Late Effects after Allogeneic Hematopoietic Cell Transplantation Among Children and Adolescents with Non-Malignant Disorders: A Report from the Center for International Blood and Marrow Transplant Research (CIBMTR)
Authors: Kahn Justine M. , Bo-Subait Stephanie , Buchbinder David K. , Hamilton Betty K. , Schoemans Helene , Brazauskas Ruta , Phelan Rachel , Satwani Prakash 
Published: November 2021

Abstract
Introduction:
Allogeneic hematopoietic cell transplantation (HSCT) is a curative treatment option for children and adolescents with non-malignant disorders. Continued advances in HSCT have led to a growing population of long-term survivors. For these survivors, late occurring chronic health conditions or so-called "late effects" remain a challenge. We examined the cumulative incidence of selected late effects at 5- and 10-years post-HSCT in pediatric and adolescent patients transplanted for non-malignant diseases.
Methods:
A retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database was performed. Eligible patients (1 - 20 years) underwent HSCT between 1995 and 2012 for treatment of non-malignant disorders including marrow failure, red cell disorders, and immunodeficiencies (Table). Late effects evaluated were: avascular necrosis (AVN), cataracts, diabetes, growth hormone deficiency, hypothyroidism, gonadal dysfunction, renal failure requiring dialysis, and neurologic events (stroke and seizure). The cumulative incidence of each late effect was calculated at 5-years and 10-years from date of first report post-HSCT.
Results:

Median follow up was 94.1 months. A total of 5,858 patients from 230 centers were included. Median age at HSCT was 5.5 years. The majority (65%) of the patients were White race/ethnicity and 9% were Black, 60% were male. Diagnoses included: Marrow failure disorders, hemoglobinopathies, immunodeficiencies and immune-dysregulation syndromes (Table). The majority (62%) of the cohort received myeloablative conditioning (MAC), and a minority (16%) received total body irradiation (TBI). Among all patients, 19% had chronic graft-versus-host-disease (GVHD).
Cumulative incidence estimates at 5- and 10-years post-HSCT are presented in the Table. One-third (28%) of patients had at least one late effect. Cumulative incidence estimates at 10 years included stroke/seizures (11.2%), renal failure (7.7%), growth hormone deficiency/disturbance (7.6%), gonadal dysfunction (4.2%), hypothyroidism (4.1%), cataracts (2.9%), and AVN (1.4%).
For AVN, renal failure, and stroke or seizures, incidence was stable between 5 and 10 years. For endocrine-associated late effects, incidence increased over time, nearly doubling from 5 to 10 years (Table). Across the cohort, the probability of growth hormone deficiency increased from 3.7% at 5-years, to 6.5% at 10-years. Similarly, hypothyroidism increased from 2.7% at 5-years, to 4.5% at 10 years. The cumulative incidence of treatment-associated diabetes was 3.1%, with most cases occurring in the first-year post-transplant. Finally, the probability of cataracts at 10 years was 2.9%, which was double the incidence at 5 years.
Conclusions

Among children and adolescents undergoing HSCT for non-malignant diseases, cumulative incidence of late effects was overall low, and did not exceed 12% at 10 years. The timing of late effect development differed, with the cumulative incidence of AVN, diabetes, renal failure, and seizure/stroke staying fairly stable after 5-years. Diabetes occurred most frequently in the first year, which may be a reflection of steroids or other medications to manage graft-versus-host-disease during the early-post transplant period. In contrast, the incidence of endocrine-associated late effects including growth disturbance, hypothyroidism, gonadal dysfunction and cataracts nearly doubled between 5 and 10-years post-transplant. Findings from this work further emphasize the need for long-term follow-up and screening for late effects, particularly diabetes, renal disease and neurologic symptoms early post-transplant, and cataracts and endocrinopathies over time.
Figure 1 Figure 1.

Disclosures
Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Schoemans: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: personal fees , Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants and personal fees; Gilead: Other: travel grants; CIBMTR: Consultancy, Other: travel grants; Janssen: Membership on an entity's Board of Directors or advisory committees; BHS: Membership on an entity's Board of Directors or advisory committees, Other: travel grants and personal fees , Research Funding; Jazz Pharmaceuticals: Other: personal fees; Takeda: Other: personal fees. Phelan: Amgen Pharmaceuticals: Research Funding.