Page 177 - Haematologica3

In vivo IL-12/IL-23p40 neutralization
production was significantly increased among ustekinum- ab-treated patients in response to third-party stimulus at day 90. IL-17 production was decreased among ustekinum- ab-treated patients in response to host at day 30, and to third-party at both days 30 and 90. These findings were likely detected due to the sensitivity of this functional assay, in contrast to that of circulating serum cytokine or periph- eral blood phenotype assays.
In contrast, this intervention failed to increase peripher- al blood Treg. This could be due to several factors. In con- trast to murine models, patients in both arms of this trial received sirolimus and tacrolimus throughout. The effect of this pharmacological immune suppression platform may have exerted effects on Treg reconstitution post HCT that overwhelmed any alteration from IL-12/IL-23p40 neutralization. In addition, cytokines relevant to Treg homeostasis were not targeted by the study intervention, and IL-6 (central to Th17/Treg balance) was not targeted by this approach. While anti-IL-6 receptor antibody (tocilizumab) therapy (together with cyclosporine and methotrexate) produced a low incidence of grade II-IV acute GvHD in a previous trial, peripheral blood Tregs were similarly not altered.23 In total, these data support the concept that targeted neutralization of IL-12/IL-23p40 or inhibition of IL-6 receptor signaling in the context of con- ventional pharmacological immune suppression fails to augment peripheral blood Tregs, and suggests that clinical benefit of these approaches is not dependent upon
increased Tregs.
These data support an acceptable safety profile for com-
bined IL-12/IL-23p40 neutralization among HCT recipi- ents. Compared to the randomized placebo control in this trial, we observed no evidence of increased toxicity, impaired donor engraftment, infectious morbidity, or death. In contrast to particular infectious risks observed among patients with genetic deficiency in IL-12/IL-23p40 or IL-12Rβ,1,24 no cases of Mycobacterium tuberculosis or Salmonella were seen, and all Candida albicans infections (oral n=4, esophageal n=1) on trial were seen among the placebo arm. In addition, there was no evidence that IL- 12/23p40 depletion increased disease relapse. This finding is important, given the relevance of IL-12 to natural killer (NK) and CD8+ cytotoxic T lymphocytes and tumor con- trol,25,26 and anti-tumor effects of IL-23 (although tumor- promoting effects of IL-23 have been demonstrated).24,27 A recent analysis of 3117 patients (with 8998 person-years of follow up) from 4 major randomized phase II and III ustekinumab trials supports the overall safety profile of this therapy with no evidence for opportunistic infections, or increased rates of malignancies or mortality above those of the general US population.28
The trial was not powered for clinical end points, and provides only initial estimates to be formally tested in a subsequent randomized trial. Specific analysis of acute GvHD target-organ differences is restricted by limited (skin) or no (liver) involvement of sites other than gas-
ABC
P=0.57 P=0.41 P=0.87
DEF
P=0.085
P=0.027
P=0.017
Figure 4. Comparison of clinical outcomes for ustekinumab versus placebo-treated subjects. (A) Cumulative incidence of grade II-IV acute graft-versus-host disease (GvHD). (B) Cumulative incidence of Naitonal Institutes of Health (NIH) moderate/severe chronic GvHD. (C) Cumulative incidence of malignancy relapse. (D) Cumulative incidence of non-relapse mortality. (E) Overall survival. (F) NIH moderate/severe chronic GvHD-, relapse-free survival (Conditional Random Fields Score, CRFS). *P-value for comparisons of cumulative incidence by Gray method; P-value for survival plots by log-rank test.
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