A 16-year-old girl with β-thalassemia major presented with painless bilateral cervical lymphadenopathies for 1 month. She had been on regular transfusion since 9 months of age and was HCV positive due to regular transfusions. Her parents were heterozygotes for β-thalassemia minor. Initial evaluations including complete blood count, biochemistry tests, Epstein barr virus infection (EBV) and toxoplasmosis studies were not conclusive. white blood cells and platelets were normal. serum ferritin levels of the patient were 3,200 ng/mL and 3,000 ng/mL at two occasions. She was receiving subcutaneous desferrioxamine at least 5 nights/week as iron chelation since 2.5 years of age. After about 3 weeks of persistent cervical lymphadenopathy, computerized tomography (CT) scan of the neck and chest was performed revealing bilateral cervical and upper anterior mediastinal lymph nodes with para-tracheal involvement. Abdominopelvic imaging was normal. An excisional lymph node biopsy was performed which was compatible with Hodgkin's lymphoma, nodular sclerosis subtype. Clinical staging revealed stage 2A (spleen was considered enlarged due to thalassemia since it was not a new finding). She was scheduled to receive systemic chemotherapy with 6 alternating cycles of MOPP/ABVD followed by radiotherapy and was off-therapy thereafter. Her mother also developed colon adenocarcinoma 6 years later and her brother (who was hematologically normal) died of brain tumor 8 years later. She also received antiviral treatments including α-interferon and ribavirin for HCV and changed to be negative. Fortunately, the patient is in remission for Hodgkin's lymphoma and still on regular blood transfusion after 10 years of follow-up.

A 13-year-old girl with β-thalassemia intermedia was referred to our clinic due to hyperleukocytosis (WBC: 154,000/mm³). She was receiving hydroxyurea since 8 years of age and had been kept transfusion independent.

At presentation she had Hb 8.5-9 gr/dL, MCV 78 fL and MCH 20 pg. Hemoglobin electrophoresis revealed HbA 45%, HbF 51% and HbA2 4%. Spleen was palpated about 4cm below costal margin. Splenomegaly was evident as it was before. Due to the persistence of hyperleukocytosis (WBC: 50,000-150,000/mm³) and aggravation of anemia, a bone marrow aspiration was performed which showed hypercellular marrow with increased myeloid to erythroid ratio. Significant degrees of reticulin stain-measured fibrosis were noted accompanying marrow eosinophilia. The histopathological findings were in favor of chronic myelogenous leukemia (CML). Real time polymerase chain reaction examination for the detection of BCR-ABL translocation on bone marrow aspirate revealed positive reaction for 342 bp amplified product compatible with t(9;22)(q34;q11.2) translocation (Philadelphia chromosome). Treatment with Imatinib mesylate (Gleevec) was started at a dosage of 400 mg/day; however, she developed accelerated blastic crisis and proceeded towards acute myeloid leukemia (AML) and did not respond to chemotherapy regimens and thus died about 3 months after diagnosis.

In this brief article, we have presented two patients with thalassemia syndromes (β-thalassemia major and β-thalassemia intermedia) who developed hematologic malignancies (Hodgkin's lymphoma and CML) during the course of the disease. A thorough review of the literature reveals that only few cases of major β-thalassemia complicated with lymphoma has been reported [6, 8-10]. CML in a patient with β-thalassemia intermedia has not yet been reported. Sallam and colleagues [7] reported a patient with sickle cell/beta⁰ thalassemia (β^S/β⁰) who was complicated with CML. Several other studies have reported two patients with intermedia β-thalassemia who developed other hematological malignancies including non-Hodgkin lymphoma [11, 12].

The occurrence of hematological malignancies such as leukemia and lymphoma in thalassemia patients could be a pure coincidence or a combination of genetic and environmental factors. Previously, definite genetic link between thalassemia syndromes and lymphoma has been rejected by Quattrin and co-workers who reported comparable incidence of leukemia in patients with β-thalassemia and general population [12]. It was further reported by Zurlo and colleagues [13] that the most common cause of death in those with major β-thalassemia was heart disease, followed by infection, liver disease, and malignancy. Currently there are few reports available and thus we cannot comment on the relationship between malignancies and thalassemia syndromes.

In our report, immunomodulation due to multiple transfusions could be considered as a probable predisposing factor in development of Hodgkin's lymphoma in the patient with major β-thalassemia. In addition since she was HCV positive, it could be also proposed as a putative agent. Another probability is familial cancer syndromes in this case as a predisposing factor superimposed by acquired factors like immunmodulation due to transfusion and viral factors such as HCV infection. The probable mechanisms for occurrence of malignancy in the girl with β-thalassemia intermedia could be the same as general population or as a result of prolonged treatment with hydroxyurea for at least 4 years. There is also a report in the literature of a patient with sickle cell disease who developed acute myeloid leukemia after 2 years of hydroxyurea therapy [14]. The short interval between treatment with hydroxyurea and occurrence of leukemia more strongly suggests of therapy-related leukemia. Our first case had prolonged hyperferritinemia and also was receiving iron chelation treatment with desferrioxamine for a long time. The effects of iron over load and treatment with iron chelating agents could be another hypothesis for development of malignancies in these patients [15]; however, low incidence of malignancies still suggest coincidental occurrence of these conditions and none of these theories could be confirmed unless prospective cohort studies with large control groups are designed and performed.

In conclusion, malignancies should be suspected and kept in mind in the patients with β-thalassemia syndromes presenting with new onset signs and symptoms including lymphadenopathy, leukocytosis and splenomegaly.