Thalassemia is a somewhat rare genetic disorder characterized by lower production of the oxygen-carrying protein hemoglobin as well as of fewer and abnormal red blood cells. There are two main types of the disorder, alpha thalassemia and beta thalassemia, the severity of which depends upon the number of genes absent to produce alpha globin (four genes) or the type of mutation affecting beta globin (two genes).
Treatment for this disorder mainly includes blood transfusions, folic acid supplementation, and iron chelation therapy with agents such as deferoxamine, deferiprone, or deferasirox. In some instances, a bone marrow transplant may be performed, particularly for children and adolescents.
Among the complications that may arise in thalassemia patients is severe iron overload, resulting from the transfusions, which can cause heart or liver disease, infections, osteoporosis, and symptomatic splenomegaly. If the spleen becomes overly enlarged, surgical removal may be necessary, which then puts the patient at an increased risk for infectious and thrombotic complications.
Effective therapies such as iron chelation and other supportive measures have had a substantial impact on longer survival for thalassemic patients and, consequently, many more reach late adulthood and may develop different neoplastic disorders. However, a thorough investigation of the occurrence of neoplasms in this patient population has not been undertaken.
Consequently, a study was initiated by Argiris Symeonidis, MD, PhD, Professor of Hematology, University of Patras in Greece, and fellow colleagues all over that country, to evaluate the frequency of neoplasms in thalassemia patients.
“Regarding hepatocellular carcinoma (HCC) and presence of hepatitis C virus (HCV) infection,” Symeonidis stated, “although the majority of thalassemia patients have been infected before 1993, there was not a time-dependent increase in the incidence of HCC and the manifestation of hepatocellular carcinoma was not related to the more or less active hepatitis infection, the duration of the chronic infection, or any specific viral genotype.”
When asked about the research setting, Symeonidis replied, “Our department consists of an in-hospital ward with 25 beds and an average covering of about 130 percent; a stem cell transplantation unit with six beds in laminar air flow rooms; a thalassemia and hemoglobinopathies unit, which accepts about 30 outpatients on a daily basis and transfuses about 70-75 percent of them; a day clinic in which about 20-30 outpatients are receiving courses of chemotherapy or other types of parenteral treatment (immunotherapies, IV immunoglobulin, enzyme replacement therapies, etc.); and one outpatient clinic providing diagnosis and treatment to chronically ill patients on average 40-50 every day.
“Our thalassemia unit has a leading role in the area of Western Greece and accepts patients treated and transfused at smaller hospitals, which are referred for consultation, upon specific clinical problems; focusing on our patient population with hemoglobinopathies, we regularly treat 180 and provide consultation to additional 140 at regular intervals.”
About the trends at these clinics, Symeonidis commented, “We have been pleased to note over the last 2 decades that there has been a continuous improvement in patient overall survival time, so that the majority enter the seventh decade of life; as a result of this prolongation of survival, the last decade we have had several patients diagnosed with a neoplastic disorder.
“The most common type of cancer in this patient population is of course HCC, and as potential causative factors, hepatitis B virus (HBV) and HCV infection, as well as increased liver iron load have been proposed,” he explained. “Besides this type of cancer, the last decade we have diagnosed several patients with hematological malignancies (mainly B-cell lymphomas), as well as with thyroid cancer.
“In view of the absence of sufficient published information, two other colleagues and I decided to perform a national retrospective survey in Greece (where the managing of patients with thalassemia and hemoglobinopathies is rather well-organized) and investigate the frequency of neoplastic disorders occurring in this patient population.”
In their earlier work, Symeonidis stated that the researchers “initiated a pilot program in five larger hospitals of the country collecting information on all thalassemic patients diagnosed with a neoplastic disorder. Among 1,972 patients, we have identified 38 cases with a neoplastic disorder.”
“The goal of this retrospective, descriptive, epidemiological study was to describe the frequency of specific neoplastic disorders and their potential predisposing factors among the Greek patient populations of various hemoglobinopathies,” Symeonidis explained.
Data from 3,813 patients followed between 1985 and 2018 were included in this study. Patients were divided into four different groups: Group I–beta-thalassemia homozygous, N=2,100; Group II–thalassemia intermedia (i.e., not completely transfusion-dependent), N=774; Group III–sickle cell disease +/- beta-thalassemia, N=764; Group IV–hemoglobinopathy-H, N=175.
