“The medical condition of thalassemia with iron overload is a well-recognized model of [a condition associated with] risk for liver cancer. Investigation into possible causes or mechanisms might be very fruitful in this model to tease out cause and effect and develop intervention studies to prevent and treat cancer,” Dr Samaniego told Hematology Advisor.

Dr Taher and colleagues theorized that some mechanisms that may contribute to an increased risk of malignancy in patients with thalassemia include iron overload-induced oxidative damage, immunologic aberrancies, immunomodulation caused by transfusions, and viral infections. Other contributing factors could be hydroxyurea use and bone marrow stimulation due to chronic anemia. In addition, blood transfusions carry a risk of oncogenic virus transmission that can lead to the development of a variety of malignancies. There are concerns about hepatitis C virus, which is correlated with hepatocellular carcinoma, and cytomegalovirus and Epstein-Barr virus, which are associated with lymphoma.

Additional Perspectives

A recent Greek study included a significant number of patients with thalassemia who died from causes related to hepatocellular carcinoma. A separate study showed that lymphomas and leukemias were more frequent in patients with thalassemia. However, many of the studies cited in this review included very few patients. “The authors [Dr Taher and colleagues] give apparently equal weight to good solid numbers and to meaningless numbers and mentioning of case reports. In order to accept the incidence of the particular medical problem being higher in one particular group, we need to know the number of cases,” argued Dr Samaniego

Richard J Jones, MD, professor of oncology and codirector of the Hematologic Malignancies Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, agreed that this review is hampered because of the scarcity of data on malignancies in this patient population. “The numbers are very small and, with the change in treatment paradigms for this disease, would only be useful if the increase in malignancy is real and not a statistical fluke,” Dr Jones told Hematology Advisor.

He noted that the increased risk for malignancy could be due to increasing lifespan rather than iron overload as the latter may be going away with new treatments. Additionally, he said many more questions need to be answered. “I’m afraid that in the absence of some insights here, [this review] may be raising issues that don’t really exist,” said Dr Jones.

Conversely, Radhika Gangaraju, MD, assistant professor of hematology-oncology at the University of Alabama at Birmingham, said this study is an important first step toward teasing out emerging trends as life expectancy continues to increase in patients with thalassemia. “The majority of case reports consist of hepatic cancer or lymphomas, and the authors have nicely elaborated on the mechanism of development for these tumors. As we know, patients with thalassemia develop transfusion-associated iron overload, which is associated with the risk of hepatocellular carcinoma, and periodic ultrasounds are done to monitor for this risk,” she said.

Charles Parker, MD, professor of medicine at the University of Utah in Salt Lake, added that cancer is a disease of aging. “As the lifespan of patients with thalassemia increases, the risk for malignancy among these patients increases, and therefore cancer surveillance is warranted accordingly. However, additional studies are needed to determine whether guidelines for cancer screening for patients with thalassemia should be modified beyond current recommendations for disease type and age,” Dr Parker said.

Reference

1.      Hodroj MH, Bou-Fakhredin R, Nour-Eldine W, Noureldine HA, Noureldine MHA, Taher AT. Thalassemia and malignancy: An emerging concern? [published online June 22, 2019]. Blood Rev. doi:10.1016/j.blre.2019.06.002