A higher prevalence of hematologic malignancies in patients with thalassemia: Background and culprits
Authors: Racha Halawi, Maria D. Cappellini, Ali Taher
Journal: American Journal of Hematology (2017)

Thalassemia is a spectrum of clinical presentations that extends from asymptomatic carriers, namely α and β-thalassemia minor, to the transfusion dependent thalassemias (TDT) which include individuals with β-thalassemia major, Bart's Hemoglobin, and severe forms of HbE/β-thalassemia. Non-transfusion dependent thalassemia (NTDT) is a condition in between that does not require blood transfusions except during periods of acute stress or in the event of growth failure; the most common subgroups of NTDT are β-thalassemia intermedia, Hemoglobin H disease, and mild to moderate forms of HbE/β-thalassemia. The prevalence of thalassemia in Northern Europe and North America has been on the rise, making this condition a global concern. With the optimization of transfusion programs and implementation of iron chelation therapy in 1975 with Deferoxamine, the life expectancy of patients with thalassemia has been extended secondary to a reduction in deaths due to anemia and cardiac dysfunction. This increase in life span has paved the way for the development and subsequent diagnosis of more cancers, some of which may go undetected if the presenting signs such as anemia and splenomegaly are attributed to the thalassemia itself. Hematologic malignancies have been reported in patients with TDT and NTDT in two large scale studies conducted in Iran and in Taiwan, and in several case series and case reports. In a multicenter retrospective study conducted between 2002 and 2007, Karimi et al. examined the co-occurrence of cancer and thalassemia in four centers spread throughout Iran and compared them to the age-specific rates.1 The population of interest included 4630 patient records, 88% with thalassemia major and 12% with thalassemia intermedia, with a mean age of 24.5 ± 1.5 years. Eleven cases of malignancies were detected, 10 of which were hematologic and consisted of 5 leukemias and 5 lymphomas. The age-specific rates of cancer incidence in this article were greater than the cancer incidence reported in the general population in Southern Iran which was considered an appropriate comparison group. The proportion of the diagnosed hematologic malignancies was higher in patients with thalassemia intermedia than in those with thalassemia major. There was no statistically significant association between the type of malignancy and that of thalassemia in this small pool of patients with cancer. In a nationwide cohort study conducted in Taiwan between 1998 and 2010 using the Longitudinal Health Insurance Database, 2655 patients with thalassemia (unknown subtypes, mean age 34.6 years) were compared with an age and gender matched cohort of 10 620 people from the general population.2 Overall, the incidence of cancer was 52% higher in the thalassemia cohort than in the comparison cohort, and more specifically, there was a 5.32-fold increased risk for hematologic malignancies compared with a 1.96-fold increased risk for gastrointestinal cancers. Also, patients with thalassemia receiving transfusion therapy with packed red blood cells were 9.31-fold more likely to develop a hematologic malignancy compared with those who were not receiving this treatment modality. Although the results of this observational study are quite remarkable, a few limitations could alter the conclusions derived from these numbers. For instance, it is questionable whether the pool of thalassemia patients represents all the spectrum of this disease given that most of them were diagnosed at >20 years of age, potentially underestimating the real incidence of cancer since all TDT and a fraction of NTDT manifest before the age of 20. In addition, because Taiwan has a high prevalence of α- and β-thalassemia traits, an association between thalassemia traits and cancer may be underestimated as those genotypes may be inadvertently included in the control cohort arm. Finally, this study does not offer a description of the types of hematologic malignancies that were noted, which limits the scientific community from deriving any potential associations. Patients with thalassemia are now living longer as a result of appropriate transfusion therapy and iron chelation. However, a new set of complications such as cancers are being increasingly diagnosed as patients with thalassemia grow older. While the increased prevalence of solid cancers, most notably hepatocellular carcinoma secondary to hepatitis C and iron overload, has been noted, the occurrence of hematologic malignancies has been proposed to be even higher.1, 2 Interestingly, sickle cell