Work

5: Changes in TNFR1 ratios in the first week post-myeloablative allogeneic BMT correlate with GVHD, TRM and OS in children

Year: 2007

Type: article

Abstract: Graft-vs-host disease (GVHD) remains the major cause of morbidity and treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HSCT). Pre-clinical studies show that inflammatory cytokines such as tumor necrosis factor-α (TNF) are significant in the pathogenesis of GVHD. We tested the hypothesis that early rises in TNF (on day 7 following allogeneic HSCT) predict the development of significant GVHD and TRM. TNF circulates as a complex bound to its receptors. We therefore measured soluble TNF receptor 1 (TNFR1) levels pre-HSCT and on day 7 post-HSCT as a surrogate marker for TNF in 82 children (median age 8.8y, range 0.8-17.8y) who underwent myeloablative HSCT. Preparative regimens included Busulfan (71%), BCNU (17%), and TBI (12%). There were 38 related donor recipients (46%), 38 unrelated donor recipients (46%) and 6 cord blood recipients (8%). GVHD median day of onset was 20d, almost two weeks after TNFR1 levels were measured. Because of the variability in baseline TNFR1 levels, we expressed the day 7 value as a ratio to pretransplant baseline. The mean day 7 TNFR1 ratio correlated with severity of GVHD. The mean day 7 TNFR1 ratio was 1.7 for patients with GVHD 0-1 (n=50), 2.6 for patients with GVHD 2 (n=19), and 3.1 for patients with GVHD 3-4 (n=13), p=0.01. We tested whether subjects whose day 7 TNFR1 ratio was in the top quartile (day 7 TNFR1 ratio > 2.5) were at increased risk of developing GVHD 2-4, 1y TRM, and 1y survival compared to subjects whose day 7 TNFR1 ratio was below the 75th percentile. Subjects with day 7 TNFR1 ratios above 2.5 were almost twice as likely to develop GVHD 2-4 and had an almost 50% increase in probability of death by 1 year. Because age is an independent risk factor for GVHD, these results were compared to a larger cohort of 355 adult patients (medain age 46.5y, range 18.3-65.2y) and a statistically significant correlation between TNFR1 day 7 ratios and GVHD 2-4, TRM and survival was also observed [Table 1]. In additional analyses, TNFR1 day 7 ratios were an important predictor independent of donor source.Table 1TNFR1 RatioGVHD 2-41 YR TRM1 YR SurvivalChildren (n=82) Median age 8.8y (range 0.8-17.8y)TNFR1 ≤ 2.5 (n=63)33%6%77%TNFR1 > 2.5 (n=19)58%26%53%p=0.02p=0.07p=0.04Adults (n=355) Median age 46.5y (range 18.3-65.2y)TNFR1 ≤ 2.5 (n=264)31%19%62%TNFR1 > 2.5 (n=91)60%41%48%p<0.001p<0.001p=0.02 Open table in a new tab We conclude that for children undergoing HSCT, the magnitude of rise in TNFR1 after myeloablative transplant correlates with the subsequent development of GVHD, TRM and survival. These informative changes are detectable on day 7, up to two weeks in advance of clinical manifestations of GVHD, and may therefore be useful in developing of a predictive laboratory test.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2006.12.007