To Lighten the Burden of Cure: Thyroid Disease in Long-Term Survivors After TBI Conditioning for Paediatric ALL

Abstract

Thyroid disorders are well-studied after allogeneic haematopoietic stem cell transplantation (HSCT) following total body irradiation (TBI)-based conditioning, occurring in 15–30% of paediatric survivors. The toxic effect of TBI is known but data on the role of immunological dysregulation (ID) and chronic graft-versus-host-disease (cGvHD) are scarce. We studied functional and structural thyroid disorders in 97 paediatric ALL patients after TBI-based HSCT, assessing their correlation with patient/transplant characteristics including cGvHD, prolonged immunosuppression and ID. The 10- and 15-year cumulative incidence (CI) of functional disorders was 50 and 60%. Univariate analysis revealed TBI in 6 vs. 8 fractions (p = 0.01), an interval between ALL diagnosis and HSCT <1 year (p = 0.038), and the application of ATG (p = 0.044) as risk factors. The 10- and 15-year CI of structural disorders was 60 and 80%. No correlation between patient/transplant characteristics and structural disorders was observed. cGvHD, prolonged immunosuppression and additional radiotherapy were not associated with any thyroid disease. We observed a significant correlation between ID and the development of thyroid dysfunction in patients with structural changes (10-year CI: 77% for patients with ID vs. 56% without ID, p = 0.02). The impact of our results on thyroid follow-up evaluations and the significance of hormonal replacement therapy are discussed.

Thyroid function disorders and secondary cancer following haematopoietic stem cell transplantation in pediatrics: State of the art and practical recommendations for a risk-based follow-up

“…As a result of a 20-year systematic endocrine follow-up held on a cohort of 244 survivors transplanted during childhood or adolescence in our institution, we have previously reported hypothyroidism with a prevalence of 17.2% (non-autoimmune 14.3%; autoimmune 2.9%) and with 10-year and 15-year cumulative incidences as high as 22.5% and 34.0%, respectively ( 18 ). These data are consistent with those reported by other authors in the setting of late effects assessment ( 19 , 20 ).…”

“…The reported 10-year cumulative incidence of either autoimmune or non-autoimmune primary hypothyroidism in cohorts of patients conditioned with TBI in childhood or adolescence for ALL ranges from 26 to 50%, with most of this variability depending on the decision to either include or exclude those patients previously exposed to cranial prophylactic radiotherapy as a part of front-line therapy prior to conditioning ( 15 , 18 , 19 , 38 ).…”

“…Few published cases reported thyroiditis in the setting of chronic GvHD and these findings have led some authors to speculate that the phenomena of immune reconstitution and dysregulation following GvHD may play a causative role on the pathogenesis of autoimmune thyroid disorders ( 61 , 62 ). Conversely, most authors have challenged the hypothesis that GvHD may act per se as an independent causative factor for the development of autoimmune thyroiditis, whereas conflicting outcomes have been reported about the detrimental role played on thyroid health by immunosuppressants administered to control GvHD ( 19 , 63 ). In a homogeneous cohort of 97 pediatric ALL patients, Zubarovskaya and colleagues found that neither prolonged immunosuppression nor chronic GvHD were positively associated with TD, while the administration of anti-thymocyte globulin (ATG), used in the early prophylaxis of GvHD, was regarded as a detrimental factor on thyroid function ( 19 ).…”

“…Conversely, most authors have challenged the hypothesis that GvHD may act per se as an independent causative factor for the development of autoimmune thyroiditis, whereas conflicting outcomes have been reported about the detrimental role played on thyroid health by immunosuppressants administered to control GvHD ( 19 , 63 ). In a homogeneous cohort of 97 pediatric ALL patients, Zubarovskaya and colleagues found that neither prolonged immunosuppression nor chronic GvHD were positively associated with TD, while the administration of anti-thymocyte globulin (ATG), used in the early prophylaxis of GvHD, was regarded as a detrimental factor on thyroid function ( 19 ). The authors speculated that the gland may be adversely affected by the systemic inflammatory response elicited by complement-dependent T-cell lysis and subsequent massive release of cytokines and chemokines that follows ATG administration.…”

“…Several studies have assessed the occurrence of thyroid nodules, either benign or malignant, among long-term survivors of pediatric HSCT, with a reported overall incidence ranging from 0 to 27%, due to differences in the composition of study cohorts, underlying diseases, conditioning regimens and duration of follow-up ( 18 , 19 , 26 , 39 , 57 , 81 ). Interestingly, it has been reported that the cumulative incidence of nodules tends to be low in the first few years after HSCT, with a progressive increase as time elapses following transplantation, with a median time between HSCT and the detection of nodules ranging from 5 to 9.9 years ( 18 , 19 , 26 , 57 , 78 , 79 , 81 , 82 ). Consistently, the detection of thyroid nodules has been reported as late as three decades following transplantation.…”