identified patients at high risk. Arrhythmias were independent of MIO but increased with atrial dilatation. CMR by a multi-parametric approach dramatically improves cardiac outcomes and provides prognostic information beyond cardiac iron estimation.
Subject(s)
Arrhythmias, Cardiac/etiology , Cardiomyopathies/diagnostic imaging , Cardiomyopathies/etiology , Magnetic Resonance Imaging, Cine/methods , beta-Thalassemia/complications , beta-Thalassemia/diagnosis , Adult , Arrhythmias, Cardiac/physiopathology , Chelation Therapy/methods , Cohort Studies , Female , Humans , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Prospective Studies , Risk Assessment , Severity of Illness Index , Time Factors , Young Adult , beta-Thalassemia/therapyABSTRACT
PURPOSE: Deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) are used in thalassaemia major (TM) patients to treat chronic iron overload. We evaluated the cost-effectiveness of DFP, compared with DFX and DFO monotherapy, from an Italian healthcare system perspective. METHODS: A Markov model was used over a time horizon of 5 years. Italian-specific cost data were combined with Italian efficacy data. Costs and quality-adjusted life years (QALYs) were calculated for each treatment, with cost-effectiveness expressed as cost per QALY. RESULTS: In all scenarios modelled, DFP was the dominant treatment strategy. Sensitivity analyses showed that DFP dominated the other treatments with a >99% likelihood of being cost-effective against DFX and DFO at a willingness to pay threshold of 20,000 per QALY. CONCLUSIONS: DFP was the dominant and most cost-effective treatment for managing chronic iron overload in TM patients. Its use can result in substantial cost savings for the Italian healthcare system.
Subject(s)
Cost-Benefit Analysis/methods , Health Care Costs , Iron Chelating Agents/economics , beta-Thalassemia/drug therapy , beta-Thalassemia/economics , Benzoates/administration & dosage , Benzoates/economics , Cohort Studies , Deferasirox , Deferiprone , Deferoxamine/administration & dosage , Deferoxamine/economics , Drug Administration Routes , Humans , Iron Chelating Agents/administration & dosage , Italy/epidemiology , Pyridones/administration & dosage , Pyridones/economics , Treatment Outcome , Triazoles/administration & dosage , Triazoles/economics , beta-Thalassemia/epidemiologyABSTRACT
OBJECTIVES: Redox imbalance and genotoxic damage are commonly observed in ß thalassaemic patients. The aim of this study was to assess the role of anaemia in oxidative and genotoxic damage in regularly transfused thalassaemic patients, undergoing iron chelation therapy. METHODS: We studied the relationships of haematological, biochemical and clinical parameters with oxidative (reactive oxygen species and 8-oxo-7,8-dihydro-2'-deoxyguanosine) and genotoxic biomarkers (Comet assay and cytokinesis-block micronucleus test) in blood samples from 105 patients. To reduce the early effect of redox-active iron, samples were collected when pharmacokinetics of the iron chelators ensured their maximum effectiveness. The transfusion regimen, cardiac and hepatic magnetic resonance imaging T2* were evaluated to characterize the patient cohort. Labile plasma iron (LPI) was also assayed. RESULTS: Haemoglobin level had a significant effect on ROS, %DNA in the tail and micronuclei-micronucleated cell frequency (p < 0.05). Higher Hb values reduced redox imbalance. LPI, detectable in 50.5% of patients, was related to the number of apoptotic and necrotic lymphocytes (p = 0.03), demonstrating the cytotoxic effect of iron. DISCUSSION: The results highlight that an adequate transfusion regimen is essential to limit oxidative and genotoxic damage in ß-thalassemic patients undergoing chelation therapy. CONCLUSION: Owing to the higher risk of cancer in the thalassaemic cohorts, specific genotoxicity/oxidative biomarkers should be monitored in order to ameliorate and formulate more personalized disease management.
