Thalassaemia International Federation | A non-profit, non-governmental patient-driven organization, founded in 1986

Ali Taher, MD Professor of Medicine, Division of Hematology and Oncology, American University of Beirut Medical Center, and Khaled Musallam, MD, American University of Beirut.

Abstract: Our understanding of the processes underlying the disease process in patients with β thalassaemia intermedia (TI) has substantially increased over the past couple of decade. There are a number of options currently available for managing patients with TI and several studies are highlighting the benefits and risks of each treatment modality. However, until solid evidence-based guidelines are available, individualised treatment should be maintained.

Patients with β thalassaemia may show a wide spectrum of clinical severity. At one end of the spectrum, we have some patients with a clinically silent, mild anaemia, known as β thalassaemia minor. At the other end, we have patients with β thalassaemia major, who at an early age present severe anaemia. These require regular blood transfusions and iron chelation therapy for life. The term β thalassaemia intermedia (TI) refers to those cases who fall in between, and who usually present the need for medical attention later in life. Yet again, patients with TI show very heterogeneous clinical characteristics, which made the understanding and management of this disease a challenging task. In the past couple of decades, significant advances have been made in this regard, which are summarised herein.

The severity of anaemia and clinical complications of the disease (phenotype) are now known to be modified by several genetic and environmental factors. The broad diversity of mutations that affect the β globin genes, co-inheritance of α thalassaemia, several newly discovered genes involved in modifying the γ chain response (which alter the production of the beneficial foetal haemoglobin), and genes directly involved in the expression of clinical complications have all been shown to modulate the severity of TI (1). Environmental factors, such as malaria infection, are also thought to be of considerable importance. The mechanism of disease in patients with TI is attributed to three main factors: inability of the bone marrow to produce normal red blood cells (ineffective erythropoiesis), chronic anaemia and destruction of red blood cells (haemolysis), and increased absorption of iron from the gut. Recent work was able to identify several genetic mutations and internal factors that also regulate these processes, and that could be future potential targets for therapy (2). The combination of these mechanisms leads to several clinical complications in TI, that may not be as frequently observed in patients with β thalassaemia major, and that could cause significant morbidity and warrant immediate attention. Ineffective erythropoiesis is associated with skeletal deformities and osteoporosis as well as compensatory formation of masses anywhere in the body (extramedullary haematopoiesis) that can cause mechanical problems. Haemolysis has mainly been associated with enlargement of the spleen; however, recent evidence suggests that haemolysis, along with other factors, causes a high frequency of thrombosis in patients with TI and may explain other complications such as pulmonary hypertension (increased pressure in lung vessels) with secondary right heart failure. The extra iron absorbed from the gut can in turn accumulate in the liver, and less so in the heart, as it has recently been observed through a new MRI technology, and may eventually lead to significant liver disease (3).

As mentioned before, the management of patients with TI remains a challenge and there are currently no solid evidence-based guidelines for management, and treatment mainly relies on new observations and expert opinion. It is very important before embarking on any form of treatment to assess the patient carefully over the first few months after the diagnosis is established and not to start any treatment modality, especially transfusion therapy, too hastily. Many patients with TI, who may not need regular transfusion, embark on a life of unnecessary treatment of this kind, particularly if they present an unusually low haemoglobin level during a period of infection. Even if a few transfusions have been administered in the acute case, immediate commitment to a transfusion program should not be undertaken. Moreover, the need for transfusion is not only dependent on the severity of the anaemia, but also on the patient’s wellbeing, particularly with respect to activity, growth, development, and the early appearance of skeletal changes or other disease-complications. Recent evidence through a large study on 584 patients with TI form the Middle East Region and Italy (the OPTIMAL CARE study) showed the beneficial role of transfusions in decreasing various complications in TI, like thrombosis, pulmonary hypertension, heart failure, leg ulcers, and extramedullary haematopiesis (4). The same study also highlighted a higher risk of many disease complications after splenectomy, thus suggesting that very careful consideration should be made prior to taking a decision for splenectomy in TI. Although the OPTIMAL CARE study showed a beneficial role for iron chelation therapy in TI, the efficacy and safety of this treatment is currently being evaluated in a large study using the oral iron chelator deferasirox. Finally, a promising role for agents that increase the production of foetal haemoglobin (like hydroxyurea) has been documented in several studies, and further research on these products is essential.

Despite being considered as having a milder form of the disease at initial presentation and diagnosis, TI patients are still at risk of acquiring several serious complications, especially as they grow older in age. Future clinical studies are always invited to assess the optimal type and timing of treatment initiation that need to be offered to this group of patients to avoid disease-related morbidity.

Key References:

Sankaran VG, Lettre G, Orkin SH, Hirschhorn JN. Modifier genes in Mendelian disorders: the example of hemoglobin disorders. Ann N Y Acad Sci, 2010;1214(1):47-56.
Gardenghi S, Grady RW, Rivella S. Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in β-thalassemia. Hematol Oncol Clin North Am, 2010;24(6):1089-107.
Taher A, Hershko C, Cappellini MD. Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies. Br J Haematol, 2009;147(5):634-40.
Taher AT, Musallam KM, Karimi M, El-Beshlawy A et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood, 2010;115(10):1886-92.

This page was last updated February 2011 by Dr Michael Angastiniotis, MD, DCH (Paediatrician)

Medical focus

Ali Taher, MD Professor of Medicine, Division of Hematology and Oncology, American University of Beirut Medical Center, and Khaled Musallam, MD, American University of Beirut.

Key References: