Risk Factors For Steroid-Refractory Acute Graft-Versus-Host Disease After Allogeneic Stem Cell Transplantation From Matched Related Or Unrelated Donors

The standard risk factors for acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (allo-SCT) from related or unrelated donors are well defined and include HLA mismatch or unrelated donor, older recipient age, and female donor for male recipient (FM). The steroid-refractory (SR) forms of aGVHD are important to consider because they often have a major deleterious impact on transplant outcome. Unfortunately, the specific risk factors for SR aGVHD are less clearly defined. To characterize these risk factors after allo-SCT from matched related or unrelated donors, we undertook a retrospective analysis of adult patients transplanted at our center between 01/01/2000 and 12/31/2012.

Steroid-refractory aGVHD was defined as aGVHD progressing after 3 days of treatment, or unchanged after 7 days, or in incomplete response after 14 days. GVHD occurring after donor lymphocytes infusion were excluded. Overall survival (OS) was calculated using the Kaplan-Meier estimate. Cumulative incidences (CI) were used for SR aGVHD in a competing risk setting with death as a competing event. The Gray test was used to compare CI curves. For multivariate analysis, the variables with p value < 0.1 were entered into a Fine-Gray model and the least significant variables were excluded in sequential fashion until all remaining factors were significant at the p=0.05 level. The variables considered were recipient age (≥ vs < 50 years, median age), female vs male donor, FM vs other combinations, matched related (MRD) vs matched unrelated donor (MUD), peripheral blood (PB) vs bone marrow (BM) graft, GVHD prophylaxis with cyclosporine (CsA)+metho vs others, myeloablative (MAC) vs reduced-intensity conditioning (RIC) regimen, antithymocyte globulin (ATG) vs no ATG, number of CD34+ cells in the graft ≥ vs < 5.6 x 10⁶/kg (median number), early (CR1, PR1, chronic phase, or untreated) vs advanced disease, CMV-seropositive vs seronegative recipient. Unrelated donors were matched at the allele level for HLA-A, B, C, DRB1, DQB1.

Six hundred and thirty four patients were identified and included in the present study. The median age was 50 years (18-67). Diseases were AML (n=230), ALL (n=104), myeloma (n=80), NHL (n=74), Hodgkin's disease (n=18), MDS (n=47), CLL (n=29), CML (n=18), aplastic anemia (n=19), and MPS (n=15). Status at transplant were CR1 or PR1 or chronic phase (n=260), > CR1 or PR1 (n=237), refractory (n=101), or untreated (n=36). Conditioning regimens were RIC (n=405) or MAC (n=229). Rabbit ATG was administered to 327 patients, of whom 298 received a RIC regimen. Donors were MRD (n=360) or MUD (n=274). Sources of stem cells were PB (n=452), BM (n=177), missing data (n=5). The prophylaxis of GVHD was CsA+metho for 339 patients.

In the whole population, 71 patients presented a SR aGVHD at a median time of 29 days (8-137) after transplant, representing a CI of 11.2% ± 1.2%. Their OS at 1 year post-transplant was 27% ± 5%. In univariate analysis, the risk factors for SR aGVHD were MAC (p=0.02), MUD (p=0.02), no ATG (p=0.01), and a trend for FM (p=0.07). Other variables considered in univariate analysis were recipient age (p=0.6), female vs male donor (p=0.6), recipient CMV status (p=0.7), status at transplant (p=0.2), PB vs BM graft (p=0.9), number of CD34+ cells (p=0.4), and GVHD prophylaxis (p=0.6). In multivariate analysis, the risk factors for SR aGVHD were MUD (HR=2.5, 95%CI: 1.5-4.1, p=0.0003), FM (HR=2, 95%CI: 1.2-3.4, p=0.008), and no ATG (HR=2.1, 95%CI: 1.3-3.4, p=0.002). Patients were then divided into 3 groups. The CI of SR aGVHD was 2.7% ± 1.6% in the low-risk group (no MUD + no FM + ATG; n=112), 21.8% ± 3.4% in the high-risk group (MUD + FM +/- ATG, or MUD + no FM + no ATG; n=147), and 9.6% ± 1.5% in the intermediate-risk group (n=375); p=10^-6.

We conclude that MUD, FM, and no ATG were independent risk factors for SR aGVHD in adult patients after allo-SCT from MRD or MUD. These data support the prevalent roles of HLA and donor T cell alloreactivity in the pathogenesis of SR aGVHD and may help identify patients at high risk of SR aGVHD, candidates for experimental first-line therapies of aGVHD.