Endocrinopathies Following Allogeneic Stem Cell Transplantation: 10 Years Follow-up in 402 Patients
Authors: Lupo Stanghellini Maria Teresa , Vita Giovanni , Assanelli Andrea , Lorentino Francesca , Serpenti Fabio , Greco Raffaella , Marcatti Magda , Giglio Fabio , Xue Elisabetta , Casirati Gabriele , Farina Francesca , Clerici Daniela , Mastaglio Sara , Liberatore Carmine , Lazzari Lorenzo , Piemontese Simona , Pavesi Francesca , Bernardi Massimo , Peccatori Jacopo , Corti Consuelo , Bonini Chiara , Ciceri Fabio , Bosi Emanuele 
Published: October 2019

Abstract
Introduction
Allogeneic stem cell transplantation (allo-HCT) survivors are at a defined relevant risk of developing long-term complications: the prevalence of chronic health conditions approaches 75% among HCT survivors. The endocrine system is one of the most frequent targets of complications, providing justification for a long-term and continuous follow-up (LTFU) to assure a timely and appropriate treatment.
The aim of our study is to evaluate the incidence of endocrinopathies in survivors in respect of sex, age, donor type, conditioning regimen and GvHD occurrence.
Methods
A standardized LTFU is applied at our center. We here analyze data consecutively collected in an Institutional database, starting from 2006, including 402 adult patients (pts) who underwent an allo-HCT between 1992 and 2016 at our Institution. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki.
We considered for the analysis pts with an overall survival >/=1y. We reviewed pts chapters with a focus on occurrence, management and treatment of diabetes, thyroid disfunctions, dyslipidemia and osteopenia / osteoporosis: diagnosis and follow-up were performed according to guidelines for long-term HCT survivors.
Results
With a median follow-up of 7y (r 2-25y) 328 pts were evaluable; donor was a match unrelated donor in 107 cases, HLA identical sibling in 88, haploidentical relative in 129 and cord blood in 4.
The 5y-incidence of diabetes type 2 was 3%, with a median time after allo-HCT of 1138 days (r 5-4181 days); 13/22 developed diabetes after diagnosis of GvHD (median time 884 days, r 30-3753 days). All pts received indication for diet modification, 11 pts were treated with insulin and 8 pts with metformin.
Thyroid disfunction was documented in 38 pts (5y-incidence 8,5%): 2 pts were diagnosed with hyperthyroidism and treated with methimazole or radioiodine treatment. Hypothyroidism was documented in 36 pts (median time after allo-HSCT 799 days, r 65-5021 days). Thirteen pts developed hypothyroidism following the diagnosis of GvHD (median time 1236 days, r 166-3540 days). Only 2 pts did not receive a specific treatment, while all the others received substitutive therapy with levothyroxine.
Furthermore 1 pt was diagnosed with a papillary thyroid cancer.
The 5y-incidende of dyslipidemia was 30% with a median time after allo-HSCT of 1433 days (r 366-7629), 47 pts developed dyslipidemia after the diagnosis of GVHD (median time 1425 days, r 134-7403 days). Diet-therapy was recommended to all the pts, 29 pts received a statin-based pharmacological treatment, 20 pts a polyenoic-fatty-acids based treatment, while a nutraceutical compound was given in 13 pts.
Osteopenia was documented in 120 pts (median time after allo-HSCT 994 days, range 31-6605 days) with a 5y-incidence of 36%. Seventy-nine pts presented osteopenia after diagnosis of GvHD (median time after GvHD diagnosis 707 days, r 13-6379 days). Eight pts did not receive a specific treatment. Two pts received treatment with biphosphonates plus oral vitamin D and calcium supplementation, the 110 remaining pts received oral vitamin D +/- calcium supplementation only.
Sixty-four pts developed osteoporosis (median time after allo-HSCT 1000 days, r 60-8836 days), the 5y-incidence was 26%. Forty-four pts developed osteoporosis following the diagnosis of GvHD (median time 724 days, r 28-8280 days). Only 4 pts did not receive any specific therapy; 31 pts received therapy with bisphosphonates, 2 pts denosumab and 27 pts oral vitamin D and calcium supplementation.
In univariate analysis no relationship between host sex, age at transplant, TBI exposure, donor or history of GvHD and development of diabetes, thyroid disfunction and dyslipidemia was outlined. Otherwise, osteopenia development was strongly associated with GvHD occurrence and osteoporosis was strongly associated with age, sex and GvHD occurrence (table 1).
Conclusions
Allo-HCT survivors are at relevant risk of endocrinopathies after transplantation, providing justification for specific monitoring to individualize treatment and follow-up. Of note, classical transplant-related variables are not enough to justify the occurrence of endocrinological disfunction: a further deeper evaluation of a misdiagnosed donor-mediated autoimmune predisposition will be essential.

Disclosures
Bonini: Intellia Therapeutics: Research Funding.