Blood Res 2013; 48(2): 149-151
Hematological malignancies complicating β-thalassemia syndromes: a single center experience
Samin Alavi1*, Alieh Safari2, Elham Sadeghi3, and Somayeh Amiri3

1Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2Tehran University of Medical Science, Tehran, Iran.

3Thalassemia Comprehensive Center, Mofid Children's Hospital, Shahid Beheshti Medical University, Tehran, Iran.

Correspondence to: Correspondence to: Samin Alavi. Pediatric Congenital Hematologic Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, PO Box 15468-15514, Tehran, Iran.
Received: February 7, 2013; Revised: May 28, 2013; Accepted: May 28, 2013; Published online: June 25, 2013.
© The Korean Journal of Hematology. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

TO THE EDITOR: Only few reports have addressed the occurrence of hematological malignancies in patients suffering from β-thalassemia. We herein report two patients with major and intermedia β-thalassemia who were complicated with Hodgkin's lymphoma and chronic myelogenous leukemia (CML) during the course of the disease, respectively. This report indicate that malignancies should be suspected and kept in mind in patients with β-thalassemia syndromes presenting with proposed signs and symptoms including unexplained lymphadenopathy, leukocytosis and splenomegaly.

β-thalassemia major is a genetic hemoglobinopathy characterized by point mutations of β-globin chain resulting in accumulation and deposition of unpaired β-globin chains in red blood cell (RBC). This causes severe hemolysis and ineffective hematopoiesis leading to severe anemia [1]. Currently the availability of proper care and appropriate treatment strategies including regular transfusions, allogeneic stem-cell transplantation, inducers of fetal hemoglobin, and precise iron chelation therapy with desferrioxamine (DFO) and/or deferiprone (DFP) have resulted in increased life expectancy and quality of life of the patients suffering from β-thalassemia major [2-4]. This increased life span increases the possibility of occurrence of other diseases such as malignancies. Although, previously malignancies were considered rare in β-thalassemia patients, but currently the number of malignancies reported in thalassemic patients is increasing [5-9]. We herein, report two patients with β-thalassemia major and intermedia who developed Hodgkin's lymphoma and chronic myelogenous leukemia (CML) during the course of the disease.

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 (βS0) 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.

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