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1.
Blood Rev ; 32(6): 473-479, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29699840

RESUMEN

Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.


Asunto(s)
Médula Ósea/metabolismo , Susceptibilidad a Enfermedades , Hierro/metabolismo , Anemia Aplásica/complicaciones , Anemia Aplásica/etiología , Anemia Aplásica/metabolismo , Anemia Aplásica/terapia , Animales , Células de la Médula Ósea/metabolismo , Microambiente Celular , Células Madre Hematopoyéticas/metabolismo , Humanos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/metabolismo , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/terapia , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/terapia
2.
Leuk Res ; 62: 108-115, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29054020

RESUMEN

Myelodysplastic syndromes (MDS) are a group of clonally-acquired blood disorders characterized by ineffective hematopoiesis leading to cytopenias. Red blood cell transfusions are an important component of supportive care in patients with MDS. Prolonged exposure to transfusions can lead to iron overload, which results in iron-induced toxicity caused by the production of reactive oxygen species (ROS). ROS accumulation has detrimental effects also on hematopoietic stem cells and may contribute to MDS progression. The observation that iron chelation improves hematologic parameters and reduces transfusion dependence further indicates that iron overload impairs hematopoiesis. Over the past decade, the mechanisms regulating iron homeostasis and the complex interplay between iron overload and toxicity, ineffective hematopoiesis, and transformation to leukemia have become clearer. In this narrative review, we provide an overview of recent findings pertaining to iron overload in patients with MDS and its effects on hematopoiesis. We also briefly discuss the position of chelation therapy in the context of the new developments.


Asunto(s)
Hematopoyesis/fisiología , Sobrecarga de Hierro/etiología , Síndromes Mielodisplásicos/complicaciones , Animales , Transfusión de Eritrocitos/efectos adversos , Humanos , Sobrecarga de Hierro/prevención & control , Síndromes Mielodisplásicos/terapia
3.
Blood Cells Mol Dis ; 47(3): 166-75, 2011 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-21843958

RESUMEN

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed.


Asunto(s)
Benzoatos/administración & dosificación , Deferoxamina/administración & dosificación , Quelantes del Hierro/administración & dosificación , Piridonas/administración & dosificación , Sideróforos/administración & dosificación , Triazoles/administración & dosificación , Talasemia beta , Terapia por Quelación/estadística & datos numéricos , Deferasirox , Deferiprona , Quimioterapia Combinada , Ferritinas/sangre , Humanos , Hierro , Hígado/metabolismo , MEDLINE , Miocardio/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Función Ventricular/fisiología , Talasemia beta/sangre , Talasemia beta/tratamiento farmacológico
4.
Anemia ; 2011: 435683, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21738864

RESUMEN

Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups.

5.
Hemoglobin ; 35(3): 206-16, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21599433

RESUMEN

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.


Asunto(s)
Deferoxamina/administración & dosificación , Piridonas/administración & dosificación , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Terapia por Quelación/métodos , Deferiprona , Deferoxamina/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Quelantes del Hierro/uso terapéutico , Masculino , Piridonas/uso terapéutico , Resultado del Tratamiento , Adulto Joven
6.
Blood Rev ; 24(6): 239-44, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20850917

RESUMEN

Increased survival in patients with ß thalassaemia major (TM) allowed for several morbidities to manifest. Renal manifestations of the disease and its treatment have been poorly evaluated. There is evidence, mainly from studies in the paediatric population, of tubular dysfunction and glomerular filtration rate abnormalities in this patient population. Long-term outcomes of these changes, however, have not been prospectively investigated. The pathogenesis of these abnormalities could be attributed to iron overload, too aggressive iron removal, and/or the underlying anaemia. These changes seem to be nonprogressive, resolve spontaneously in most part, or may require iron chelator dose modifications. Relative iron depletion may explain renal function changes attributed to chelation therapy; thus, sudden removal of iron or overchelation should be avoided. Future studies should aim to evaluate the natural history of kidney function in TM patients to help understand the mechanisms and long-term sequelae of the observed renal changes.


Asunto(s)
Sobrecarga de Hierro/complicaciones , Enfermedades Renales/etiología , Riñón , Reacción a la Transfusión , Talasemia beta/complicaciones , Humanos , Riñón/patología , Pruebas de Función Renal
7.
Blood Cells Mol Dis ; 45(2): 136-9, 2010 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20678715

RESUMEN

Myocardial iron overload is the leading cause of death in patients with beta-thalassemia major. An intensification monotherapy with deferoxamine (DFO) as well as a combination therapy with DFO and deferiprone (DFP) reduces myocardial iron and improves cardiac function. However, the prognosis for thalassemia major patients with established cardiac disease switched from DFO monotherapy to combined DFP/DFO chelation is unknown. Twenty-eight thalassemia major patients with cardiac disease were enrolled in a prospective study lasting 42+/-6 months. Fifteen (9 high-ferritin and 6 low-ferritin) were placed on DFP/DFO (DFP, 75 mg/kg t.i.d.; DFO, 40-50mg/kg over 8-12h at night 5-7 days/week), while 13 (5 high- and 8 low-ferritin) received DFO alone. No cardiac events were observed among high-ferritin patients on combination therapy, whereas 4 cardiac events (p=0.0049), including three deaths, occurred in high-ferritin patients on DFO monotherapy. These findings demonstrate that in thalassemia major patients with well-established cardiac disease combined iron-chelation therapy with DFP/DFO is superior to DFO monotherapy.


Asunto(s)
Cardiomiopatías/tratamiento farmacológico , Deferoxamina/uso terapéutico , Quimioterapia Combinada , Quelantes del Hierro/uso terapéutico , Piridonas/uso terapéutico , Talasemia beta/tratamiento farmacológico , Adulto , Cardiomiopatías/inducido químicamente , Terapia por Quelación , Deferiprona , Femenino , Humanos , Hierro/sangre , Quelantes del Hierro/administración & dosificación , Sobrecarga de Hierro/tratamiento farmacológico , Masculino , Estudios Prospectivos , Tasa de Supervivencia , Talasemia beta/mortalidad
8.
Blood ; 116(16): 2875-83, 2010 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-20551378

RESUMEN

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.


Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Talasemia/complicaciones , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/transmisión , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/transmisión , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Talasemia/tratamiento farmacológico , Talasemia/epidemiología
9.
Blood Cells Mol Dis ; 42(3): 247-51, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19233692

RESUMEN

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.


Asunto(s)
Terapia por Quelación , Quelantes del Hierro/uso terapéutico , Piridonas/uso terapéutico , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Transfusión Sanguínea , Causas de Muerte , Niño , Terapia Combinada , Deferiprona , Deferoxamina/administración & dosificación , Deferoxamina/uso terapéutico , Quimioterapia Combinada , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Humanos , Quelantes del Hierro/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/mortalidad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Piridonas/administración & dosificación , Esplenectomía , Tasa de Supervivencia , Adulto Joven , Talasemia beta/complicaciones , Talasemia beta/mortalidad , Talasemia beta/terapia
10.
Mediterr J Hematol Infect Dis ; 1(1): e2009034, 2009 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-21415999

RESUMEN

Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients.

11.
Curr Med Res Opin ; 24(7): 1905-17, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18507891

RESUMEN

OBJECTIVES: Iron chelation treatment (ICT) in beta-thalassemia major (beta-TM) patients undergoing blood transfusions can cause low satisfaction, low compliance, with possible negative consequences on treatment success, patients' wellbeing, and costs. The purpose was to estimate the societal burden attributable to beta-TM in terms of direct and indirect costs, health-related quality-of-life (HRQoL), satisfaction and compliance with ICT in patients undergoing transfusions and ICT. RESEARCH DESIGN AND METHODS: The naturalistic, multicenter, longitudinal Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) cost-of-illness study was conducted involving patients of any age, on ICT for at least 3 years, who were enrolled at 8 Italian Thalassemia Care Centers. Costs were estimated from the societal perspective, quantified with tariffs, prices, or net earnings valid in 2006. RESULTS: One-hundred and thirty-seven patients were enrolled (median age = 28.3, 3-48 years, 49.6% male) and retrospectively observed for a median of 11.6 months. Mean direct costs were euro1242/patient/month, 55.5% attributable to ICT, 33.2% attributable to transfusions. Relevant quantity and quality of productivity was lost. Both physical and mental components of HRQoL were compromised. Little difficulties remembering to take ICT and positive satisfaction with the perceived effectiveness of therapy were declared, but not good levels of satisfaction with acceptance, perception of side effects and burden of ICT. CONCLUSIONS: The management of beta-TM patients undergoing transfusions and ICT is efficacious, although costly, but overall benefits were not always perceived as optimal by patients. Efforts must be focused to improve patients' acceptance and satisfaction with their therapy; this would contribute to a better compliance and hence an increase in treatment effectiveness and patients' overall wellbeing, with expected improved allocation of human and economic resources.


Asunto(s)
Terapia por Quelación/economía , Terapia por Quelación/psicología , Cooperación del Paciente , Satisfacción Personal , Talasemia beta/tratamiento farmacológico , Talasemia beta/economía , Adolescente , Adulto , Transfusión Sanguínea , Niño , Preescolar , Análisis Costo-Beneficio , Femenino , Humanos , Italia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento
12.
Pediatr Endocrinol Rev ; 6 Suppl 1: 208-13, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19337180

RESUMEN

Iron overload, characterized by excessive iron deposition, occurs commonly in patients with hereditary or refractory anemias such as beta-thalassemia major, sickle cell anemia, and myelodysplastic syndromes, whose anemia is managed with frequent blood transfusions. Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate potentially fatal iron levels. Myocardial siderosis and resulting cardiac complications are among the leading causes of death in such patients. Unfortunately, even with the administration of effective subcutaneous iron chelation therapy with desferrioxamine (DFO), over 50% of patients die before the age of 35 years, largely because of poor compliance with subcutaneous chelation regimens. Recently introduced oral chelation agents, deferiprone and deferasirox, are associated with higher compliance rates, and greater reductions in cardiac iron levels, than those achieved with DFO. This article reviews the pharmacologic properties and clinical efficacy of currently available iron chelation therapies in the management of transfusional chronic iron overload.


Asunto(s)
Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/metabolismo , Talasemia/metabolismo , Humanos , Cooperación del Paciente
13.
Haematologica ; 91(10): 1420-1, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16963395

RESUMEN

This retrospective one to one matched case-control study was aimed at evaluating risk factors for death in beta-thalassemic patients followed in Italian centers between 1997 and 2001. The mortality risk was lower in patients with good compliance to iron chelation therapy and in those treated with deferiprone.


Asunto(s)
Talasemia beta/etiología , Talasemia beta/mortalidad , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Talasemia beta/tratamiento farmacológico
14.
Blood Cells Mol Dis ; 28(2): 196-208, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12064916

RESUMEN

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.


Asunto(s)
Deferoxamina/administración & dosificación , Quelantes del Hierro/administración & dosificación , Piridonas/administración & dosificación , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Deferiprona , Deferoxamina/toxicidad , Femenino , Ferritinas/sangre , Humanos , Quelantes del Hierro/toxicidad , Sobrecarga de Hierro/tratamiento farmacológico , Cirrosis Hepática/patología , Masculino , Piridonas/toxicidad , Equivalencia Terapéutica , Resultado del Tratamiento , Talasemia beta/complicaciones
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