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Association of Chronic Graft-versus-Host Disease with Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy
Lee, C. J., Wang, T., Chen, K., Arora, M., Brazauskas, R., Spellman, S. R., Kitko, C., MacMillan, M. L., Pidala, J. A., Auletta, J. J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality-of-life among long-term survivors of pediatric HCT. Late effects of HCT are well documented in this population and cGVHD has been reported as a risk factor for subsequent neoplasms (SN) and several non-malignant late effects. However, the correlation between cGVHD and late effects varies between studies. OBJECTIVE We compared late effects occurring ≥ 2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of late effects. STUDY DESIGN This was a systematic retrospective analysis using data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large and representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant and non-malignant late effects following a diagnosis of cGVHD versus those who never developed cGVHD. The cumulative incidence (CI) of any first LE, subsequent neoplasm (SN), and non-malignant LE (NM-LE) was estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD vs. no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first late effects. RESULTS The estimated 10-year cumulative incidence of any late effect in patients with and without cGVHD was 43% (95% CI, 38%-48.2%) vs. 32% (95% CI, 28.5%-36.3%) (P<0.001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any late effect (HR 1.38, 95% CI, 1.13-1.68, P=.001) and non-malignant late effects (HR 1.37, 95% CI, 1.10-1.70, P=.006), but not SN (HR 1.30, 95% CI, 0.73-2.31, P=.38). Chronic GVHD-related factors linked with the development of a non-malignant late effect included having extensive grade (HR 1.60, 95% CI 1.23 - 2.08, P=.0005), severe cGVHD (HR 2.25, 95% CI 1.60 - 3.17, P<.0001), interrupted onset type (HR 1.57, 95% CI 1.21 - 2.05, P=.0008), and both mucocutaneous and visceral organ involvement (HR 1.59, 95% CI 1.24 - 2.03, P=.0002). No significant association between cGVHD-specific variables and SN was identified. Lastly, duration of cGVHD treatment with systemic immunosuppression was not significantly associated with SN or non-malignant late effects. CONCLUSIONS cGVHD was more closely associated with non-malignant late effects than SN amongst survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SN was strongly associated with myeloablative total body irradiation. Chronic GVHD-related characteristics consistent with a state of higher immune dysregulation were more closely linked to non-malignant late effects.