The Multicentre, Double-Blinded, Placebo-Controlled Clinical-Trial (Pre-GvHD) for Prediction and Pre-Emptive Treatment of Acute GvHD

Allogeneic stem cell transplantation (HSCT) is a curative treatment for adult patients with hematologic malignancies, but is limited by severe, life-threatening complications such as acute graft-versus-host disease (aGvHD). We have developed a proteomic urine pattern "aGvHD_MS17", consisting of 17 differentially excreted peptides, capable to predict aGvHD grade II or more (1, 2). In 2008, a multicenter, randomized, placebo-controlled, double blind clinical trial (Pre-GvHD) was initiated testing aGvHD_MS17 for prediction of aGvHD and to initiate pre-emptive therapy using prednisolone 2-2.5mg/kg. Patients and Methods: Eleven German transplant-centres contributed 267 patients. Urine was collected weekly from day +7 to +35 and on days +50 and +80 (all +/-3 days) frozen, shipped to Hannover and analyzed using capillary electrophoresis coupled on-line to mass spectrometry (CE-MS) within 72h as described (1). aGvHD_MS17 was considered positive, when the dimensionless classification factor (CF) was +0.1 or more. Eight patients were excluded from analyses, either due to no medication (n=5) or protocol violations (n=3) and 92 were randomized according to the positivity of aGvHD-MS17 to receive either prednisolone (2-2.5mg/kg, n=44) or placebo (n=48) for 5 days followed by a taper for 19 days, if no aGvHD occurred. The remaining 167 patients formed the observation group according to pattern negativity. About half of the patients had acute leukemia (placebo group: n=24/48 (50%), prednisolone group: n=21/44 (50%); observation group: n= 91/167 (54%)) and were in complete remission/chronic phase (CR/CP) (placebo n=23/48 (47%), prednisolone n=27/44 (61%) and observation n=68/167 (41%). The majority was transplanted from matched donors (placebo: n=42/48 (87%); prednisolone: n=37/44 (84%); observation: 146/167 (87%), using reduced intensity conditioning regimens (RIC; 64%), and a calcineurin-inhibitor based GvHD-prophylaxis with MTX or MMF). Results : Prospective and blinded evaluation of aGvHD_MS17 revealed that the first analysis time point (day +7; range: 2-17) most accurately predicted aGvHD grade II or more with a sensitivity of 87% and a specificity of 81% prior to clinical signs with a CF of +0.1 (2). Patients with samples positive for aGvHD_MS17 in the early analyses time points had a 21-fold higher risk to develop aGvHD grade II or more ((p Conclusions: Taken together our results indicate that pre-emptive treatment of imminent aGvHD based on proteomic-pattern-diagnostic with prednisolone 2-2.5mg/kg appears to be safe, but did not influence severity or incidence of aGvHD grade II or more. The prospective evaluation of aGvHD_MS17 confirms the highly reproducible results in the early analysis time points (day +7 to +21) for prediction of aGvHD (day +7; range 2-17). Patients with aGvHD_MS17 positive samples have a 21-fold risk to develop severe GvHD (grade II-IV). Moreover, patients with one sample positive for aGvHD_MS17have a 3-fold increased risk of death by day +500 after HSCT. (1) Blood 2007 :109(12):5511-9. (2) Leukemia, 2014: , 28(4):842-52 Disclosures Jochen: Mosaiques GmbH: Employment. Schmid: Jazz: Membership on an entity9s Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; MoilMed: Membership on an entity9s Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Bethge: Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding. Raad: Mosaiques GmbH: Employment. Durban: Mosaiques GmbH: Employment.