Incidence of Acute Graft-Versus-Host Disease and Survival after Allogeneic Hematopoietic Cell Transplantation over Time: A Study from the Transplant Complications and Chronic Malignancies Working Party of the EBMT
Authors: Greinix Hildegard T. , Eikema Dirk-Jan , Koster Linda , Penack Olaf , Yakoub-Agha Ibrahim , Montoto Silvia , Chabannon Christian , Styczynski Jan , Nagler Arnon , Robin Marie , Robinson Stephen , Chalandon Yves , Mikulska Malgorzata , Schönland Stefan , Peric Zinaida , Ruggeri Annalisa , Lanza Francesco , Mohty Mohamad , Basak Grzegorz W , Nicolaus Kroger 
Published: October 2019

Abstract
INTRODUCTION: Acute graft-versus-host disease (aGvHD) remains a serious complication of allogeneic hematopoietic cell transplantation (HCT) and negatively impacts on patients' outcome. Over recent years improvements in GvHD prophylaxis, HLA typing, donor selection, treatment and supportive care have been achieved. However, it is unknown whether these changes have resulted in improved outcome of patients undergoing allogeneic HCT and particularly in those patients diagnosed with aGvHD and in need of systemic immunosuppressive therapy.
METHODS: We examined outcome following diagnosis of grades II-IV and grades III-IV aGvHD according to time period and investigated effects according to maximum overall grade of aGvHD. Between 1990 and 2015, 126 838 patients with a median age of 46.4 (range, 18-83.8) years with malignant disease received a first allogeneic sibling (53.9%) or unrelated donor (46.1%) blood (74.5%) or marrow (25.5%) transplant after myeloablative (58.9%) or reduced-intensity (41.1%) conditioning. Sixty-two percent of patients were in complete remission (CR) at HCT.
RESULTS: Incidences of aGvHD grades II-IV by 100 days significantly (p<0.001) decreased from 40% for 1990-1995, to 37% for 1996-2000, 31% for 2001-2005, 29% for 2006-2010 and 28% for 2010-2015. In univariate analysis for the whole study population, incidence of aGvHD grades II-IV was higher in patients with an unrelated donor (33% vs 29%, p<0.001), a female donor compared to a male donor for a male recipient (33% vs 31%, p<0.001), and patients not in CR at HCT (33% vs 29%, p<0.001) whereas reduced-intensity conditioning (RIC) (27% vs 33%, p<0.001), and in vivo T-cell depletion (TCD) (27% vs 33%, p<0.001) were associated with a lower incidence. Incidences of aGvHD grades III-IV by 100 days significantly (p<0.001) decreased from 17% for 1990-1995, to 15% for 1996-2000, 13% for 2001-2005, 11% for 2006-2010 and 11% for 2010-2015.
The median (range) follow-up was 217.6 (213.4-221.7) months, 169.9 (167.6-172.9) months, 129 (127.3-130.8) months, 81.3 (80.5-82.1) months and 29.7 (29.2-30.2) months for 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. For the total study population, 3-year overall survival (OS) significantly (p<0.001) increased from 49% for 1990-1995, to 50% for 1996-2000, 51% for 2001-2005, 53% for 2006-2010 and 54% for 2010-2015, respectively. 3-year nonrelapse mortality (NRM) significantly (p<0.001) decreased from 33% for 1990-1995, to 29% for 1996-2000, 24% for 2001-2005, 23% for 2006-2010 and 23% for 2010-2015. In univariate analysis, OS was better after related donor HCT (55% vs. 49%, p<0.001), and HCT in CR (58% vs 41%, p<0.001) whereas female donor compared to male donor for a male recipient (50% vs 52%, p<0.001), use of antithymocyte globulin (ATG) (51% vs 53%, p<0.001), and in vivo TCD (51% vs 55%, p<0.001) were associated with worse OS.
The OS of patients experiencing aGvHD grades II-IV was 66% at 6 months and decreased to 43% at 36 months after HCT. Survival at 36 months after aGvHD grades II-IV increased significantly (p<0.001) from 39% to 40%, 43%, 44% and 45% after HCT in the periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. In univariate analysis, aGvHD grades II-IV-associated 3-year OS was significantly improved after myeloablative conditioning (45% vs 41%, p<0.001), related donor HCT (45% vs. 41%, p<0.001), and HCT in CR compared to no CR (49% vs 33%, p<0.001) whereas female donor for a male recipient (40% vs 43%, p<0.001), use of ATG (42% vs 44%, p<0.001), and in vivo TCD (41% vs 45%, p<0.001) were associated with worse aGvHD-associated OS. aGvHD grades III-IV-associated OS was 46% at 6 months and decreased to 27% 36 months after HCT. Survival at 36 months after aGvHD grades III-IV increased significantly (p<0.001) from 49% to 50%, 51%, 53% and 54% after HCT in the periods 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2010-2015. In univariate analysis, aGvHD grades III-IV-associated 3-year OS was improved after related donor HCT (29% vs. 25%, p<0.001), and HCT in CR compared to no CR (31% vs 26%, p<0.001) whereas use of ATG (25% vs 28%, p<0.001), and in vivo TCD (25% vs 29%, p<0.001) were associated with worse aGvHD grades III-IV-associated OS.
CONCLUSIONS: Incidences of aGvHD grades II-IV and grades III-IV decreased over time and aGvHD-associated survival increased over recent years resulting in improved survival of patients undergoing allogeneic HCT for malignant disease.

Disclosures
Greinix: Gilead: Speakers Bureau; Roche: Speakers Bureau; Therakos: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Mohty:MaaT Pharma: Consultancy, Honoraria.