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score at both chronic GvHD onset and maximal severity
(Online Supplementary Table S2).
Infectious complications
Standard institutional infectious prophylaxis and moni- toring was performed in all cases. There was no significant difference between ustekinumab and placebo groups for time from HCT to first systemic infection (median 27 vs. 26 days; P=0.7), total number of infections (n=14 vs. n=10; P=0.9), infection sites or organisms identified, or infection density (defined as infections per survival time, median 0.21 vs. 0.22; P=0.8). There was no significant difference in number with cytomegalovirus (CMV) reactivation more than 1000 copies (n=2 vs. n=1) and median time to CMV reactivation (57 vs. 24 days; P=0.3), Epstein-Barr virus (EBV) reactivation more than 1000 copies (n=0 vs. n=2) and median time to EBV reactivation (45 vs. 80 days; P=1), or HHV-6 reactivation more than 1000 copies (n=1 vs. n=2) and median time to HHV-6 reactivation (83 vs. 73 days; P=1.00).
Patient-reported outcomes
There was no significant difference in change in Quality of Life between study arms (P=0.15) (Online Supplementary Figure S1). The Functional Assessment of Cancer Therapy- Bone Marrow Transplant (FACT-BMT) Trial Outcome Index (TOI) scores demonstrated transient worsening in both groups (P<0.001). Between-group comparisons at
each time point revealed no significant group differences in Quality of Life pre-HCT (P=0.32) or 30 days post HCT (P=0.98), although the placebo arm demonstrated better Quality of Life at 90 days post HCT (P=0.04). Mean Standard of Error (SE) FACT-BMT TOI scores at 90 days post HCT were 58.47 (3.19) in the ustekinumab arm and 68.51 (3.43) in the placebo arm.
Discussion
Th1 and Th17 lymphocytes have been implicated in acute GvHD pathogenesis, and prior pre-clinical work has demonstrated that targeted disruption of key lineage-defin- ing transcription factors (Tbet, RORy) or IL-12/IL-23p40 cytokine neutralization polarizes T-cell differentiation and mitigates GvHD lethality. In an original translational effort, targeted IL-12/IL-23p40 neutralization was tested in a blinded randomized trial to discern the biological impact of this intervention and to examine the clinical safety and ini- tial efficacy in acute GvHD prevention. With the examined dose and schedule of ustekinumab delivered, IL-12/IL- 23p40 was neutralized through the early post-HCT period in vivo. Consistent with murine experimental data, donor alloresponse was polarized. Specifically, IFN-y production was significantly reduced among ustekinumab-treated patients in response to third-party stimulus at day 30, while response to HLA-matched host was low, as expected. IL-4
A
C
B
D
Figure 3. Regulatory T cell (Treg) numbers and suppressive function at 30 days post HCT. (A) number of peripheral blood Treg/total CD4+ T cells at day 30 post HCT; (B) absolute number of Treg/μL at day 30 post-HCT. (C) Representative Treg suppression assay, demonstrating reduced proliferation of T-responder cells in presence of escalating Treg:T-effector ratio; D) absolute Treg numbers to achieve IC-25.
haematologica | 2018; 103(3)