Subject(s)
Anemia/etiology , DNA Damage , Oxidative Stress , beta-Thalassemia/genetics , beta-Thalassemia/metabolism , Adult , Anemia/therapy , Biomarkers , Blood Transfusion , Comet Assay , Female , Humans , Iron/blood , Iron/metabolism , Iron Overload/diagnosis , Iron Overload/drug therapy , Iron Overload/etiology , Liver/metabolism , Liver/pathology , Lymphocytes/metabolism , Male , Micronucleus Tests , Middle Aged , Reactive Oxygen Species/metabolism , beta-Thalassemia/complications , beta-Thalassemia/therapySubject(s)
Chelation Therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Polycythemia/etiology , Graft vs Host Disease/drug therapy , Graft vs Host Disease/etiology , Humans , Iron Overload/etiology , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Middle Aged , Polycythemia/diagnosis , Transfusion ReactionABSTRACT
BACKGROUND: Patients with haematopoietic disorders requiring long-term blood transfusions are at risk of iron overload. This study aimed to investigate the efficacy and safety of long-term deferasirox monotherapy in patients with transfusion-dependent anaemia in the routine clinical practice setting. METHODS: This was a retrospective analysis of patients who commenced deferasirox therapy at the Hospital Bianchi Melacrino Morelli in Reggio Calabria, Italy. Data collected included cardiac and hepatic iron load (assessed by magnetic resonance imaging); left ventricular ejection fraction (LVEF). Patients were divided into two groups for analysis: group A (baseline information collected prior to deferasirox initiation) and group B (baseline information collected after deferasirox initiation). RESULTS: Forty-six patients were included (group A: n=25; group B: n=21). The overall population was 63% male, with a mean age of 33 years. The majority of patients (65%) had thalassaemia major. In the overall population, cardiac iron levels between the baseline and first follow-up visits improved in both groups A and B (29.2 vs. 32.5 ms; p=0.04 and 28.4 vs. 31.4 ms; p=0.038). Liver iron levels improved significantly from baseline to visit 1 in group A (7.2 vs. 12.1 ms; p<0.004) and from baseline to visit 3 (6.9 vs. 10.7; p=0.049) in group B. Generally, there was no correlation between cardiac and liver iron levels. LVEF remained stable throughout the study period. Deferasirox was well tolerated and was not associated with significant adverse events. CONCLUSION: Long-term treatment with deferasirox is effective and safe in patients with transfusion-dependent haemoglobinopathies monitored in the clinical practice setting.
Subject(s)
Benzoates/therapeutic use , Hemoglobinopathies/complications , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron Overload/etiology , Transfusion Reaction , Triazoles/therapeutic use , Adolescent , Adult , Benzoates/administration & dosage , Benzoates/adverse effects , Child , Deferasirox , Female , Ferritins/blood , Hemoglobinopathies/therapy , Humans , Iron/metabolism , Iron Chelating Agents/administration & dosage , Iron Chelating Agents/adverse effects , Iron Overload/blood , Iron Overload/physiopathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Middle Aged , Myocardium/metabolism , Retrospective Studies , Stroke Volume , Treatment Outcome , Triazoles/administration & dosage , Triazoles/adverse effects , Ventricular Function, Left , Young AdultABSTRACT
BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a key role in the management of thalassemia major patients, but few data are available in pediatric population. This study aims at a retrospective multiparametric CMR assessment of myocardial iron overload, function, and fibrosis in a cohort of pediatric thalassemia major patients. METHODS AND RESULTS: We studied 107 pediatric thalassemia major patients (61 boys, median age 14.4 years). Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. All scans were performed without sedation. The 21.4% of the patients showed a significant myocardial iron overload correlated with lower compliance to chelation therapy (P<0.013). Serum ferritin ≥2000 ng/mL and liver iron concentration ≥14 mg/g/dw were detected as the best threshold for predicting cardiac iron overload (P=0.001 and P<0.0001, respectively). A homogeneous pattern of myocardial iron overload was associated with a negative cardiac remodeling and significant higher liver iron concentration (P<0.0001). Myocardial fibrosis by late gadolinium enhancement was detected in 15.8% of the patients (youngest children 13 years old). It was correlated with significant lower heart T2* values (P=0.022) and negative cardiac remodeling indexes. A pathological magnetic resonance imaging liver iron concentration was found in the 77.6% of the patients. CONCLUSIONS: Cardiac damage detectable by a multiparametric CMR approach can occur early in thalassemia major patients. So, the first T2* CMR assessment should be performed as early as feasible without sedation to tailor the chelation treatment. Conversely, late gadolinium enhancement CMR should be postponed in the teenager age.
