Radioactive Iodine–Related Clonal Hematopoiesis in Thyroid Cancer Is Common and Associated With Decreased Survival

Laura Boucai; John Falcone; Jenny Ukena; Catherine C. Coombs; Ahmet Zehir; Ryan Ptashkin; Michael F. Berger; Ross L. Levine; James A. Fagin

Disclosures

J Clin Endocrinol Metab. 2018;103(11):4216-4223. 

In This Article

Abstract and Introduction

Abstract

Context: Radioactive iodine (RAI) has been epidemiologically associated with the development of hematologic malignancies. Clonal hematopoiesis (CH) is a precursor clonal state that confers increased risk of leukemia and occurs at an elevated rate in patients with thyroid cancer relative to other solid tumors.

Objective: We explore if the high prevalence of CH may be a result of RAI exposure and whether CH may be a surrogate in the association between RAI and leukemia.

Design: CH, CH-potential driver (CH-PD), and overall survival were evaluated in 279 patients with advanced thyroid carcinoma.

Results: The prevalence of CH in patients with thyroid cancer was 37%, and that of CH-PD was 5.2%. Age was the strongest predictor of CH and CH-PD. For every year increase in age, there was a 5% and 13% increase in the odds of CH and CH-PD, respectively. RAI dose was significantly associated with CH and CH-PD, even after adjustment for age, external beam radiation therapy, and chemotherapy. For every 10 mCi increase in the dose of RAI administered, there was a 2% and 4% increase in the odds of CH and CH-PD, respectively. Patients with CH-PD previously exposed to RAI had a significantly poorer survival, even when stratified by age (heart rate = 3.75, 95% CI = 1.23 to 11.5, P = 0.02).

Conclusions: RAI was associated with a high prevalence of CH, and CH is a precursor state of hematologic malignancies. The implications of this study may favor identification of CH in patients where the risks might outweigh the benefits of receiving RAI therapy for thyroid cancer.

Introduction

Radioactive iodine (RAI) administration, following total thyroidectomy, has been traditionally used as an adjuvant treatment of all stages of well-differentiated thyroid carcinoma. More recently, the benefits of such therapy have been questioned in low- and intermediate-risk patients with thyroid cancer, given reports of marginal or no improvement of recurrence or mortality rates in this setting.[1–3] Based on these reports and others,[4,5] the American Thyroid Association and the National Comprehensive Cancer Network guidelines recommend a tailored administration of RAI based on a risk-adapted approach, where factors, such as risk of disease-specific mortality, recurrence, benefit in initial staging, and follow-up, are weighted against the potential side effects of RAI.

Complications from RAI range from minor short- and long-term sialadenitis, nasolacrimal duct obstruction, and reproductive disturbances to more serious but rare forms of leukemia, myelosuppression, and aplastic anemia.[6–10] When controlling for other treatment exposures and taking into account dose-response effects, RAI appears to confer a modest increased risk of secondary hematologic malignancies, particularly at higher dose exposures, as evidenced in multiple cohorts worldwide.[9–13] These studies have grouped all hematologic malignancies under one broad category, but a recent analysis from the Surveillance, Epidemiology, and End Results registries suggests that RAI is associated with an increased early risk of acute myeloid leukemia (AML) and chronic myeloid leukemia but not of leukemias of lymphoid origin or of multiple myeloma.[14]

Clonal hematopoiesis (CH) refers to recurrent somatic mutations in leukemia-associated genes that are commonly acquired in aging human hematopoietic stem cells. Large-scale studies of asymptomatic individuals without known hematologic disease have identified somatic mutations in DNMT3, TET2, and ASXL1 that promote clonal expansion of progenitor cells in the absence of overt hematologic transformation,[15–18] and these mutations persist over time. Healthy individuals with CH have been shown subsequently to develop hematologic cancers at a rate of ~0.5% to 1.0% per year compared with <0.1% in non-CH controls, and CH has been linked to decreased overall survival (OS).[15,16] Hence, CH is a precursor clonal state that confers increased risk of developing leukemia.

The prevalence of CH has been recently found to be 25% among patients with cancer, with 4.5% of these harboring presumptive leukemia driver mutations at higher clonal burden [CH-potential driver (CH-PD)].[19] The most common solid tumor associated with CH was thyroid carcinoma, with a prevalence of 36%.[19] CH was associated with increased age, prior radiation therapy, and tobacco use. CH and CH-PD led to an increased incidence of subsequent hematologic malignancies, and CH-PD was associated with shorter patient survival.[19] We designed the current study to explore why CH was enriched in patients with thyroid cancer. We hypothesized that the higher prevalence of CH among patients with thyroid cancer compared with other solid malignancies may be explained by the exposure of patients with thyroid cancer to RAI. If confirmed, CH may be a surrogate marker to validate the epidemiologic association seen between RAI and hematologic malignancies.

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