The aims and the actors of Equality Project: The management of thalassemia

  • Background
  • The aims and the actors of Equality Project
  • The development of Equality Project
  • The management of thalassemia
 

BACKGROUND

Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. β -thalassaemia is characterised by the reduced synthesis (β +) or absence (β o) of the β-globin chains in the HbA molecule, resulting in accumulation of excess unbound α-globin chains that precipitate in erythroid precursors in the bone marrow and in the mature erythrocytes, leading to ineffective erythropoiesis and peripheral haemolysis (Figure).

hemoglobin-mutation


Approximately 1.5% of the global population are heterozygotes (carriers) of the β-thalassemias: there is a high incidence in populations extending from the Mediterranean basin throughout the Middle East, the Indian subcontinent, Southeast Asia, Melanesia and into the Pacific Islands (Figure; in yellow the areas after immigrations).

global-level

More than 30,000 babies are born with homozygous β- thalassaemia worldwide each year and there are 100 million individuals who are asymptomatic β-thalassaemia carriers. Three clinical and haematological conditions of increasing severity are recognized: the β -thalassemia carrier state, β-thalassemia intermedia (Non Transfusion DependentThalassemia; NTDT) and β-thalassaemia major (TM).Today in developed countries, survival of patients on conventional treatment increased to 40–50 years; it is also expected in the near future to extent further to the senility (Figure).

survival-analysis

Parallel to the significant amelioration of the main clinical features of the disease (severe anemia, bone changes, hepatosplenomegaly, and stunting of growth), adult patients suffer from complications that are mainly related to transfusions and the huge amounts of transfusional iron input that affect the heart, liver, and endocrine glands.These complications, especially those of the endocrine glands are very common among the long‑lived patients, requiring special health care andfollowed by specialists.Recent advances in the management of thalassemia syndromes have led to improved survival and better quality of life among thalassemics world wide.However, multi-transfused thalassemic patients continue to have several complications among which endocrinopathies contribute to significant morbidity (Table).

endocrine-complications

Apart from iron overload (Figure; adapted from Modell B, Mathews R. BirthDefects Orig Artic Ser. 1976; 12:13), other factors responsible for organ damage have been previously pointed out, including chronic hypoxia, due to anaemia, that may potentiate the toxicity of iron deposition in endocrine glands. 


THE AIMS OF THE EQUALITY PROJECT

The aims of program are to prepare a guidance, including regular following up of patients, to train doctors in growth disorders and endocrinecomplications in thalassemia and to reach a better quality life of patients. 


THE ACTORS OF EQUALITY PROJECT

Because an early recognition of the associated complications, institution of appropriate treatment including transfusion regimen and chelation therapy, and specific treatment of each complication are the keys to successful management, in 2015, a project called Equality was submitted by 3 countries (Turkey, Spain and Italy) and approved by the European Union (EU) with the aim to train doctors and nurses, taking care of youth and young adults thalassemia major (TM) patients, in the prevention, diagnosis, and management of endocrine disorders. The training program is unique and diverse; though holds to a common goal to provide a better quality of life of TM patients with growth disorders and endocrine complications.To achieve this goal, the training programs hold to the following main objectives: to provide the clinical experiences and educational opportunities necessary to build a solid foundation of medical knowledge, critical thinking abilities, diagnostic acumen and technical skills, and to create specialists able to practice the culturally competent medical care necessary in our increasingly situations encountered by paediatricians or haematologists, training materials is going to be developed, such as: guideline, leaflets, video and medical publications.


THE DEVELOPMENT OF EQUALITY PROJECT

Equality project will be developed in the couse of 2 years (up to 2018). The project is carried out under the coordination of Akdeniz Kan Hastalıkları Vakfı (Mediterranean Blood Diseases Foundation, (AKHAV) with three local partners and two European partners (Spain and Italy). The main coordinator is Prof. Dr. Duran Canatan, pediatric hematologist and geneticist and President of AKHAV. As local partners were selected the Center for EU Projects of Governorship of Antalya (CEUPA), the Adem Tolunay Thalasemia Center of Antalya Training and Research Hospital and Antalya Thalassemia Association.The associated partners are the Red Blood Cell and Haematopoietic Disorders Unit. Institute for Leukaemia Research Josep Carreras (IJC) and University of Barcelona (Prof. Dr.JL. Vives Corrons,Spain) and the Paediatric and Endocrine Out-patient Clinic, Quisisana Hospital of Ferrara (Prof. Dr. V. De Sanctis).CONVENTIONAL TREATMENT: TRANSFUSION THERAPY The aim of transfusion therapy is to permit normal growth and activity level and to prevent skeletal changes associated with marrow hyperplasia (Figure).

effects-of-transfusion 

Adequate transfusion therapy will also reduce splenomegaly and hypersplenism and decrease absorption of dietary iron. The product of choice is packed red blood cells depleted of leucocytes and matched with the patient’s red antigen phenotype for at least D, C, c, E, e, and Kell. Whole blood or blood without leukodepletion is unsuitable for regular transfusions, since non-hemolytic transfusion reactions are common. When possible, large units less than two weeks of age are recommended.

The goal of transfusion is to shut off erythropoiesis as much as possible. Transfusions should generally be given at an interval of three to four weeks.Appropriate goals of transfusion therapy and optimal safety of transfused blood are the key concepts in the protocol for routine administration of red blood cells to patients with thalassemia.The major goals are:

1. Maintenance of red cell viability and function during storage, to ensure sufficient transport of oxygen

2. Use of donor erythrocytes with a normal recovery and half-life in the recipient

3. Achievement of appropriate hemoglobin level

4. Avoidance of adverse reactions, including transmission of infectious agents.


CONVENTIONAL TREATMENT:

IRON CHELATION THERAPY

The most serious disadvantage of life-saving transfusions is the inexorable accumulation of iron within tissues. To prevent organ complications due to iron overload the patient must be chelated, as the human body has many mechanisms for absorbing, transferring, and storing iron, but none for its excretion.Iron toxicity appears when the iron load, in a particular tissue and blood, exceeds the binding capacity of iron and consequently free non-transferrin iron appears (Figure).NTBI-in-plasma

To date, there are 3 major classes of iron chelators: hexadentate (deferoxamine - DFO), in which 1 atom of iron is bound to 1 DFO molecule; bidentate (deferiprone- DFP), in which 1 atom of iron is bound to 3 DFP molecules; and tridentate (deferasirox - DFX), in which 1 atom of iron is bound to 2 DFX molecules. The goals of iron chelation therapy and the properties of different iron chelating agents are reported in the next two figures.

deferoxamine-deferiprone-deferasirox

Effective chelation reduces or prevents iron accumulation and iron-mediated organ damage, resulting in a consistent decrease of morbidity andmortality. Combined therapy (use of two chelators on the same day), may induce negative iron balance and may reverse hypogonadism and endocrine complications in severe iron overloaded TM subjects.Long-term studies have shown that deferiprone and deferoxamine (DFO) accelerate iron chelation by rapidly reducing liver iron, serum ferritin, and myocardial siderosis.Combination chelation therapy with deferasirox and DFO has also been shown to be beneficial.