Work

Day7 TNFR1 Levels Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplant (HCT) Predict For Acute GVHD

Year: 2009

Type: article

Abstract: Tumor necrosis factor-α (TNF) is significant in the pathogenesis of GVHD. We have previously shown that early rises in soluble TNF receptor 1 (TNFR1) levels measured on day 7 following myeloablative (MA) allogeneic HCT predict the development of GVHD and TRM. In the setting of reduced intensity conditioning (RIC) GVHD rates are similar to MA even though GVHD onset is often delayed. We therefore hypothesized that TNFR1 levels on day 7 would correlate with GVHD after RIC. TNFR1 levels were measured on day 7 post-HCT in 156 pts (median age 56.6y, range 7–71y) who underwent RIC HCT between 2000 to 2008. Pre-HCT conditioning was Fludarabine (125–180 mg/m2) and Busulfan (6.4–8.0 mg/kg) ± total lymphoid irradiation (2–4 Gy) in 142 pts, with minor variations in 14 pts, including 6 that received ATG. GVHD prophylaxis was tacrolimus (day -3 to 180) and short-course methotrexate (5 mg/m2 on day 1,3,6,11 in 99 pts) or mycophenolate (day 0–28 in 57 pts). There were 47 related donor (RD) pts (30%), 109 unrelated donor (URD) pts (70%) and 34 pts received single antigen mismatched HCT (6 RD, 28 URD). The incidence of GVHD 2–4 was 49% in URD and 39% in RD. The median day of GVHD onset was 32d (range 6–162d); 56d in the RD and 30d in the URD (p = 0.02). The logarithm of TNFR1 levels was used for the analysis in order to normalize right-skewed values. Regression analysis revealed that a doubling in day 7 TNFR1 levels increased the risk of GVHD 2–4 by 1.36 times (p = 0.007), however, the risk appeared to be primarily in the URD pts [Table 1]. Consistent with this observation, the median day 7 TNFR1 level was significantly higher in pts developing GVHD 2–4 after URD (11.4 vs 11.0, p = 0.01), but not after RD RIC HCT (11.3 vs 11.1, p = 0.38). Using the median TNFR1 level in URD HCT as a threshold, we found that pts with day 7 TNFR1 levels above the median were more likely to develop GVHD 2–4 (p = 0.008). This correlation remained significant (p = 0.01) after adjustment for pt age, gender and HLA match. We conclude that for pts undergoing RIC HCT, a higher day 7 TNFR1 level correlates with incidence of GVHD 2–4. This effect of TNFR1 on GVHD was strongest in the URD setting where donor response to host alloantigens is more robust and GVHD develops more quickly. The informative value of a day 7 TNFR1 level decreases in RD pts who develop GVHD a median of 7 weeks later, suggesting that GVHD in the RD RIC setting is not strongly dependent on conditioning induced TNF release.Tabled 1Association of TNFR1 with Risk of GVHD 2-4DonorRisk Ratio∗Risk Ratio is for a doubling of TNFR1 levelsp-valueOverall (n=156)1.360.007RD (n=47)1.220.44URD (n=109)1.420.006∗ Risk Ratio is for a doubling of TNFR1 levels Open table in a new tab

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.395