Cytokeratin (CK)-18 and CK18 Fragments As Sensitive and Specific Biomarkers of Acute Hepato-Intestinal Gvhd: Results of a Prospective Observational Study

• Published in: Blood 2015-12, Vol.126 (23), p.3083-3083
• Main Authors: Sauer, Sandra, Radujkovic, Aleksandar, Hegenbart, Ute, Ho, Anthony D, Dreger, Peter, Luft, Thomas
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.3083.3083

Introduction: Preliminary data have suggested that CK18, a highly abundant protein in liver and gut epithelial cells, and its apoptotic degradation product CK18 fragments (CK18F) could indicate apoptotic end organ damage induced by acute hepato-intestinal GVHD and, thus, may be used as an acute GVHD biomarker (Luft et al, Blood 2011; 118:1685). Here, we present the first results of a clinical study aiming at prospective validation of the capacity of CK18/ CK18F to predict acute hepato-intestinal GvHD activity and its response to treatment. Patients and methods: Main endpoints of the study were (1) prediction of imminent acute hepato-intestinal GvHD by comparing CK18/CK18F serum levels measured 7 to 14 days prior to symptom onset to with baseline levels (pre-conditioning, at transplant and one week after alloSCT) of the same subject; and (2) prediction of response to GVHD treatment by measuring CK18/CK18F kinetics 3, 7 and 14 days after start of immunosuppressive therapy for hepato-intestinal GvHD. Eligible were all adult patients undergoing allogeneic stem cell transplantation (alloSCT) at our institution from December 2008 onwards. Target sample size was 100. Blood samples were collected in the study population prior to the initiation of the conditioning regimen and from the day of transplantation on a weekly basis for one year. The M30-Apoptosense ELISA kit was used for measuring serum levels of CK18 fragments, CK18 was analyzed with the M65 (EpiDeath) ELISA Kit (both provided by PEVIVA, Nacka, Sweden). Serum levels measured at the pre-specified landmarks were compared by Wilcoxon's signed rank test. The study was registered at ClinicalTrials.gov (Identifier: NCT00935324). Results: Between December 2008 to February 2011, 109 patients were enrolled. The median age was 53 years (range 19 - 69), 72 were male. The underlying disease was acute myeloid leukemia in 39 patients, myeloproliferative / myelodysplastic disorders in 18 patients, acute lymphoblastic leukemia in 10 patients, and lymphoproliferative malignancies in 42 patients. Donors were matched related (36), matched unrelated (52), or mismatched unrelated (21). Stem cell source was peripheral blood in 100 patients and bone marrow in 9 patients. Reduced intensity conditioning protocols (n = 89) prevailed over myeloablative (n = 7) and aplasia conditioning protocols (n = 13). Immunosuppression was based on a calcineurin inhibitor (CNI) backbone with mycophenolate or short-course methotrexate, plus ATG