disease, a qualitative disease of the hemoglobin, has also been found to exhibit an increased risk of malignancies overall and mostly hematological.3 Despite the differences in pathophysiology, thalassemia and sickle cell disease are both associated with iron overload and share similar modalities of treatment such as blood transfusions. It is therefore plausible that several mechanisms, aside from the increase in lifespan, may be implicated in increasing the risk of cancers in general and hematologic malignancies in particular (Figure 1). Proposed mechanisms implicated in the development of hematologic malignancies in patients with thalassemia. [Color figure can be viewed at wileyonlinelibrary.com] Patients with TDT and NTDT are at a substantial risk for developing iron overload. Whereas the etiology in the former is chronic blood transfusions, iron overload occurs in the latter secondary to hepcidin suppression by anemia and ineffective erythropoiesis, resulting in increased iron absorption from the gut as well as its release from the reticuloendothelial system. Generally, when the iron binding capacity exceeds 75%, non-transferrin bound iron (NTBI) becomes present in the plasma along with its redox active labile plasma iron (LPI). This results in increased levels of storage iron and labile cellular iron which is toxic and redoxactive. When the level of labile cellular iron increases beyond the ferritin synthesizing capacity of the cells, reactive oxygen species may be generated leading to mutations, cell death, and organ damage. In patients with thalassemia, a host of organs are affected by iron toxicity resulting in several complications such as cardiomyopathy, cirrhosis, and endocrinopathies. There is also data to suggest correlation between iron overload and the development of hepatocellular carcinoma, but the role of iron overload in the development of hematologic malignancies has not been formally investigated in thalassemia. Studies in the MDS population suggest that iron overload mediated by NTBI/LPI aggravates genomic instability of this pre-leukemic state hence contributing to the development of AML and accelerating transformation to acute leukemia, as well as plays a role in disease progression, relapse, and survival in patients following allogeneic hematopoietic stem cell transplantation.4 Iron overload has also been proposed to trigger an immune regulatory imbalance such as a decrease in antibody mediated immune responses, altered T cell ratios, and modulation of cytokine activity, all of which may promote cancer development.5 In patients with thalassemia, establishing a relationship between iron overload and the development of hematologic malignancies will require large scale studies. Of note, while ferritin could be used to estimate the iron stores in patients with thalassemia major, evaluation of iron stores in patients with NTDT is more complex and requires imaging, complicating the acquisition of data in areas with limited resources. Blood transfusions are associated with the transmission of oncogenic viruses that may trigger the development of hematologic malignancies. Herpes viruses such as Epstein-Barr virus and Cytomegalovirus have been detected in patients with thalassemia receiving transfusions and are known to be associated with either Hodgkin's or non-Hodgkin's lymphoma. Similarly, the Human T-lymphotropic virus type-1 (HTLV-1), is a virus that is implicated in the development of adult T-cell lymphoma/leukemia and has been detected in patients with thalassemia receiving blood transfusions. When compared with blood donors, U.S. thalassemic patients exhibited a significantly higher seroprevalence of HTLV-1, but the transmission was thought to have occurred prior to the implementation of blood product screening for HTLV-1 in 1988.6 It has been suggested that these oncogenic viruses contribute to lymphomagenesis by directly promoting lymphocyte proliferation through oncogene expression or apoptosis inhibition or by providing a chronic source of antigenic stimulation hence increasing the proliferation rate.7 While no association could be derived, it is important to reiterate that patients with thalassemia receiving blood transfusions were found to be at a 9.31-fold increased risk of developing hematologic malignancies compared with their non-transfused counterparts.2 Since this finding could be linked to the transmission of oncogenic viruses, it is important to mention that there are increasing efforts to provide safe blood transfusions to patients with thalassemia, such as HTLV-1 testing in the United States and other countries in Europe, East Asia, and the Middle East. A host of abnormalities involving the immune systems have been described in