Hematologic malignancies in thalassemia: Adding new cases to the repertoire
Authors: Racha Halawi, Hassan Beydoun, M. Domenica Cappellini, Valeria Ferla, Ali Taher
Journal: American Journal of Hematology (2017)

Thalassemia is an inherited quantitative disorder of the hemoglobin that is among the most common genetic diseases worldwide. Clinically, thalassemia spans a spectrum encompassing asymptomatic carriers, individuals with non-transfusion dependent thalassemia (NTDT), and the chronically transfused with transfusion dependent thalassemia (TDT). The prevalence of this condition has been on the rise in North America and Northern Europe due to migration effect, making this disease a global concern. Several case reports describing the occurrence of hematologic malignancies in patients with thalassemia have been published in the literature and reviewed by Zanella et al.1 The association between thalassemia and hematologic malignancies has been investigated in two large scale cohort studies, both of which proposed an increased risk compared with the population.2, 3 In the Taiwanese cohort study, a 5.32-fold increased risk for hematologic malignancies was noted in patients with thalassemia when compared with an age and gender matched control cohort, which rose to 9.32 in those who are receiving transfusion therapy with packed red blood cells.3 The authors of this manuscript have previously published several cases of hematologic malignancies arising in patients with thalassemia, including Hodgkin's and non-Hodgkin's disease in TDT and NTDT.4, 5 In this correspondence, we report new cases diagnosed in the Milan Thalassemia Center in Italy, which currently treats 370 patients (215 with TDT and 155 with NTDT). To our knowledge, we are herein reporting the first cases of monoclonal gammopathy of undetermined significant (MGUS), diagnosed in four patients with thalassemia intermedia between the ages of 34 and 48 (Table 1). At the time of diagnosis, two out of the four patients were maintained on Hydroxyurea therapy, and three out of four had been exposed to blood transfusions at some point and received iron chelation. One patient had an active hepatitis C infection. These patients are currently being monitored and have not progressed to multiple myeloma. On the other hand, a 52-year-old female with HbH was found to have multiple myeloma after presenting with lymphadenopathy. This patient had been exposed to blood transfusions but never received iron chelation. In the same center, a 45-year-old female with HbE disease was diagnosed with AML following a work-up for fatigue and splenomegaly. This patient had negative EBV and CMV serologies and had not received blood transfusions nor iron chelation. The increase in lifespan of patients with thalassemia due to appropriate blood transfusion practices and iron chelation therapy has paved the way for the emergence of a host of complications such as cancer. The occurrence of solid malignancies and most notably hepatocellular carcinoma has been studied in more depth in the thalassemia population, but based on the above-mentioned cohort studies, patients with thalassemia may be more prone to developing malignancies of the hematologic type. Different risk factors are thought to be implicated and include iron overload, blood transfusion mediated immunomodulation and transmission of viruses, Hydroxyurea, and bone marrow stress due to chronic anemia. Interestingly, patients with sickle cell disease share these risk factors and have been also noted to exhibit an increased risk of malignancies, mostly of the hematologic type.6 Aside from blood donor screening to decrease the risk of transmission of viruses such as HTLV-1, CMV, and Hepatitis C, optimization of iron chelation practices, and leukoreduction of the transfused blood, there are currently no specific recommendations as far as risk factor modification is concerned. There are no screening guidelines for hematologic malignancies in patients with thalassemia. While the association between thalassemia and hematologic malignancies remains in its early stages, it will be important to continue to explore the field and conduct more large scale studies with long-term follow-up. It is also paramount to remain very attentive to new signs and symptoms patients with thalassemia exhibit that may indicate a hematologic malignancy, with the understanding that some of these findings may overlap with those of thalassemia, such as worsening anemia, fatigue, and splenomegaly.