Incidence and Risk Factors of Chronic Graft-Versus-Host Disease After Unrelated Cord Blood Transplant In Children and Adults. A Retrospective Study on Behalf of EUROCORD and Late-Effect Working Party of EBMT
Authors: Crotta Alessandro , Michel Gerard , Sanz Guillermo F. , Socie Gerard , O'Brien Tracey A. , Arcese William , Blaise Didier , Bertrand Yves , Diaz Miguel A. , Vora Ajay J. , Fagioli Franca , Dini Giorgio , Dalle Jean-Hugues , Mohty Mohamad , Labopin Myriam , Gluckman Eliane , Tichelli André , Rocha Vanderson 
Published: October 2019

Abstract
Abstract 219
Chronic GvHD disease (cGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Unrelated cord blood transplant (UCBT) is associated with a reduced incidence of chronic GvHD when compared to other sources of stem cells, however risk factors analysis for incidence is scarce in the literature. We retrospectively analyzed 792 patients, 447 children (age<18) and 345 adults, receiving first single (n=667) or double UCBT (n=125) in EBMT centers, between 1994 and 2009, for malignant and non-malignant diseases, who engrafted and survived at least 100 days from transplantation. Median age was 13 years (0.1-68); the most common disease was acute leukemia (62%), 18% of patients were transplanted for a non-malignant disease. Conditioning regimen was myeloablative (MAC) in 79% of cases (TBI>6Gy in 30%), RIC in 21%. Busulphan-based conditioning was used in 50% and ATG was added in 81% of cases. CsA+steroid was the most common GvHD prophylaxis (49%); CsA+mycophenolate mofetil was used in combination in 46% of adults. Eleven percent of units were HLA-identical (antigen level for HLA-A and B, allelic for DRB1), while 39% and 50% had 1 or 2–3 mismatches, respectively. Median total nucleated cell (TNC) infused was 4.5−107/kg. Median follow-up was 39 months (3-158). Cumulative incidence (CI) of cGvHD at 2 years in the whole population was 31±2% (n=251). Chronic GvHD was extensive in 53% of children and adults. Regarding cGvHD organ involvement, skin and gastro-intestinal tract were the most frequent organ affected, 64% and 38% of cases respectively followed by liver (15%) and lung involvement (7%). Eighty-six percent of patients were treated with systemic therapy. Out of 251 patients who developed cGvHD, 137 had previously acute GvHD (77 out of 113 children and 60 out of 138 adults). Factors associated with a decreased incidence of cGvHD were: 0–1 HLA mismatched units (p<0.001) and age<18 years (p<0.001). In fact, CI of cGvHD at 2 years was 24±2% in children and 40±3% in adults. Therefore, risk factors analysis was performed separately for children and adults. In children, in multivariate analysis, factors associated with decreased incidence of GvHD were: age less than 5 years at transplant (HR=0.64, p=0.01), TBI based-conditioning (HR=0.5, p=0.003) and no previous aGvHD (HR=0.24, p<0.001). In adults, in multivariate analysis, 0–1 HLA mismatched grafts (HR=0.86, p=0.016), TNC infused >2.2 ×10⋀7/kg (HR=0.6, p=0.016) and no previous aGvHD (HR=0.49, p<0.001) were independent factors associated with a decreased incidence of cGvHD. At 3 years, CI of transplant-related mortality (TRM) after 100 days was 15±2% and 30±3% in children and adults respectively. Chronic GvHD, analyzed as time dependent variable, was an independent factor associated with an increased TRM in children (HR=3.03, p<0.001) and adults (HR=2.04, p=0.001). Estimated overall survival (OS) at 3 years after 100 days of UCBT was 71±2% and 49±3% in children and adults respectively. In multivariate analysis, in children factors independently associated with a decreased OS were: presence of chronic GvHD (HR=1.5, p=0.039), malignant disease (HR=2.26, p=0.001) and patient's CMV positive serology (HR=1.54, p=0.014). In adults, factors decreasing OS were: chronic GvHD (HR=1.42, p=0.042), advanced phase of disease (HR=1.5, p=0.016) and TNC infused <2.8 ×10⋀7/kg (HR=1.4, p=0.045). Two hundred ninety-four patients died, in 39% of cases deaths were related to relapse of original disease, 53% to transplant related causes. In conclusion, after UCBT, incidence of cGvHD was decreased in children compared to adults, however the frequency of limited and extensive cGvHD was the same in both groups. An increased risk of cGvHD was associated with previous acute GvHD in both groups, whereas it was associated in children with older age (>5 years) and no use of TBI, and in adults with a mismatched CB unit (4/6 or more) and TNC infused <2.2 ×10⋀7/kg. In children as well as in adults UCBT recipients, chronic GvHD increases TRM and decrease OS. Further prospective studies should evaluate better GvHD prophylaxis after UCBT.

Disclosures:
No relevant conflicts of interest to declare.