Implementation of NIH Criteria for Standardization of Chronic Graft-Versus-Host Disease in Croatia: Two-Year Experience
Authors: Desnica Lana , Pulanic Drazen , Serventi Seiwerth Ranka , Matic Nikolina , Mravak Stipetic Marinka , Bilic Ervina , Ceovic Romana , Ljubas Kelecic Dina , Rajic Ljubica , Bilic Ernest , Durakovic Nadira , Peric Zinaida , Klepac Pulanic Tajana , Vukic Tamara , Petricek Igor , Dusek Davorka , Bojanic Ines , Prenc Ema , Prah Iva Ozana , Grce Magdalena , Zadro Renata , Batinic Drago , Vrhovac Radovan , Pavletic Steven Z. , Nemet Damir 
Published: October 2019

Abstract
Background: Chronic graft-versus-host disease (cGVHD) is a disorder that affects many organ systems in highly variable fashion occurring in approximately 50% of patients following allogeneic hematopoietic stem cell transplantation (alloHSCT). It is the major cause of non-relapse morbidity and mortality after alloHSCT in individuals otherwise cured of their hematologic diseases, inducing poor quality of life, impaired functional status, inability to work, and need for ongoing chronic care, which has also important impact to health-related costs. cGVHD Consensus Conference held in 2005 at the National Institutes of Health (NIH), USA, produced recommendations regarding cGVHD diagnosis, staging, histopathology, response criteria, biomarkers, ancillary and supportive care, and design of clinical trials. In 2014, second cGVHD NIH Consensus Conference updated these recommendations, published during 2015 as 6 papers in Biology of Blood and Marrow Transplantation (BBMT) journal. Although practitioners are generally familiar with the NIH recommendations, many barriers prevent their greater uptake in clinical practice. In order to overcome these challenges, in 2013 multidisciplinary clinic infrastructure was organized at the University Hospital Center (UHC) Zagreb, Croatia, in collaboration with the NIH leading scientists, using established cGVHD-related grading scales and measurements.
Methods: Division of Hematology, UHC Zagreb, Croatia, has experience with alloHSCT since 1983, and 827 patients received alloHSCT until the end of 2014. Since the establishment of multidisciplinary cGVHD team in 2013, patients were enrolled into the Unity through Knowledge Fund (UKF) study protocol (funded by World Bank and Croatian Ministry of Science, Education and Sports) and examined by multiple subspecialists, firstly seen by hematologist, with detailed history and physical exam. Standard cGVHD scoring forms are filled according to NIH Consensus recommendations, and extensive laboratory analyses were done. Patients are seen and evaluated by other sub-specialists (Dental, Dermatology, Rehabilitation, Neurology, Ophthalmology, Gynecology, and other) with further workup as needed. Quality of life questionnaires are filled during the visit. All data are collected in a specially developed database and weekly team meetings were established. Blood and small biopsy tissue samples (skin, mouth) are stored for further research.
Results: Using multidisciplinary approach since 2013, 46 (6 pediatric) cGVHD patients were assesed, median age was 41 years; range [9-71], 24 were male and 22 were female. The median time from transplant to enrollment was 20 months [2-258], from cGVHD diagnosis to enrollment 7 months [0.03-234] and from transplant to cGVHD diagnosis 10 months [2-128]. Additional 17 post-alloHSCT patients were eveluated, but without confirmation of cGVHD diagnosis. Among cGVHD patients, 31 (67%) of them received transplants from matched related donors, 27 (59%) of them had myeloablative conditioning, and 26 (57%) received peripheral blood stem cells as graft source. Thirty-five (76%) patients had previous acute GVHD, 11 (24%) had de novo cGVHD, 21 (46%) quiescent and 14 (30%) progressive onset; 41 (89%) were classified as classic and 5 (11%) as overlap; 23 (50%) patients had severe, 19 (41%) moderate, and 4 (9%) mild global cGVHD score. The most involved organs were skin (54%), eyes (50%), lungs (48%) and mouth (39%). Due to internationally peer reviewed UKF grant awarded in 2013 doctoral and postdoctoral researcher were hired, and visits of young clinicians to NIH and other cGVHD centers were realized. Several new research subprojects emerged since formation of our cGVHD team and applications to the new project calls were submitted. Also, 2 international cGVHD symposiums were organized in Zagreb, Croatia, in last 2 years stimulating education and networking.
Conclusion: Implementation of NIH criteria for standardizationof cGVHD in Croatia showed remarkable results, not just improving quality of medical documentation and management of these long-terms survivors with complex and long-lasting health issues, but also facilitating further international clinical research and collaboration with cGVHD community, with potential positive impact to health-related costs and benefit to society.

Disclosures
Nemet: Pliva: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria.