Patients with β-thalassemia major (TM) and other refractory anemias requiring regular blood transfusions accumulate iron that damages the liver, endocrine system, and most importantly the heart. The ...prognosis in TM has improved remarkably over the past 10 years. This improvement has resulted from the development of magnetic resonance imaging (MRI) techniques, especially T2*, to accurately measure cardiac and liver iron, and from the availability of 3 iron-chelating drugs. In this article we describe the use of MRI to determine which adult and pediatric patients need to begin iron chelation therapy and to monitor their progress. We summarize the properties of each of the 3 drugs, deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX), including their efficacy, patient acceptability, and side effects. We describe when to initiate or intensify therapy, switch to another drug, or use combined therapy. We also discuss the management of refractory anemias other than TM that may require multiple blood transfusions, including sickle cell anemia and myelodysplasia. The development of a potential fourth chelator FBS 0701 and the combined use of oral chelators may further improve the quality of life and survival in patients with TM and other transfusion-dependent patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Iron deficiency, even in the absence of anemia, can be debilitating, and exacerbate any underlying chronic disease, leading to increased morbidity and mortality. Iron deficiency is frequently ...concomitant with chronic inflammatory disease; however, iron deficiency treatment is often overlooked, partially due to the heterogeneity among clinical practice guidelines. In the absence of consistent guidance across chronic heart failure, chronic kidney disease and inflammatory bowel disease, we provide practical recommendations for iron deficiency to treating physicians: definition, diagnosis, and disease-specific diagnostic algorithms. These recommendations should facilitate appropriate diagnosis and treatment of iron deficiency to improve quality of life and clinical outcomes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to ...advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.
Oral iron chelators Cappellini, Maria Domenica; Pattoneri, Paolo
Annual review of medicine,
01/2009, Volume:
60
Journal Article
Peer reviewed
Deferoxamine (DFO) was the standard of care for transfusional iron overload for >40 years, requiring subcutaneous infusion for 8-12 h/day, 5-7 days/week. Oral iron chelators are an important ...development, offering the potential to improve compliance and patients' quality of life. The oral, three-times-daily agent deferiprone appeared to be a promising advance; however, its use has been limited owing to serious adverse events, such as neutropenia and agranulocytosis. Therapy combining deferiprone with DFO has proved effective in the management of severe cardiac siderosis. Deferasirox is a novel, orally active agent that provides 24-h chelation with a once-daily dose. An extensive clinical trial program has demonstrated that deferasirox at appropriate doses is effective in reducing or maintaining iron burden in adult and pediatric patients. The clinical program demonstrated that deferasirox has a safety profile that is clinically manageable with regular monitoring.
Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia ...syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.
Fyn is a tyrosine kinase belonging to the Src family (Src-Family-Kinase, SFK), ubiquitously expressed. Previously, we report that Fyn is important in stress erythropoiesis. Here, we show that in red ...cells Fyn specifically stimulates G6PD activity, resulting in a 3-fold increase enzyme catalytic activity (kcat) by phosphorylating tyrosine (Tyr)-401. We found Tyr-401 on G6PD as functional target of Fyn in normal human red blood cells (RBC), being undetectable in G6PD deficient RBCs (G6PD-Mediterranean and G6PD-Genova). Indeed, Tyr-401 is located to a region of the G6PD molecule critical for the formation of the enzymatically active dimer. Amino acid replacements in this region are mostly associated with a chronic hemolysis phenotype. Using mutagenesis approach, we demonstrated that the phosphorylation status of Tyr401 modulates the interaction of G6PD with G6P and stabilizes G6PD in a catalytically more efficient conformation. RBCs from Fyn-/−mice are defective in G6PD activity, resulting in increased susceptibility to primaquine-induced intravascular hemolysis. This negatively affected the recycling of reduced Prx2 in response to oxidative stress, indicating that defective G6PD phosphorylation impairs defense against oxidation. In human RBCs, we confirm the involvement of the thioredoxin/Prx2 system in the increase vulnerability of G6PD deficient RBCs to oxidation. In conclusion, our data suggest that Fyn is an oxidative radical sensor, and that Fyn-mediated Tyr-401 phosphorylation, by increasing G6PD activity, plays an important role in the physiology of RBCs. Failure of G6PD activation by this mechanism may be a major limiting factor in the ability of G6PD deficient RBCs to withstand oxidative stress.
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•In red cells, Fyn acts as an oxidative sensor.•Fyn specifically stimulates G6PD activity by phosphorylating tyrosine (Tyr)-401.•In Fyn-/-mice, failure of G6PD activation increases red cell vulnerability against oxidation.•Fyn targeting G6PD protects Prx2 recycling, which is required to remove peroxides.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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
New measures of iron accumulation in liver and heart (superconducting quantum inference device and magnetic resonance imaging), and oral iron chelators (deferiprone and deferasirox) are available for managing iron overload in thalassemia major. To assure appropriate use of these new health technologies, the Italian Society of Hematology appointed a panel of experts to produce clinical practice-guidelines for the management of iron overload in thalassemia major and related disorders. The analytical hierarchy process, a technique for multicriteria decision analysis, was applied to relevant key questions in order to identify the alternative strategies, generate explicit criteria for their evaluation, and check how well the alternatives fulfilled the criteria. The result of a comprehensive systematic review of articles released from 1990 to 2007 was used as a source of scientific evidence to compare the decisional options pairwise, and select the final recommendation. Every step in the model was developed from questionnaires and group discussion. The resulting recommendations advise about which examination to carry out in order to plan iron chelation therapy, when to start iron chelation, which iron chelator to choose in regularly transfused patients, how to monitor iron chelation therapy, and when and how to switch standard therapy.
Key words: clinical practice guidelines, systematic review, thalassemia major, sickle cell anemia, deferoxamine, deferiprone, deferasirox.
Patients with non-transfusion-dependent thalassemia (NTDT) experience many clinical complications despite their independence from frequent transfusions. Morbidities in NTDT stem from the interaction ...of multiple pathophysiological factors: ineffective erythropoiesis, iron overload (IOL), and hypercoagulability. Ineffective erythropoiesis and hemolysis are associated with chronic hypoxia and a hypercoagulable state. The latter are linked to a high prevalence of thromboembolic and cerebrovascular events, as well as leg ulcers and pulmonary hypertension. IOL in NTDT patients is a cumulative process that can lead to several iron-related morbidities in the liver (liver fibrosis), kidneys, endocrine glands (endocrinopathies), and vascular system (vascular disease). This review sheds light on the pathophysiology underlying morbidities associated with NTDT and summarizes the mainstays of treatment and some of the possible future therapeutic interventions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•β-THAL is one of the most prevalent blood disorders in some regions of the world.•However, given its prevalence, in the EU and the US it is classified as a rare disease.•A wide array of therapeutic ...approaches has been developed over the past decades.•β-THAL is a learning case on the potential global impact of Orphan Legislations.•Gene therapy for β-THAL is promising, but scenarios for global access are missing.
In many countries, β-thalassemia (β-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for β-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of β-THAL; at the same time, and even though only one-fifth of β-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for β-THAL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.
Seventy-one patients in the EPIC cardiac substudy elected to continue into the ...3(rd) year, allowing cardiac iron removal to be analyzed over three years.
Mean deferasirox dose during year 3 was 33.6 ± 9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ± 39.1% at baseline to 17.1 ms ± 62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%).
Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.
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