“In Group III, 16 patients with homozygous sickle cell disease have been included, as it is clear the majority of Greek patients with sickle cell disease are double heterozygotes (thalassemia/sickle cell disease),” Symeonidis stated.
“We approached all the existing thalassemia and hemoglobinopathy treating centers in Greece, a total of 38, and we asked the doctors to retrieve all the medical records of the patients diagnosed and followed, and [then] verify if they had manifested any neoplastic disorder between Jan. 1, 1985, and June 30, 2018, (for the abstract) or Oct. 31, 2018 (for the poster).”
The prevalence of each type of neoplasia and the whole number of neoplastic disorders was described for each of these four groups. “We only collected histologically confirmed diagnoses, not speculative or vaguely described cases,” Symeonidis stated. “However, cases of in situ described neoplasias or of basal cell carcinoma of the skin were not collected.” Physicians were also asked to provide medical information on the specific disease background and patient background and profile, including the possible existence predisposing factors.
“From the available patient information,” he explained, “we investigated the presence of the 13 well-characterized, underlying, potential predisposing factors, including familial history of neoplasia; occupational exposure to known mutagens; previous autoimmunity; previous splenectomy; tobacco smoking; alcohol use; HBV, HCV, or HIV infection; iron overload; hydroxyurea treatment; previous irradiation for extramedullary hematopoietic tumors; and systemic use of androgens/estrogens.”
“Initially, 28 thalassemia units responded to our requests and, from that, we constructed the abstract for our presentation, reporting 165 documented cases among 3,562 patients. However, by the time the poster was created, an additional six units treating 161 patients had responded, so that finally we have presented data from 33/38 thalassemia units, in which 174 cases of neoplastic disorders have been diagnosed among 3,813 patients,” Symeonidis clarified. “Since these figures represent about 85-87 percent of the total Greek thalassemia patient population screened, these data are considered fully representative of the whole country.”
Regarding their results, “We found higher prevalence of neoplasia among patients of the Groups I and II (4.95% and 5.04%, respectively vs. 3.40% and 2.29% among patients of the Groups III and IV, p<0.05). Of the 174 cases of neoplastic disorders, the majority of cases were solid tumors (N=148 or 85%) and the remaining were hematological malignancies (N=26 or 15%).”
When noting the study's most interesting findings, Symeonidis stated, “As expected, the dominant malignancy was HCC diagnosed in 66 patients, followed surprisingly by thyroid cancer (N=18), non-Hodgkin lymphoma (N=13), and renal cell carcinoma (N=11). There was a strong positive association between HCV infection and HCC, and a negative one between HCV infection and thyroid and renal cancer, meaning that the latter two types of malignancies were mainly diagnosed among thalassemic patients not infected by HCV. Of particular interest, lung cancer was only classified in the tenth place of most frequent neoplasms, despite the fact that about 35-40 percent of the tested population were cigarette smokers.”
About the correlation between HCV infection and HCC, he noted, “Active HCV infection was found in 91 patients overall (52.3%) who had received multiple transfusions, compared to an estimated prevalence of about 25 percent among the whole thalassemic patient population.
“HCC was more frequently diagnosed in men with a male-to-female ratio of 2:1, typically in the fourth and the fifth decade (median age–45 years) with thalassemia homozygous or intermedia (92% of the cases), and with long-standing, untreated HCV infection (76%), irrespective of the burden of hepatic iron load (estimated with MRI T2∗).”
“Indeed, no difference in the prevalence of HCC, as well as of any other type of cancer, was found in relation to liver iron concentration,” Symeonidis stated. “Moreover, no preponderance of any HCV genotype was identified, but interestingly, all 1b HCV genotype-associated neoplasms were HCCs (seven cases). Finally, no association between any of the remaining potential risk factors with the manifestation of any specific neoplastic disorder was observed.”
“Since the association of HCV infection with HCC is well-known and has been confirmed,” Symeonidis noted, “the most important findings of this survey to my opinion are:
- the absence of direct association between iron overload and HCC;
- the emergence of rarer cancers for the general population, such as thyroid and renal cell cancer in the second and the fourth place of higher frequency;
- the higher-than-expected prevalence of cancers of lymphoid origin; and
- the absence of association of any other of the tested potential predisposing factors with the manifestation of any type of cancer.”