Subject(s)
Cardiomyopathies/diagnosis , Hemosiderosis/diagnosis , Iron/analysis , Magnetic Resonance Imaging, Cine , Myocardium/chemistry , beta-Thalassemia/complications , Adolescent , Age Factors , Cardiomyopathies/etiology , Cardiomyopathies/metabolism , Cardiomyopathies/physiopathology , Cardiomyopathies/prevention & control , Child , Contrast Media , Female , Fibrosis , Gadolinium DTPA , Hemosiderosis/etiology , Hemosiderosis/metabolism , Hemosiderosis/physiopathology , Hemosiderosis/prevention & control , Humans , Iron Chelating Agents/therapeutic use , Italy , Liver/chemistry , Male , Medication Adherence , Myocardium/pathology , Predictive Value of Tests , Retrospective Studies , Ventricular Function, Left , Ventricular Function, Right , Ventricular Remodeling , beta-Thalassemia/diagnosis , beta-Thalassemia/drug therapy , beta-Thalassemia/metabolismABSTRACT
The aim of this study was to evaluate, in a large cohort of chronically transfused patients, whether the presence of extramedullary hematopoiesis (EMH) accounts for the typical patterns of cardiac iron distribution and/or cardiac function parameters. We retrospectively selected 1,266 thalassemia major patients who had undergone regular transfusions (611 men and 655 women; mean age: 31.3 ± 8.9 years, range: 4.2-66.6 years) and were consecutively enrolled within the Myocardial Iron Overload in Thalassemia network. The presence of EMH was evaluated based on steady-state free precession sequences; cardiac and liver iron overloads were quantified using a multiecho T2* approach; cardiac function parameters and pulmonary diameter were quantified using the steady-state free precession sequences; and myocardial fibrosis was evaluated using the late gadolinium enhancement technique. EMH was detected in 167 (13.2%) patients. The EMH+ patients had significantly lower cardiac iron overload than that of the EMH- patients (P = 0.003). The patterns of cardiac iron distribution were significantly different in the EMH+ and EMH- patients (P < 0.0001), with a higher prevalence of patients with no myocardial iron overload and heterogeneous myocardial iron overload and no significant global heart iron in the EMH+ group EMH+ patients had a significantly higher left ventricle mass index (P = 0.001) and a significantly higher pulmonary artery diameter (P = 0.002). In conclusion, in regularly transfused thalassemia patients, EMH was common and was associated with a thalassemia intermedia-like pattern of cardiac iron deposition despite regular transfusion therapy.
Subject(s)
Hematopoiesis, Extramedullary , Iron Overload/metabolism , Iron/metabolism , Myocardium/metabolism , Transfusion Reaction , beta-Thalassemia/metabolism , Adolescent , Adult , Aged , Child , Child, Preschool , Cross-Sectional Studies , Female , Heart Ventricles/metabolism , Heart Ventricles/pathology , Humans , Iron Overload/etiology , Iron Overload/pathology , Liver/metabolism , Liver/pathology , Male , Middle Aged , Myocardium/pathology , Retrospective Studies , beta-Thalassemia/pathology , beta-Thalassemia/therapyABSTRACT
Anemia has an important role in exercise performance. However, the direct link between rapid changes of hemoglobin and exercise performance is still unknown.To find out more on this topic, we studied 18 beta-thalassemia major patients free of relevant cardiac dysfunction (age 33.5±7.2 years,males = 10). Patients performed a maximal cardiopulmolmonary exercise test (cycloergometer, personalized ramp protocol, breath-by-breath measurements of expired gases) before and the day after blood transfusion (500 cc of red cell concentrates). After blood transfusion, hemoglobin increased from 10.5±0.8 g/dL to 12.1±1.2 (p<0.001), peak VO2 from 1408 to 1546mL/min (p<0.05), and VO2 at anaerobic threshold from 965 to 1024mL/min (p<0.05). No major changes were observed as regards heart and respiratory rates either at peak exercise or at anaerobic threshold. Similarly, no relevant changes were observed in ventilation efficiency, as evaluated by the ventilation vs. carbon dioxide production relationship, or in O2 delivery to the periphery as analyzed by the VO2 vs. workload relationship. The relationship between hemoglobin and VO2 changes showed, for each g/dL of hemoglobin increase, a VO2 increase = 82.5 mL/min and 35 mL/min, at peak exercise and at anaerobic threshold, respectively. In beta-thalassemia major patients, an acute albeit partial anemia correction by blood transfusion determinates a relevant increase of exercise performance, observed both at peak exercise and at anaerobic threshold.
Subject(s)
Anaerobic Threshold , Blood Transfusion , Exercise , Hemoglobins/metabolism , Oxygen/blood , beta-Thalassemia , Adult , Female , Humans , Male , beta-Thalassemia/blood , beta-Thalassemia/physiopathology , beta-Thalassemia/therapyABSTRACT
AIMS: [Formula: see text] multislice multiecho cardiac magnetic resonance (CMR) allows quantification of the segmental distribution of myocardial iron overload (MIO). We evaluated whether a preferential pattern MIO was preserved between two CMR scans in regularly chelated thalassaemia major (TM) patients. METHODS AND RESULTS: We evaluated prospectively 259 TM patients enrolled in the MIO in Thalassaemia (MIOT) network with a CMR follow-up (FU) study at 18 ± 3 months and significant MIO at baseline. The [Formula: see text] in the 16 segments and the global value were calculated. Four main circumferential regions (anterior, septal, inferior and lateral) were defined. We identified two groups: severe (n = 80, global [Formula: see text] <10 ms) and mild-moderate MIO (n = 179, global [Formula: see text] = 10-26 ms). Based on the CMR reports, 56.4% of patients changed the chelation regimen. For each group, there was a significant improvement in the global heart as well as in regional [Formula: see text] values (P < 0.0001). At the baseline, the mean [Formula: see text] value over the anterior region was significantly lower than the values over the other regions, and the mean [Formula: see text] over the inferior region was significantly lower than the values over the septal and the lateral regions. The same pattern was present at the FU, with a little difference for patients with mild-moderate MIO. CONCLUSION: A preferential pattern of iron store in anterior and inferior regions was present at both CMRs, with an increment of [Formula: see text] values at FU due to a baseline CMR-guided chelation therapy. The anterior region seems the region in which the iron accumulates first and is removed later.
Subject(s)
Chelation Therapy/methods , Heart Diseases/therapy , Iron Overload/therapy , Magnetic Resonance Imaging, Cine/methods , beta-Thalassemia/therapy , Adult , Cohort Studies , Female , Follow-Up Studies , Heart Diseases/diagnosis , Humans , Iron Overload/diagnosis , Male , Middle Aged , Prospective Studies , Risk Assessment , Treatment Outcome , beta-Thalassemia/diagnosisABSTRACT
Chronic anemia and tissue hypoxia increase intestinal iron absorption and mitochondrial impairment in thalassemic patients. Regular blood transfusions improve hemoglobin levels but determine an iron overload that induces reactive oxygen species (ROS) overproduction. The aim of this study was to assess cellular oxidative damage by detection of ROS, lipid peroxidation, 8-oxo-dG, and mitochondrial transmembrane potential (Δψ(m)) in transfused and untransfused thalassemic patients. We have also evaluated genotoxicity by CBMN and comet assay. Our data show that ROS and lipid hydroperoxides are significantly higher in thalassemic patients than in controls, especially in untransfused thalassemia intermedia patients. Moreover, the latter have a significant decrease in Δψ(m) that highlights the energetic failure in hypoxic state and the ROS overproduction in the respiratory chain. 8-OHdG levels are higher in thalassemics than in controls, but do not differ significantly between the two patient groups. Both genotoxicity biomarkers highlight the mutagenic potential of hydroxyl radicals released by iron in the Fenton reaction. Values for percentage of DNA in the comet tail and micronuclei frequency, significantly higher in transfused patients, could also be due to active hepatitis C virus infection and to the many drug treatments. Our biomonitoring study confirms the oxidative damage in patients with thalassemia major and shows an unexpected cellular oxidative damage in untransfused thalassemic patients. In addition to iron overload, the results highlight the important role played by hypoxia-driven mitochondrial ROS overproduction in determining oxidative damage in ß-thalassemias.
