New trends in the treatment of β-thalassemia

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Abstract

Thalassemia is the world’s most common hereditary disease, and is a paradigm of monogenic genetic diseases. Because of increased population mobility, the disease is found today throughout the world, even in places far from the tropical areas in which it arose. Therapy of thalassemia has in the past been confined to transfusion and chelation. Recently, novel modes of therapy have been developed for thalassemia, based on the pathophysiology and molecular pathology of the disease, both of which have been extensively studied. This review will discuss the therapeutic modalities currently in use for the supportive treatment of thalassemia, both those that are standard therapy and those that are in clinical trials. We will include transfusion, chelation (intravenous and oral), antioxidants and various inducers of fetal hemoglobin (hydroxyurea, erythropoietin, butyrates, hemin). Most of the newer therapies are suitable primarily for thalassemia intermedia patients. In addition, the treatment modalities currently in use for the curative treatment of thalassemia major will be discussed, including bone marrow transplantation in its various forms. Experimental therapeutic methods, such as intrauterine bone marrow transplantation and gene therapy, are included. Physicians caring for thalassemia patients have an increasing variety of treatment options available. Future clinical studies will determine the place of newer agents and modalities in improving the quality of life as well as the life expectancy of thalassemia patients.

Introduction

Thalassemia is the world’s most common monogenic disease [1], and due to migration, it is no longer confined to the tropical areas in which it arose. Since thalassemia is present in nearly all parts of the modern world, more interest has developed in the treatment of this group of diseases. Therapeutic modalities for the supportive or curative treatment of thalassemia have been expanded, offered a wide variety of therapeutic options, some currently in use, others for future application. Concurrently, as the lifespan of affected patients has been extended by improvements in supportive care, the age distribution of the patient population has dramatically altered [2]. Furthermore, in many countries, the use of DNA-based prenatal diagnosis has substantially reduced the number of births of affected individuals, and has accentuated the trend of increasing age of thalassemia patients. Approaching the new millenium, clinicians who care for thalassemia patients thus have at their disposal new treatment options, but they also face the challenges of an older, more complex patient population.

Over the last decades, thalassemia research has flourished, with many important insights as to the molecular etiology and pathophysiology of the disease. Several years ago [3], we extensively reviewed the pathophysiology and treatment of β-thalassemia. Our last review [3] can be referred to for background on the molecular genetics, cellular pathophysiology, and basic treatment modalities of the disease. This review will concentrate on updating the therapeutic options available for thalassemia, including those used for conventional treatment as well as those which are either experimental or only as yet theoretical.

Section snippets

Therapeutic decisions in thalassemia: the spectrum of the disease

Thalassemia has a very wide clinical range of severity, from transfusion dependency beginning in infancy, to a mild condition requiring little if any medical intervention. Thalassemia major (TM) is the severe form of the disease, presenting with transfusion-dependent anemia, generally in the first year of life. Thalassemia intermedia (TI) is the less severe form of the disease, and is highly variable.

The hallmark which can be used to differentiate TI from TM is the lack of transfusion

Transfusion therapy

The mainstay of supportive care for the anemic patient with β-thalassemia is blood transfusion. The three principles guiding transfusional support of the thalassemia patient in the 1990s, which will be guidelines for the future as well, are: (a) to transfuse to the minimum hemoglobin needed to assure growth and good quality of life, thus minimizing iron overload; (b) to assure that blood is free of blood-borne viral agents (insofar as is possible); (c) to use leukocyte filters for their many

Conventional allogeneic bone marrow transplantation

More than a thousand allogeneic transplantations have been reported to have been performed for thalassemia since the first case was done in 1982 by Thomas [57]. As we have discussed previously [3], the decision to perform allogeneic bone marrow transplantation is generally considered appropriate only for those patients who have a fully HLA-matched donor (at most, 30–40% of all patients). The decision to refer a patient for BMT is a therapeutic dilemma fraught with many ethical questions which

Conclusions

The therapeutic options for the thalassemias are expanding with each passing year, though progress is slower than we would like on many fronts. The prediction for the next decade is for a great increase in the number of thalassemia patients due to lower mortality from infections and other preventable diseases, and better supportive care during early childhood [1]. The overall outlook for thalassemia patients includes a greatly increased life expectancy, which brings with it new manifestations

Reviewers

Griffin P. Rodgers, MD, Chief, Molecular and Clinical Hematology Branch, 10 Center Dr.-MSC 1812, Bldg 10, Room 9n-119, National Institutes of Health, Bethesda, MD 20892-0001, USA.

Dr Stanley L. Schrier, Professor of Medicine, Stanford University Medical Center, Medicine/Hematology, S-161, Stanford, California 94305-5112, USA.

Deborah Rund received her degree from Columbia University College of Physicians in 1980 where she went on to complete her training in hematology/oncology. Her research has concentrated on the genetics of both α- and β-thalassemia, including genotype-phenotype interactions, as well as gene therapy of thalassemia. She currently holds the title of Associate Professor at Hebrew University-Hadassah Medical School and is on the staff of the Hematology Department of Hadassah University Hospital, Ein

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    Deborah Rund received her degree from Columbia University College of Physicians in 1980 where she went on to complete her training in hematology/oncology. Her research has concentrated on the genetics of both α- and β-thalassemia, including genotype-phenotype interactions, as well as gene therapy of thalassemia. She currently holds the title of Associate Professor at Hebrew University-Hadassah Medical School and is on the staff of the Hematology Department of Hadassah University Hospital, Ein Kerem, Jerusalem, Israel.

    Professor Eliezer Rachmilewitz received his MD degree from Hebrew University-Hadassah Medical School in 1960. He completed his training in Internal Medicine and later in Hematology, at Hadassah University Hospital, where he holds the title of full professor. He has collaborated in many research endeavors with colleagues from a great many academic institutions, and has been instrumental in performing clinical trials of novel therapies for patients with thalassemia. Professor Rachmilewitz is widely published in the field, both in the field of basic pathophysiology of thalassemia, and in the field of therapeutic interventions.

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