Late Endocrine Effects Remain Prevalent Despite Reduced Intensity Chemotherapy for Hematopoietic Stem Cell Transplantation in Children and Young Adults

Background: Myeloablative conditioning regimens used for hematopoietic stem cell transplant (HSCT)  are known to affect endocrine function, most commonly causing primary hypothyroidism and hypogonadism. Little is known regarding these late effects after newer reduced intensity conditioning (RIC) regimens without irradiation. Our study goal was to evaluate late endocrine effects after RIC HSCT in pediatric and young adult patients. 

Methods:  An IRB approved retrospective chart review was performed of 120 children and young adults at our center, who received a single RIC without radiation for HSCT between 2004 and 2012 and survived at least 1 year.  Analysis was grouped by age (<2 years and ≥ 2 years), and diagnosis (HLH/XLP, other immune disorders (PID), and metabolic or genetic disorders).  Steroid therapy was defined as glucocorticoids administered either before HSCT or beyond 2 months following HSCT. Height for age z-score (HAZ) and BMI z-scores (BMI-Z) were examined separately using linear mixed effects models.

Results:  Subjects age 2-17y with height (n=103) and weight (n=120) data both prior to and at least 1 year following HSCT were analysed for growth.  The mean follow-up was 3.2 years. All groups displayed short stature before (HAZ = -1.33) and after HSCT (HAZ = -1.35) (p=0.66). After HSCT, younger children with HLH/XLP grew better (HAZ =-3.36 vs -1.35, p= 0.002), while older subjects had worsening (HAZ =-.61 vs -.99, p= 0.004), although all remained short.  Overall, subjects receiving steroid therapy were shorter than untreated patients (p = 0.02). After HSCT, older subjects with HLH/XLP became thinner (BMI-Z= 1.29 vs. 0.61, p=0.003), and similarly in metabolic or genetic disorders (BMI-Z=  0.56 vs. -0.77, p<0.001). There was a trend toward increased BMI-Z among younger children in these same groups. Thyroid function testing was performed on 77 subjects following HSCT.  Eleven (14%) had evidence of primary hypothyroidism, 5 (7%) had central hypothyroidism, and 2 (3%) had evidence of primary hyperthyroidism. Of the 66 subjects with 25-OH vitamin D levels, 46 (70%) were low (<30 ng/mL).  Bone densitometry by DXA scan was below -1 SD in 16 of 21 evaluable subjects with an average Z-score of -1.8 SD (0.7 to -4.9 SD) at median duration after HSCT of 2.2 years.

Conclusions: Despite using RIC, children and young adults still have significant late endocrine effects following transplant. Algorithms for early detection of endocrine late effects should be implemented for RIC transplant survivors. Further research is required in order to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols.