Elevations of tumor necrosis factor receptor 1 at day 7 and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning

Acute GVHD has remained a significant cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning. The role of TNF-alpha in the biology of acute GVHD after nonmyeloablative conditioning has not been studied thus far. Here, we measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-alpha in 106 patients before the start of the conditioning regimen (baseline) and 7 days after allogeneic HCT with nonmyeloablative conditioning. The nonmyeloablative regimen consisted of 2Gy TBI alone (n = 15), 2Gy TBI plus fludarabine 90 mg/m(2) (n = 73), or 4Gy TBI plus fludarabine 90 mg/m(2) (n = 18). TNFR1 levels increased significantly from baseline to day 7 after nonmyeloablative HCT (P<0.0001). Patients conditioned with 4Gy TBI had higher TNFR1 day 7/baseline ratio than those conditioned with 2Gy TBI (median 1.65 versus 1.25; P = 0.01). In a multivariate Cox model, high TNFR1 day7/baseline ratio was associated with grades II-IV (HR = 2.2, P = 0.01) and grades III-IV (HR = 2.9, P = 0.007) acute GVHD, but had no impact on overall survival (P = 0.8). In summary, our data suggest that nonmyeloablative conditioning induces the generation of TNF-alpha, and that the magnitude of TNF-alpha generation depends on the conditioning intensity (2 Gy versus 4Gy TBI). Further, assessment of TNFR1 levels before and on day 7 after nonmyeloablative HCT provided useful information on subsequent risk of experiencing acute GVHD. Bone Marrow Transplantation (2010) 45, 1442-1448; doi:10.1038/bmt.2009.360; published online 11 January 2010