patients with thalassemia who are receiving blood transfusion therapy. Some of these alterations involve the B lymphocytes which are activated, higher in numbers, and characterized by impaired differentiation and increased level of immunoglobulins, as well as defects in chemotaxis and phagocytosis, all thought to be stemming from chronic exposure to antigenic stimulation via blood transfusions.8 Leukoreduced blood may be associated with less immunomodulation and less cancer recurrence, however the data is old, limited, and inconclusive.8 While no correlation could be derived unless one conducts a randomized study comparing different transfusions strategies (allogenic vs. autologous with options of leukoreduced and non-leukoreduced blood), it remains important to restrict blood transfusions to protocol guidelines in TDT and only when indicated in NTDT, as well as to transfuse leukoreduced blood. Hydroxyurea is an antimetabolite used for decades in patients with myeloproliferative diseases and sickle cell anemia. Hydroxyurea is also utilized in the thalassemia realm in order to decrease transfusion needs. It interferes with both DNA synthesis and repair mechanisms leading to the accumulation of mutations and subsequent chromosomal damage. Clinically, concerns have been raised regarding the carcinogenic potential of this drug. No studies have yet investigated the relationship between hydroxyurea and the development of cancers in thalassemia, but since it is one of the mainstays of treatment of sickle cell disease, similar concerns have emerged with regards to its leukemogenic potential in that population. This was refuted in the BABY-HUG clinical trial which did not suggest any increased risk of genotoxicity compared with placebo treated controls.9 Overall, there is no evidence to suggest an increased risk of carcinogenesis in patients with thalassemia or sickle cell disease treated with hydroxyurea and further studies will need to be designed to establish any potential relationship. Patients with thalassemia major who are inadequately transfused exhibit dramatic expansion of their hematopoietic marrow as well as extramedullary hematopoiesis. Red blood cell transfusions significantly decrease ineffective erythropoiesis, limiting these complications. Patients with NTDT are by definition a chronically anemic population that does not receive regular blood transfusions, resulting in hypoxia and ineffective erythropoiesis, and ultimately inducing a JAK2/STAT5-erythropotein driven erythroid hyperplasia. It is possible that the increased bone marrow stimuli implicated in the proliferation of erythroid progenitor cell lines are also resulting in the expansion of other cell lines, potentially inducing genetic aberrations implicated in the development of hematologic malignancies. In fact, both CD34+ cells and colony forming units-granulocyte/macrophage (CFU-GM) were increased in the blood of patients with thalassemia compared with non-thalassemic controls, also more so in splenectomized patients.10 One may suggest that the increased proliferation of progenitor cells may underlie the putative propensity of thalassemic patients to develop hematologic malignancies but this is a largely underexplored hypothesis. The study of the association between thalassemia and hematologic malignancies continues to be in its early stages. The host of cases reported to date are shedding further light on this issue, and the two available retrospective studies conducted in Iran and Taiwan have suggested that patients with thalassemia are at a higher risk for developing hematologic malignancies compared with the general population, and that the risk may even vary based on thalassemia type and transfusion status. While it is possible that these malignancies are manifesting and becoming more apparent due to the significant increase in life span of this population, a number of potential predisposing risk factors do exist. In fact, the shared concern in patients with sickle cell disease certainly encourages us to continue to explore this field and strengthen the evidence. Furthermore, while some mechanisms may explain the development of those cancers in patients with TDT and NTDT, it is yet unclear whether the reports of patients with thalassemia traits are of any significance or are just due to coincidence. Further elucidation of any existing correlation requires long-term follow-up of a very large sample of patients with thalassemia, in order to yield a sizeable number of malignancies. Regardless, it is imperative to remain very attentive to any new signs or symptoms patients with thalassemia may develop such as fevers, fatigue, splenomegaly as those may be the manifestation of an underlying malignancy.