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


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

In This Article


A total of 309 patients with thyroid carcinoma underwent MSK-IMPACT testing between 16 May 2014 and 20 July 2017. The overall prevalence of CH was 37% (115/309 patients) and that of CH-PD was 5.2% (16/309). Table 1 shows the prevalence of CH and CH-PD according to histologic subtype. There was no statistically significant difference in CH or CH-PD among the different subtypes of thyroid carcinoma. Ten percent of our patients (n = 30) had medullary thyroid carcinoma. Because patients with medullary thyroid carcinoma do not receive RAI as part of their treatment, they were excluded from our subsequent analyses. Out of 47 patients with anaplastic thyroid carcinoma, 10 (21.3%) had received RAI. The proportion of patients with anaplastic thyroid carcinoma who developed CH or CH-PD was comparable with the overall cohort, and therefore, they were included in our analyses. A total of 279 patients with follicular cell-derived thyroid carcinoma were analyzed.

The median age of our population was 64 years (median, interquartile range = 64, 57 to 71). Older age was significantly associated with the presence of CH and CH-PD (Table 2). CH occurred more often in black patients and less often in Asians (P = 0.023). We did not find a statistically significant association between smoking status and CH (P = 0.916). Seventy-five percent of our population was treated with RAI. A higher administered dose of RAI was significantly associated with CH and CH-PD. The median time from exposure to RAI to testing for CH or CH-PD was 1349 days (minimum 19 days; maximum 12,691 days). Other therapies, including external beam radiation therapy (EBRT) and chemotherapy, were not significantly associated with CH or with CH-PD (Table 2).

To explore further the association between administered dose of RAI and CH or CH-PD, we built multivariate logistic regression models (Table 3). We found that age and dose of RAI were significantly associated with CH and CH-PD when adjusted for EBRT and chemotherapy. Specifically, for every year increase in age, there was a 5% increase in the odds of having CH and a 13% increase in the odds of having CH-PD when adjusted for RAI administration, EBRT, and chemotherapy. RAI was also independently associated with CH and CH-PD. For every 10 mCi increase of RAI administered, there was a 2% increase in the odds of having CH and a 4% increase in the odds of having CH-PD when adjusted for age, EBRT, and chemotherapy. There was no significant association between EBRT or chemotherapy and CH or CH-PD (Table 3).

We next sought to identify any potential associations among RAI, CH, and leukemia. We only had one CH-positive case of myelodysplastic syndrome, one CH-negative case of myelofibrosis, and two of monoclonal gammopathy of uncertain significance in the follow-up period (one CH positive; one CH negative). We found higher median doses of RAI administered to patients who subsequently developed these hematologic disorders compared with those who did not (316 vs 151 mCi), but this association was not statistically significant (P = 0.27). This may be, in part, a result of the short follow-up period of our cohort.

We assessed whether the presence of CH had an effect on OS. With the consideration of the entire population, we did not find a statistically significant association between CH and OS [heart rate (HR) = 1.3, 95% CI = 0.76 to 2.32, P = 0.319]. However, among patients who had been exposed to any dose of RAI, CH conferred a borderline, significantly poorer survival (HR = 2.16, 95% CI = 0.95 to 4.94, P = 0.06). This weak association did not persist after stratifying by age (P = 0.11). CH-PD had a borderline-significant association with decreased OS in the overall cohort (HR = 2.4, 95% CI = 0.96 to 6.2, P = 0.06), but when considered only for patients exposed to RAI, CH-PD had a strong association with adverse survival (HR = 4.1, 95% CI = 1.4 to 12.1, P = 0.01), which persisted after stratifying by age (HR = 3.75, 95% CI = 1.23 to 11.5, P = 0.02). Figure 1 shows Kaplan-Meier survival estimates of patients exposed to RAI with and without CH-PD. Figure 1A shows the entire cohort of patients, and Figure 1B shows patients with differentiated thyroid carcinoma, excluding those with anaplastic thyroid cancer.

Figure 1.

Kaplan-Meier survival estimates of patients exposed to RAI, with and without CH-PD. (A) Entire cohort; (B) excluding patients with anaplastic thyroid carcinoma (ATC). DTC, differentiated thyroid carcinoma.