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Tocilizumab for the prevention of acute GvHD
Figure 2. Cytokine levels in control population that received tacrolimus and methotrexate for GvHD prophylaxis. Concentration of IL-6, sIL-6R, IL-2, IL-4, IL-10, IL-17, TNF-α, and IFN-g in the serum of patients (n=11) who received Tac/MTX for the prevention of aGvHD prior to the start of conditioning, and at days 7, 14 and 28. *P<0.05, ***P<0.001. IL: interleukin; sIL: soluble interleukin; TNF-α: tumor necrosis factor α; IFN-g: interferon g.
grades II-IV aGvHD at day 180 between patients who received MA (17%, 95% CI 4-37) versus reduced intensi- ty (18%, 95% CI 4-39) conditioning regimens (Figure 1E). The median time to onset for aGvHD in recipients of MA versus reduced intensity transplants was 44 and 78 days, respectively. The incidence of cGvHD at 12 months was 38% (95% CI 21-55) in this patient popula- tion (Figure 1F). The median follow up for surviving patients was 15 months. TRM was 14% (95% CI 5-28) at 12 months and was attributable to GvHD (n=3), sepsis (n=1), aspergillus pneumonia (n=1), idiopathic pneumo- nia syndrome (n=1), and respiratory failure (n=1). The one-year cumulative incidence of relapse was 29% (95% CI 15-44). DFS and OS at 12 months was 57% (95% CI 42-70) and 68% (95% CI 53-79), respectively, (Figures 1G,H).
Side effects and infectious complications
There were no infusion-related reactions associated with the administration of Toc. The major immediate Toc- associated side effect within the first 28 days post-trans- plantation was the development of grade III liver toxicity. Nine patients (26%) had ≥ grade III ALT elevations, two patients (6%) had ≥ grade III AST levels and one patient had a grade IV bilirubin elevation. Transaminase eleva- tions typically peaked 7-10 days after infusion, and were transient in all patients, eventually returning to baseline. The marked bilirubin level in one patient was ascribed to total parenteral nutrition administration after a biopsy revealed no evidence of GvHD or any other underlying pathology. No patient developed veno-occlusive disease of the liver. A total of 23 grade III or higher infectious com- plications were observed in 13 patients during the first 100 days. Fifteen of these were due to bacterial infections, of which 11 were bloodstream (staphylococcus epidermidis [n=6], bacillus cereus [n=1], strep oralis [n=1], strep mitis
[n=1], polymicrobial sepsis [n=1], vancomycin-resistant enterococcus [n=1]), two urinary tract (staphylococcus epi- dermidis [n=1], vancomycin-resistant enterococcus [n=1]), one respiratory (staphylococcus epidermidis), and one attrib- utable to clostridium difficile. Cytomegalovirus (CMV) reactivation occurred in two of 12 (17%) seropositive recipients. Other viral infections consisted of human her- pes virus 6 (HHV-6) encephalitis (n=1), enterovirus (n=1), and BK virus (n=3). One patient developed invasive aspergillus pneumonia.
Inflammatory cytokine analyses
To examine how the administration of Toc altered inflammatory cytokine production, we assayed serum cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor α [TNF-α] and interferon g [IFN-g]) and sol- uble (s)IL-6R levels in the peripheral blood of patients who received Toc (n=35) as well as a control population (n=11) which had the same trial eligibility criteria, but did not receive this agent (see patient demographics in Online Supplementary Table S2). In the control population, we observed that IL-6 was the only cytokine that was increased above baseline during the first 28 days (i.e., nine-fold increase on day 14 post-transplantation) (Figure 2). Conversely, sIL-6R levels were significantly decreased on days seven and 14 before rebounding back to baseline on day 28. In the Toc cohort, IL-6 levels were increased in patients who received Toc at days seven, 14, and 28 when compared to baseline (Figure 3A). Levels were augment- ed above baseline in both MA and RIC recipients (Figure 3A), although IL-6 concentrations were higher in patients who received ablative compared to reduced intensity reg- imens on days seven and 14, but not day 28 (Online Supplementary Figure S2A). sIL-6R levels were also signifi- cantly increased beginning on day seven post-transplanta- tion, and were still elevated by day 28 (Figure 3B). Levels
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