Page 173 - Haematologica3

In vivo IL-12/IL-23p40 neutralization
hematopoietic stem cell transplantation (HCT) comorbidity (HCT-CI) ≥ 3.13 Eligible related or unrelated donors matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing provided filgrastim-mobilized peripheral blood stem cells (PBSC) for transplantation according to standard practices. All patients received tacrolimus and sirolimus for GvHD prophylaxis. The trial was conducted under the approval of the University of South Florida Institutional Review Board.
Trial design and treatment plan
Both HCT recipients and their donors provided consent for par- ticipation in the study. Eligible patients were randomized (1:1 allo- cation, stratified by donor relation) to ustekinumab versus placebo (clinicaltrials.gov identifier: 01713400). Study investigators, clinical staff, and patients were blinded throughout to study arm assign- ment. Ustekinumab was delivered as a subcutaneous injection on day -1, and again on day +20 post HCT at a dose of 45 mg (for those with weight ≤ 100 kg) or 90 mg (weight > 100 kg). Placebo
was a subcutaneous injection of sterile saline of identical volume, character, and packaging as the investigational agent administered on the same schedule.
Clinical outcomes
Neutrophil engraftment was defined by an absolute neutrophil count over 500 per microliter of blood sustained for at least three days, and platelet engraftment was defined by platelet count over 20 per microliter of blood sustained for at least seven days without transfusion support. Mucositis was graded per Common Toxicity Criteria (CTC) v.4.0. Diagnosis and severity grading of thrombotic microangiopathy (TMA) adhered to Bone Marrow Transplantation Clinical Trials Network consensus.14 Hepatic veno-occlusive disease (VOD) was diagnosed according to stan- dard clinical criteria.15 Acute GvHD was scored weekly from HCT to day 100 according to consensus guidelines.16 Chronic GvHD scoring used National Institutes of Health (NIH) Consensus Criteria for diagnosis and staging.17
A
4000
3000
2000
1000
0 Base
B
20
15
10 5
0
P = 0.003 P = 0.001 P = 0.001
P = 0.004
Ustekinumab Placebo
30 25
P = 0.021 7 21 35 49 63 77 91
Collection day
Ustekinumab Placebo
P = 0.004
P = 0.005
Base 7 21 35 49 63 77 91 Collection day
Figure 1. Pharmacokinetic and pharmacody- namics measurements. (A) Concentration of anti-IL-12/IL-23p40 antibody over time post hematopoietic stem cell transplantation (HCT). (B) Concentration of circulating IL-12/IL-23p40 over time post HCT.
haematologica | 2018; 103(3)
533
ng/mL
ng/mL