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W.R. Drobyski et al.
Figure 4. Comparative analysis of serum cytokine production in tocilizumab-treated versus patients that received Tac/MTX only. Concentration of IL-6, sIL-6R, IL-2, IL-4, IL-10, IL-17, IFN-g, and TNF-α in the serum of patients that were treated with Toc/Tac/MTX (, n=35) or Tac/MTX (control) (, n=11) for the prevention of aGvHD prior to the start of conditioning and at days 7, 14 and 28. *P<0.05, **P<0.01, ***P<0.001. IL: interleukin; sIL: soluble interleukin; TNF-α: tumor necrosis factor α; IFN-g: interferon g.
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pared to a matched control population that only received Tac/MTX.
Despite the reduction in grades II-IV aGvHD, however, there was no difference in TRM or OS between these two groups. There are several possible explanations for this observation. First, this was not a randomized trial, and the matching process could have resulted in unperceived dif- ferences between the two cohorts that could have impact- ed transplant outcome. Secondly, we observed two late GvHD deaths beyond six months, suggesting that the salutary effects conferred by Toc may be temporally lim- ited. That there was no difference in the incidence of cGvHD is compatible with this interpretation. This does not, in our view, diminish the results, but rather highlights that effective prophylactic strategies for GvHD are likely to require a multi-tiered approach of which the mitigation of aGvHD within the first six months would be one important step.
A notable finding in this study was the very low inci- dence of aGvHD that occurred in the lower GI tract. Specifically, there were no cases within the first 100 days, and only one case which occurred by day 180. Pre-clini- cal studies have shown that IL-6 messenger ribonucleic acid (mRNA) levels are significantly increased in the colons of mice,7 and the blockade of the IL-6 signaling pathway is able to significantly reduce the severity of GvHD in this tissue site.7,8 IL-6 has also been identified as a plasma biomarker that predicts for severity and non- relapse mortality in patients with GI GvHD.31 Our find- ings further support the premise that IL-6 plays an impor- tant role in mediating tissue damage in the lower GI tract. Given that the incidence of liver GvHD has been declin- ing over time,32 involvement of the GI tract has emerged
as the primary driver of morbidity and mortality in patients with this disease. In fact, the development of lower GI tract GvHD carries significant prognostic impli- cations for OS. Patients with lower tract GvHD are more likely to be steroid-resistant,33 which itself is associated with increased mortality.34 Furthermore, patients with higher clinical and histological grades of lower GI tract GvHD have an increase in non-relapse mortality that results in reduced OS.35,36 Thus, given the poor prognosis associated with severe GI GvHD,37,38 therapeutic strate- gies that are focused on preventing the development of this complication have the potential to impact the overall course of this disease and improve transplant outcome. While we observed patients with upper GI tract GvHD, recent studies have shown that disease in this tissue site is generally responsive to modest doses of steroids, and does not impact OS.39,40
We observed that IL-6 was the only measured serum cytokine that was significantly increased above baseline in a control population of patients that received Tac and MTX but not Toc. The administration of Toc resulted in much higher serum IL-6 levels, above that seen in the con- trol population, in recipients of both MA and RIC regi- mens. This was likely due to decreased consumption of IL-6 when Toc binds to the IL-6R. IL-6 signaling occurs through two distinct mechanisms; IL-6 can bind to a membrane receptor that is expressed on hematopoietic cells and hepatocytes,41 and also bind to a soluble form of the IL-6 receptor, which can in turn bind to glycoprotein (gp)130, which is ubiquitously expressed on most cells.42,43 As further support for this premise, we observed that sIL- 6R levels were also significantly augmented in patients who received both MA and RIC regimens. Of note, the
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