Chronic Graft-Versus-Host Disease in Double Cord Blood Transplantation According to National Institutes of Health 2005 Criteria: A Study on Behalf of Eurocord and Cord Blood Committee of Cellular Therapy and Immunobiology Working Party of the EBMT
Authors: Hayashi Hiromi , Ruggeri Annalisa , Rafii - El Ayoubi Hanadi , Cornelissen Jan J. , Socié Gerard , Andersen Niels S. , Michallet Mauricette , Karakasis Dimitrios , Petersen Eefke , Veelken Joan Hendrik , Cahn Jean Yves , Rohrlich Pierre-Simon , Mercier Melanie , Volt Fernanda , Kenzey Chantal , Xavier Erick , Rocha Vanderson , Gluckman Eliane 
Published: October 2019

Abstract
Chronic Graft-versus-Host Disease (cGVHD) has a negative impact on transplant related death and quality of life after hematopoietic stem cell transplantation. In an attempt to thoroughly assess cGVHD after double umbilical cord blood transplantation (dUCBT), we used the major revised consensus criteria (NCC 2005) proposed by the National Institutes of Health (NIH) in 2005.
Material and methods: This is a retrospective study using Eurocord-EBMT database. A specific questionnaire including the NCC 2005 characteristics and features was sent to each transplant centers for collecting data. Eligible pts were adults >18years, who received dUCBT for hematological malignancy in an EBMT center between 2006 and 2014, achieved neutrophil engraftment, survived ≥100 days and developed cGVHD.
Results: A total of 154 pts were included. Median age at dUCBT was 43 years (18-70). The primary diagnosis was acute myeloid leukemia in 40%, acute lymphoblastic leukemia in 21%, myelodysplastic/myeloproliferative disease in 19%, and other hematological disorders in 20%. The majority of pts was transplanted in CR, including 51% in CR1, 37% in CR2. Reduced intensity conditioning regimen (mainly with low dose total body irradiation) was used in 60% of cases. 24% pts received anti-thymocyte globulin before transplant.
Cyclosporine and mycophenolate mofetil (MMF) was the most common (79%) combination for GVHD prophylaxis. 70% (n=107) of pts received gender mismatched grafts, and 59% had 1-2 major ABO incompatibility. Most (>80%) grafts had 2 HLA mismatches with the recipients. Median number of total nucleated cells at cryopreservation was 5.1(2.3-13.3) ×107/Kg.
All pts achieved neutrophil engraftment in a median of 25 days and 89% had full donor chimerism at day 100. Median follow-up was 27.5 (3-103) months, 45 pts relapsed and 60 pts died (28 of relapse, 12 of GVHD and 20 of other TRM).
Grade II-IV acute GVHD occurred in 88 pts in a median time of 24 (6-106) days. Grade III-IV aGVHD was reported in 43 pts, mainly with skin and gastrointestinal (GI) tract involvement.
Median time for cGVHD onset was 219 (47-2056) days, and most of these were reported within the first 1.5-2 years. Based on Seattle criteria, cGVHD was limited in 73 (47%) pts and extensive in 81 (53%) pts. According to NIH criteria (NCC2005), global cGVHD severity was scored as mild in 67 (44%), moderate in 53 (35%) and severe in 33 pts (21%).
cGVHD presented mainly as one or two organs involvement, with skin being the most common site. 56% pts (n=86) had a single organ involvement (mainly skin n=60; 38%). Skin, GI tract, and oral mucosa were the top three affected sites (93%; n=143), both in solo and multiple involvements. 23 patients had > 3 affected organs, skin being most common (n=20; 87%). No joint or fascia involvement was reported as a single organ involvement in any grade.
Mild and moderate cGVHD presented as one or two organs involvement, mainly affecting skin, GI and oral mucosa. Severe cGVHD often involved skin, GI, lung and liver. Severe GI tract cGVHD was mostly reported as a single organ involvement. Severe lung involvement was reported in 12 pts (8%).
Major functional impact by scoring grade 3 was observed in skin (n=7), GI (n=8), liver (n=5), eye (n=3), oral mucosa (n=2), and lung (n=5).
Twenty %pts (n=31) received only topical or no treatment, for 1 or 2 organs involvement and mild to moderate grade cGVHD. The first line treatment of cGVHD included systemic steroids +/- calcineurin inhibitors (CNI) or MMF based regimen, and was used in 72% pts (n=111).
cGVHD resolved in 94 pts (61%), and remained clinically significant in 57 pts (mild, n=14; moderate, n=20 and severe, n=23). Among the 12 pts who died of cGVHD, there was multiple organs involvement in most cases; and 6 pts had severe lung cGVHD.
Conclusion: According to NCC 2005 criteria, we report that, after dUCBT, cGVH was usually mild with skin being the most common site resulting, in this small group of patients, in a relatively low incidence of severe cGVH with as a consequence a better survival and quality of life.

Disclosures
Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.