“This is particularly interesting because some treatment options for these patients (e.g., the routine use of hydroxyurea, the administration of low doses or gamma irradiation to eliminate extramedullary hematopoietic tumors, and the administration of exogenous hormonal medications to facilitate fertility) may still be administered or applied with some degree of skepticism and a deeper anxiety of the caregiver and the patient. Another important observation is the relatively low prevalence of hormone-related cancer, such as breast cancer, ovarian cancer, and testicular cancer.
“Potential limitations of our analysis might be the relatively low proportion of patients with heavy liver iron overload, particularly after the broad application of oral iron chelators deferiprone and deferasirox, as well as the smaller period of time (almost only 1 decade) for which we have in our hands quantification of the liver iron stores, estimated with MRI T2∗. If we could have been able to have data with MRI-T2∗ for longer periods, then our findings of the absence of association of liver iron overload and HCC would be stronger.”
When asked what conclusions could be drawn from the neoplasms observed in their study, Symeonidis replied, “We need to further investigate and understand why thyroid cancer, B-cell malignancies, and renal cell cancer show higher-than-expected prevalence, and to identify other obscure predisposing factors. To do this, we need a deeper histological analysis of these neoplasms and a prospective case-control study, with a comparator arm of non-thalassemic patients.
“We also need to see whether our findings will be confirmed by other countries with high prevalence of thalassemia, because, as I have mentioned previously, we do not have published information on this issue as yet.”
Concerning the presence of B-cell malignancies, he observed, “The high frequency of B-cell lymphoproliferative disorders implies the existence of possible underlying immune deficiency. This might be a result of frequent RBC transfusions, which these patients receive, since it has been confirmed that chronic and repeated transfusions induce immunosuppression. Although the precise underlying mechanism has not clearly identified, it has been assumed that this emerges as a result of chronic and repeated antigenic stimulation.”
In their own research, “We have recently demonstrated that thalassemic patients that have had multiple transfusions develop long-term microchimerism, which is not prevented by any filtration system; this work has been presented at the ASH 2017 Meeting (Blood 2017;130:3740).
“It is therefore possible that allogeneic soluble DNA or nucleoprotein molecules provide chronic antigenic stimulation, which finally induce tolerance and immunosuppression, and permit the emergence and perpetuation of clonal B-lymphocytes and hence of B-lymphoproliferative disorders.
“Our findings will definitely have an impact on the care of thalassemia patients,” Symeonidis stated. “First, there is a prominent need for elimination of HCV infection by using the newer anti-HCV agents such as daclatasvir, sofosbuvir, bocebrevir, or telaprevir. Indeed, there is a national program against hepatitis C and by now about 70 percent of the patients have been treated. It is anticipated that, during 2019, the remaining patients will take advantage of this program and they will be effectively treated. We therefore, need to see whether the elimination of the HCV from the thalassemic patient population will be followed by a decrease in the incidence and prevalence of hepatocellular carcinoma. At this point, our study could be used as a historical marker representative of the era before effective HCV treatment.
“Second, the demonstration of high frequency of thyroid and renal cell cancer, as well as of lymphoproliferative disorders of B-cell origin among thalassemics, will alert both patients and treating physicians (hematologists or pediatricians) to seek routine expert evaluation for those patients at normal intervals, even for primary prophylaxis, in the absence of any suspicious relevant symptom or sign,” Symeonidis explained.
“Finally, the higher-than-expected frequency of B-cell lymphoproliferative disorders as a result of possibly multi-transfusion-associated immunosuppression might force caregivers to alter their transfusion policy and establish as a task the restriction or the complete abolishment of RBC transfusion, where possible, in particular with the emerging application of the newer drugs, activin-receptor ligand traps, such as luspatercept, in an effort, not only to restrict transfusions and improve the quality of life of thalassemic patients, but most importantly, to restrict the late and devious adverse effects of them.”
When queried as to the next logical steps to their research, Symeonidis replied, “We have first to fulfill our national survey and publish these results, and then we have to focus on the most common neoplastic disorders and try to more deeply analyze the underlying pathogenesis, i.e., if this could be related to conditions existing or iatrogenically induced in thalassemic patients.
“To this point, prospective case-control studies might be useful to demonstrate any real predisposition of thalassemic patients towards the development of specific types of cancer such as thyroid and renal cancer as well as B-cell lymphomas. Finally, we could ask colleagues from neighboring countries with high prevalence of thalassemia, such as Italy, Turkey, Lebanon, Cyprus, and Egypt, to see their populations, extract their epidemiological data, and perform comparative analysis as was done with our data.”
Richard Simoneaux is a contributing writer.