Subject(s)
Blood Transfusion , DNA Damage , Deoxyguanosine/analogs & derivatives , Lipid Peroxidation , Membrane Potential, Mitochondrial , Reactive Oxygen Species/blood , Thalassemia/blood , Thalassemia/therapy , 8-Hydroxy-2'-Deoxyguanosine , Adult , Biomarkers/blood , Cell Hypoxia , Comet Assay , Deoxyguanosine/blood , Erythrocytes/chemistry , Erythrocytes/cytology , Female , Humans , Iron/blood , Iron Overload/etiology , Male , Oxidative Stress , Thalassemia/complications , Thalassemia/metabolismABSTRACT
Neridronate is a third generation bisphosphonate with established efficacy in metabolic bone disease. In this randomized, open-label study, 118 adults with ß-thalassaemia and bone mineral density (BMD) Z scores ≤-2·0 were randomized 1:1-500 mg calcium with 400 international unis (iu) vitamin D daily or 500 mg calcium with 400 iu vitamin D daily plus neridronate 100 mg intravenously every 90 d. Significant increases in BMD at the lumbar spine and total hip were noted in the neridronate group at 6 and 12 months from baseline (P < 0·001), and values were significantly higher than the control group at both time intervals. Neridronate also significantly decreased serum bone alkaline phosphatase and C-telopeptide of collagen type 1 levels from as early as 3 months (P = 0·04 and P < 0·001, respectively), reaching significantly lower values at 12 months compared with the control group (P < 0·05). Reductions in back pain and analgesic use were also evident, starting 3 months from commencing treatment. Treatment was well tolerated by all patients. In this largest randomized trial in thalassaemia-induced osteoporosis to date, neridronate was safe and effective in reducing bone resorption and increasing BMD. The associated reduction in back pain and improved quality of life will encourage adherence to therapy. (Clinicaltrials.gov identifier NCT01140321.).
Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Density/drug effects , Diphosphonates/therapeutic use , Osteoporosis/drug therapy , beta-Thalassemia/complications , Adolescent , Adult , Alkaline Phosphatase/blood , Back Pain/etiology , Back Pain/prevention & control , Biomarkers/blood , Bone Density Conservation Agents/adverse effects , Bone Remodeling/drug effects , Collagen Type I/blood , Diphosphonates/adverse effects , Female , Femur Neck/physiopathology , Hip Joint/physiopathology , Humans , Lumbar Vertebrae/physiopathology , Male , Middle Aged , Osteoporosis/etiology , Osteoporosis/physiopathology , Peptides/blood , Quality of Life , Treatment Outcome , Young AdultABSTRACT
In ß-thalassemia major (ß-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in ß-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some ß-TM patients who may not be able to receive other forms of chelation treatment.
Subject(s)
Deferoxamine/administration & dosage , Pyridones/administration & dosage , beta-Thalassemia/drug therapy , Adolescent , Adult , Chelation Therapy/methods , Deferiprone , Deferoxamine/therapeutic use , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Iron Chelating Agents/therapeutic use , Male , Pyridones/therapeutic use , Treatment Outcome , Young AdultABSTRACT
A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8-12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP-DFO patients compared with DFP-alone patients (P = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0.3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP-DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs.
Subject(s)
Deferoxamine/administration & dosage , Iron Chelating Agents/administration & dosage , Pyridones/administration & dosage , Thalassemia/drug therapy , Administration, Oral , Adolescent , Adult , Deferiprone , Deferoxamine/therapeutic use , Drug Therapy, Combination , Female , Ferritins/blood , Follow-Up Studies , Humans , Infusions, Subcutaneous , Iron Chelating Agents/therapeutic use , Kaplan-Meier Estimate , Male , Pyridones/therapeutic use , Thalassemia/blood , Thalassemia/mortality , Treatment Outcome , Young AdultABSTRACT
The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.
Subject(s)
Chelation Therapy , Iron Chelating Agents/therapeutic use , Pyridones/therapeutic use , beta-Thalassemia/drug therapy , Adolescent , Adult , Blood Transfusion , Cause of Death , Child , Combined Modality Therapy , Deferiprone , Deferoxamine/administration & dosage , Deferoxamine/therapeutic use , Drug Therapy, Combination , Female , Heart Failure/etiology , Heart Failure/mortality , Humans , Iron Chelating Agents/administration & dosage , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/complications , Neoplasms/mortality , Proportional Hazards Models , Prospective Studies , Pyridones/administration & dosage , Splenectomy , Survival Rate , Young Adult , beta-Thalassemia/complications , beta-Thalassemia/mortality , beta-Thalassemia/therapyABSTRACT
Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.