The full spectrum of thyroid late effects following hematopoietic stem cell transplantation in pediatrics: insights from a large multicenter cohort

Introduction Thyroid disorders are among the most prevalent late sequelae of hematopoietic stem cell transplantation (HSCT). While total body irradiation (TBI) is an established risk factor, the toxicity of alkylating agent-based conditioning regimens remains poorly characterized. The present study aimed to: i) quantify the cumulative incidence (CI) of thyroid late effects in a large multicenter pediatric cohort; ii) identify the independent risk determinants of HSCT-related thyroid disorders; iii) assess the specific detrimental role of chemo-only conditioning regimens; iv) characterize longitudinal thyroid volumetric trajectories following HSCT. Methods Multicenter retrospective observational study enrolling 637 pediatric HSCT survivors transplanted between 1999 and 2023 across three referral Centers. Conditioning regimens included: TBI (40%), busulfan (32%), treosulfan (18%), other (10%). Endocrine surveillance encompassed 6–12-monthly thyroid function tests and ultrasound assessment over a mean follow-up of 11.0 ± 6.4 years. Results The 20-year CI achieved 43.1% for thyroid function disorders (TFD) and 71.2% for nodules. Concerning the conditioning regimen, the 20-year CI of TFD was 54%, 35% and 21% for TBI, busulfan and treosulfan, respectively (p=0.026). The CI of TFD was statistically lower following treosulfan than busulfan (p=0.039). Compared to treosulfan, both TBI (HR 2.39, p=0.006) and busulfan (HR 1.77, p=0.08) conferred an increased risk of TFD on multivariate analysis. Concerning ultrasonographic findings, the 18-year CI of thyroid nodules following TBI overtly exceeded chemo-only regimens, while treosulfan and busulfan showed comparable longitudinal trendlines (p 0.82). The right lobe anteroposterior diameter (RLD) Z-score was used as an indirect indicator of thyroid volume. Longitudinal ultrasonographic assessment revealed significantly greater RLD Z-scores following treosulfan compared with busulfan (p=0.002) and TBI (p<0.001). Finally, age<10 years at HSCT (p=0.013), severe graft versus host disease (p=0.036), TBI (P = 0.05) and elevated BMI (p=0.04) were independent determinants of the need for hormonal replacement therapy. Conclusions Treosulfan-based conditioning is associated with the lowest cumulative functional thyroid morbidity and the most favorable longitudinal volumetric profile among myeloablative regimens, outperforming busulfan on both endpoints and a lesser degree of thyrocyte damage.