Early T-Cell Chimerism Is Valuable in Predicting Early Mortality from Steroid-Resistant Acute Graft Versus Host Disease after Myeloablative Allogeneic Haematopoietic Cell Transplantation

The aim of this study was to evaluate the impact of early chimerism status on incidence and clinical course of acute GVHD in allogeneic transplant recipients. From March 2008 to February 2013, 106 eligible patients were included in the study. Median patient age was 40 (16-58) years with 66 (62%) males and 40 (38%) females. Pre-transplant diagnoses were AML (44 patients, 42%), ALL (29 patients, 27%), MDS (17 patients, 16%), CML (8 patients, 8%), NHL (2 patients, 2%) and other (6 patients, 6%). Donors were HLA-identical siblings in 33 (31%) patients and matched unrelated donors in 73 (69%) patients. Stem cell sources were bone marrow (61 patients, 58%) and peripheral blood (45 patients, 42 %). Patients were conditioned with Cyclophosphamide and TBI 12 Gy (63 patients, 59%), VP16 and TBI 12 Gy (31 patients, 29%), Cyclophosphamide and Busulfan (10 patients, 9%), moreover 1 patients received Busulfan and Melphalan and another patient Busulfan and VP16.

T-cell line specific chimerism was analysed by PCR-VNTR and chimerism samples were measured on day 35. Donor chimerism (DC) was defined as 95% or more cells of donor origin within CD4 and CD8 T-cells and mixed chimerism (MC) as less than 95% donor CD4 and CD8 T-cells.  At a follow-up time of 767 (140-1940) days 71 (67%) patients were still alive. Among deceased patients, cause of death was TRM in 23 (66%) patients and relapse in 12 (34%) patients. Acute GVHD occurred in 68 (64%) patients with 49 (46%) patients diagnosed with grade II-IV aGVHD. The incidence and grade of aGVHD was not different in DC versus MC patients. Early survival probability at day 180 estimated by Kaplan-Meier showed significantly better outcome for patients with MC compared to DC (p=0.04). Death from TRM with relapse as competing risk analysed with cumulative incidence emphasized poorer outcome for MC patients compared to DC patients (p=0.03).We then analysed the clinical course in MC and DC patients diagnosed with aGVHD grade II-IV who later on died from TRM. Of these 21 patients, 12/14 DC patients compared to 1/7 MC were under treatment with either high dose Prednisolone (≥ 1.5 mg/kg body weight) or Infliximab by their time of death (p=0.007, figure 1), associating early T-cell DC with steroid-resistant aGVHD. This suggest, that even though the incidence and grade of aGVHD were not different between patients with DC versus MC, the clinical course of aGVHD seem to differ significantly in the two groups with higher mortality from steroid-resistant aGVHD in DC patients compared to MC patients. Early T-cell DC may be an early predictor of development of steroid-resistant GVHD.