Outcome of Children Developing Grade III-IV Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Report on Behalf of the EBMT Paediatric Diseases Working Party
Authors: Bertaina Alice , Locatelli Franco , Lawitschka Anita , Balduzzi Adriana , Dalle Jean-Hugues , Sedlacek Petr , Willasch Andre Manfred , Yaniv Isaac , Peters Christina , Bader Peter 
Published: April 2021

Abstract
Introduction
Acute graft versus host disease (aGvHD) still remains one of the major causes of procedure-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Information on the outcome of paediatric patients experiencing this complication is limited. For this reason, we conducted a retrospective registry-based analysis on 2519 children who developed grade III-IV acute GVHD and were reported to the European Blood and Marrow Transplantation (EBMT) registry.
Patients and methods
Included in the study were children below age of 18 years who were transplanted between 2004 and 2014. Median year at transplantation was 2009. Of these children, 826 children had a non-malignant disorder, while 1689 were affected by malignancies. The donor was an HLA-identical sibling in 707 cases and an unrelated donor in 1081 cases. Umbilical cord blood (UCBT) was employed as stem cell source in 396 cases, while a relative other than a compatible sibling was utilized in 202 cases. Overall, 1281 patients were given bone marrow (BM), while 800 received peripheral blood stem cells (PBSC).
Results
Grade III acute GvHD occurred in 1607 patients (64% of the overall population), while grade IV acute GvHD was diagnosed in 908 (36%). Chronic GvHD occurred in 649 patients (26 % of the overall number of children who developed grade III-IV aGVHD). It was extensive in 333 (13%) and of limited severity in 269 (11%). At time of last follow-up, 1341 patients were alive (53%), while 1178 were dead (47 %). Fifty-seven patients were lost to the follow-up. Relapse of the original disorder occurred in 219 children (19.7% of patients experiencing grade III-IV aGvHD). Transplant-related causes were responsible for the death of 902 patients (76.5%), while 6 (0.5%) patients developed a secondary malignancy. The 3-year Kaplan-Meyer probability of overall survival (OS) was 46.7% (confidence interval 95, 44.1-49.5) and 50.9% (confidence interval 95, 47.1-54.9) in patients affected by malignant and non-malignant disorders, respectively. Patients who received as stem cell source BM had a better outcome in comparison to those who received PBSC (3-year OS, 53.2 vs 40.4%, P&lt;0.0001). In the overall cohort, in comparison to patients who developed limited cGvHD, the extensive form of the disease had a detrimental effect on the outcome, being the 3-year OS 74.2% and 41.6%, respectively (P&lt;0.0001). In multivariate analysis, the only variables affecting overall survival were the age at transplant (P&lt;0.0001) and the type of donor (sibling vs UD, CB, MMFD, P&lt;0.0001). The 3-year Kaplan-Meyer probability of non-relapse mortality (NRM) was 37.4% (confidence interval 95, 34.9-39.9) and 45.9% (confidence interval 95, 42-49.7) in malignant and non-malignant disorders, respectively. Also in this case, use BM instead of PBSC seems to be an advantage, being the 3-year NRM 35.1% and 47.8%, respectively. In multivariate analysis, besides the age at transplant (P&lt;0.0001) and the type of donor (sibling vs UD, CB, MMFD, P&lt;0.0001), the use of a myeloablative conditioning regimen (MAC) chemo-based (P&lt;0.0001) and the development of extensive chronic GvHD (P&lt;0.0001), had a detrimental effect on NRM.
Conclusion
These data indicate that the occurrence of grade III-IV aGVHD is associated with a dismal outcome also in paediatric patients. The main cause of fatality is represented by non-relapse mortality, while leukemia recurrence affected outcome of a lower number of children. Although the outcome of children experiencing grade III-IV aGvHD is improving over time, strategies aimed at preventing this immune-mediated complication and at optimizing its treatment are desirable.

Disclosures
Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.