Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy

Introduction

Beta-thalassaemia major is a hereditary anaemia resulting from defects in β-globin production. The coexistence of hereditary persistence of foetal haemoglobin (HbF) during adult life in patients with β-thalassaemia reduces the severity of the disease; these patients have a mild disorder, sometimes not even requiring chronic transfusions. The clinical benefit of increased HbF, first inferred in 1976¹, is due to a decrease in the imbalance between β and non-β-chains and the consequent reduction of haemolysis. Many drugs have been studied as inducers of HbF for patients with β-thalassaemia and sickle cell disease. Hydroxyurea is currently used in moderate to severe forms of sickle cell disease^2,3 and in some cases of thalassaemia intermedia^4,5. Other inducers of HbF synthesis, such as butyrate⁶, 5-azacytidine⁷ and, more recently, decitabine, have also been shown to induce HbF in patients with sickle cell disease⁸. However, these HbF inducers have shown only a modest effect in the majority of β-thalassaemia patients as well as some degree of toxicity. As a result, they have not been used routinely in clinical practice. Thalidomide, a drug known for its immunomodulating and anti-angiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells^9,10. Only one patient affected by β-thalassaemia major treated successfully with thalidomide has been described so far¹¹.

We report here the case of a young girl with β-thalassaemia (β+/β°) in a very severe clinical condition who could not be given any further transfusions because of the occurrence of severe post-transfusion reactions and who showed an outstanding response to thalidomide.

Case description

The patient, affected by β-thalassaemia major IVS1-6/cd44-C, was born in Albania and is now 20 years old. From the age of 1 year, she was transfused in Albania every 3–4 months, maintaining very low haemoglobin values (in the range of 5–7 g/dL). Splenectomy was performed when she was 4 years old. She came to Italy at 9 years of age, affected by severe anaemia with a haemolytic component (Hb: 4.5 g/dL, HbF: 38%, very low haptoglobin levels), significant erythroblastosis (320×10³/mL), dilated cardiomyopathy, severe bone deformities (particularly of the lower limbs and face) and enormous hepatic enlargement accompanied by significant pain in the region of the liver. Repeated transfusion attempts proved ineffective because of massive post-transfusion acute haemolysis, despite negative compatibility matches. Direct and indirect Coombs’ tests were not conclusive for an antibody-mediated haemolytic process. Treatment with high-dose steroids and cyclophosphamide was started, with no improvement.

At 10 years of age, she was started on 10 mg/kg/die of hydroxyurea, with a partial response in terms of haemoglobin levels (Hb: 6.5–7 g/dL, HbF: 50%) and an improvement of hepatic function, although haemolytic indices remained high. The possibility of a bone marrow transplant from an unrelated donor (both brothers were HLA incompatible) was excluded because of the patient’s very poor general condition. Given the impossibility of ruling out an autoimmune aetiology of the haemolytic component of the anaemia (direct Coombs’ test seldom slightly positive) and based on the severity of her clinical condition, the girl was again treated with immunosuppressive therapy (high-dose steroids and cyclophosphamide) at 12 years of age, without any response. At 15 years old she was treated with three cycles of rituximab, without any relevant response in terms of haemoglobin levels. After an extensive immuno-haematological investigation, a specific Scianna-1 allo-antibody was identified in the serum.

At 16 years old, the girl was transfused with two units of Scianna-negative red blood cells, which were found through the International Blood Bank (American Donor Program), but even these did not produce an increase in haemoglobin levels and induced further haemolysis (Hb pre-transfusion: 5 g/dL, Hb post-transfusion: 3.5 g/dL). At this point, it was agreed that the patient should not be transfused any more.

The girl was treated with diuretics, ACE-inhibitors, digitalis for congestive chronic heart failure, a platelet anti-aggregant drug for thrombocytosis (platelet count: 900 – 1,000 × 10⁹/L), bisphosphonates and calcium for severe osteoporosis and folic acid.

The dose of hydroxyurea was progressively increased to 30–35 mg/kg/die maintaining values of Hb between 5–6 g/dL with HbF 40%.

The clinical picture remained stable (allowing the girl to walk for short distances and to attend school, although not regularly) until March 2008 (age: 20 years), when a progressive decrease in haemoglobin values was detected, reaching a nadir of 3.7 g/dL in May. There were no signs of infection but there was important clinical worsening with severe heart failure and initial lung oedema. The patient was treated with high doses of diuretics, digitalis and ACE-inhibitors. On the basis of a similar case reported¹² and considering the lack of therapeutic options available, the girl was started on treatment with thalidomide 75 mg/kg/die. Informed consent was obtained regarding the experimental nature of the treatment and its possible teratogenic effects. The patient was advised of the risks in pregnancy and she accepted this limitation. The dose of hydroxyurea was progressively reduced until the drug was discontinued in December 2008.

Haemoglobin values progressively and rapidly increased (1 month after starting thalidomide treatment Hb: 7.2 g/dL; after 8 months: Hb: 9.0 g/dL, HbF: 73%). The levels of erythroblasts remained high, although showing a slight decrease (53×10³/mL). The response to thalidomide is impressive Therapy was well tolerated and no signs of neuropathy appeared. At the time of writing this report (January 2009) the patient’s haematological and clinical conditions are good and even the cardiological therapy has been tapered down.

Discussion

The mechanisms by which thalidomide increases erythropoiesis and induces γ-globin gene expression and HbF production^9,10 as well as its possible synergistic effect with hydroxyurea¹¹, have been described recently, the immunomodulatory action of the drug being well-recognised. A possible role of thalidomide and its derivatives (pomalidomide and lenalidomide) in the treatment of sickle cell disease and other β-haemoglobinopathies has been suggested^10,12, but clinical experience is limited to just one young Mexican woman with β-thalassaemia major, who responded brilliantly to thalidomide¹¹.

We believe that thalidomide should be considered in dramatic cases of thalassaemias which cannot be treated with transfusions and do not respond to hydroxyurea. Extensive biological and clinical studies are required to define the potential use of thalidomide in thalassaemia and other haemoglobinopathies, and to evaluate and monitor its possible side effects.

Figure 1.

Haemoglobin (Hb) and foetal haemoglobin (HbF) values with different treatments throughout the years.