Pre-emptive treatment of acute GVHD: a randomized multicenter trial of rabbit anti-thymocyte globulin, given on day+7 after alternative donor transplants

Abstract

We have previously shown that hemopoietic stem cell transplant (HSCT) recipients can be stratified on day þ 7 as having low, intermediate or a high risk of transplantrelated mortality (TRM). With the aim of reducing TRM and GVHD, intermediate and high-risk patients (n ¼ 170) were randomized to receive anti-thymocyte globulin (ATG, thymoglobuline) on day þ 7 (n ¼ 84) or no treatment (n ¼ 86) (controls). There was a reduction of TRM from 35% in controls to 29% in ATG patients (P ¼ 0.3), of acute GVHD III-IV from 15 to 5% (P ¼ 0.02) and of chronic GVHD from 26 to 11% (P ¼ 0.03); survival was comparable. The predictive value of the day þ 7 score on TRM was confirmed for controls (19 vs 42% for intermediate vs high risk, respectively, P ¼ 0.03), whereas ATG abrogated this predictive effect (29 vs 29%). ATG reduced GVHD (P ¼ 0.006) in high-risk patients, but not in patients with an intermediate risk.In conclusion, we confirm that TRM can be predicted on the basis of day þ 7 laboratory values, after alternative donor HSCT; in high-, but not intermediate-risk patients, the administration of ATG on day þ 7 reduces GVHD. These results may represent a platform for risk-adapted post transplant immune modulation.

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD

“…This represents the first biomarker of cGVHD measured early post transplant, that is, at the time when the risk of developing cGVHD may be reduced over twofold using ATG, at least in patients who received ATG also during conditioning. 20 The mechanism of low IL15 level predisposing HCT recipients to cGVHD is not clear. One of the following three mechanisms might apply:…”

“…How ATG, given peritransplant, prevents cGVHD, [13][14][15]20,31,44,45 which typically develops at X3 months post transplant, has been a mystery. The correlation between ATG and IL15 levels and the inverse correlation between IL15 levels and CD8 T-cell counts ( Figure 3) and the published inverse correlation between day 7 or 28 ATG levels and day 28 CD8 T-cell counts 37 suggest that ATG kills or prevents expansion of CD8 T cells, some of which (alloreactive CD8 T cells?)…”

“…6 (2) An important candidate drug for preemptive therapy for cGVHD is ATG, which may prevent not only cGVHD but also late aGVHD. The reason we think so is that ATG is known to prevent aGVHD in general, 12,13,20,43,44 and because in the study showing benefit of preemptive ATG on cGVHD, 20 cGVHD was defined as post-day 100 GVHD, thus presumably including late aGVHD.…”

“…The cytokines were chosen as their levels have been reported to be associated with cGVHD and/or acute GVHD (aGVHD being a strong predictor of cGVHD). [21][22][23][24][25][26][27][28][29] g-glutamyl transpeptidase, cholinesterase, total protein and urea were chosen as their levels early post transplant had been reported to predict non-relapse mortality 20,30 and cGVHD is a major contributor to non-relapse mortality. ATG was chosen as its levels early post transplant have been reported to predict aGVHD and/or cGVHD.…”

“…19 We focused on potential biomarkers that can be measured in serum early post transplant, as it has been recently shown that ATG administered early post transplant can prevent development of cGVHD. 20 Potential biomarkers evaluated in this study included the cytokines B-cell activating factor (BAFF), vascular endothelial growth factor, soluble TNF-a receptor 1, soluble IL2 receptor a, IL5, IL6, IL7 and IL15, and g-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG levels. The cytokines were chosen as their levels have been reported to be associated with cGVHD and/or acute GVHD (aGVHD being a strong predictor of cGVHD).…”