Late Toxicities After Allogeneic HCT for Non-malignant Disorders

Source: Kahn J, Brazauskas R, Bo-Subait S, et al. Late effects after allogeneic haematopoietic cell transplantation in children and adolescents with non-malignant disorders: a retrospective cohort study. Lancet Child Adolesc Health. 2024;8(10):740-750; doi: 10.1016/S2352-4642(24)00167-6.Investigators from multiple institutions conducted a retrospective study to determine the cumulative incidence of late effects in children after allogeneic hematopoietic cell transplantation (HCT) for non-malignant disease (NMD) and identify risk factors for specific long-term conditions. For the study, they abstracted data from the Center for International Blood and Marrow Transplant Research, which includes information on patients receiving HCT from more than 450 centers throughout the world. Study participants were youths who had received a first HCT for NMD when they were <21 years old between 2000 and 2017. Data collected on these patients included demographics, type of NMD, type of pre-transplant conditioning (myeloablative or reduced intensity), receipt of total body radiation, donor type, acute and chronic graft versus host disease (GVHD), and late effects. The 7-year cumulative incidence was determined for the following late effects: avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth disturbance, hypothyroidism, renal failure, and stroke or seizure. Multivariate Cox hazard regression was used to identify independent risk factors for each of the specific late effects.A total of 5,790 youths with a median age of 5.5 years at time of HCT were included in study analyses. The most common NMDs in these children were aplastic anemia (21.2% of participants), non-severe combined immune deficiency (non-SCID, 14.6%), SCID (11.2%), and Fanconi anemia (9.8%). Overall, 83.6% of patients received total body irradiation and 54.6% myeloablative conditioning. The donor was an HLA-identical sibling in 56.8% of cases. Among all participants 1,127 (19%) had at least 1 late effect. The most common late effect was stroke or seizure, with a 7-year cumulative incidence of 9.4% (95% confidence interval [CI], 8.6, 10.2), followed by renal failure (8.1%; 95% CI, 7.4, 8.9), growth disturbance (5.0%; 95% CI, 4.4, 5.7), and diabetes (4.9%; 95% CI, 4.3, 5.6). In the multivariate models, older age at the time of HCT was associated with an increased risk for diabetes, gonadal dysfunction, avascular necrosis, and stroke or seizure. Having a donor type other than an HLA-identical sibling tended to increase the risk for diabetes, gonadal dysfunction, hypothyroidism, growth disturbance, avascular necrosis, renal failure, and stroke or seizure. Receipt of total-body irradiation, particularly in higher doses, was associated with an increased risk of diabetes, gonadal dysfunction, and growth disturbance. Acute and/or chronic GVHD were associated with an increased risk for most late effects, although the statistical significance of the association varied.The authors conclude that the cumulative incidence of late effects was low overall.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Almost 600 children with NMDs receive allogeneic HCT annually in the US.1 Overall survival rates have improved to an estimated 80% with contemporary conditioning regimens, graft sources, and GVHD prophylaxis.1 NMDs indications for HCT are rare, diverse, and life-threatening without supportive interventions. These disorders include inherited immunodeficiencies, histiocytic diseases, hemoglobinopathies, metabolic diseases, platelet abnormalities, bone marrow failure syndromes, and severe aplastic anemia.2Due to the heterogeneity of this population, previous studies from single centers or small cohorts have reported asymptomatic to severe late effects in the majority of patients.3 Long-term complications have included dental problems, cognitive deficits, pulmonary dysfunction, infertility, endocrinopathies, immunodeficiencies, and chronic GVHD sequelae.3 Depending on the NMD, common comorbidities prior to HCT can include pulmonary, hepatic, and/or infectious problems.4Although the current study of a large, international cohort did not assess pre-HCT organ dysfunctions or acute post-HCT toxic effects, several HCT-related risk factors were associated with long-term toxicities. To improve quality of life for HCT survivors, research efforts are being made to limit primary or secondary graft failure, GVHD, and immune cytopenias.5 Similar to children undergoing HCT for malignancies, personalized long-term, multidisciplinary follow-up care is essential to determine which toxicities arise from which treatments.6There is a low overall risk of late toxic effects among children and adolescents who underwent HCT for NMDs. Rick factors include older age at HCT, unrelated donor source, pre-HCT total-body irradiation, and GVHD.The observant reader will recall our recent publication relating gene therapy for boys with cerebral adrenoleukodystrophy, resulting in prolonged survival without major neurologic disability (See AAP Grand Rounds. 2025;53[2]:21.)7 We would speculate that increased availability of stem-cell gene therapy may diminish future use of allogenic HCT for additional NMDs, especially for patients without a sufficiently matched HCT donor.