Page 172 - Haematologica3

J. Pidala et al.
Crohn disease. In humans, ustekinumab has clinical activ- ity in several immune-mediated disorders, including steroid-refractory acute GvHD.10 A sirolimus (SIR)-based pharmacological immune suppression program provides an ideal platform for examining the biological effect of IL- 12/IL-23p40 neutralization: SIR inhibits differentiation of Th1 and Th17 cells, and promotes generation of Tregs from naïve T cells. Tregs proliferate and survive in the presence of SIR, as they do not activate the phosphatidyl inositol 3-kinase (PI3-K)/AKT pathway.11,12
The primary objective of the trial was to examine the biological impact of IL-12/IL-23p40 neutralization. We anticipated disruption of Th1 and Th17 with sparing of
Table 1. Patient, disease, and transplantation variables.
Th2 and Tregs. Secondary objectives were to determine safety of this investigational GvHD prevention approach and examine initial evidence of clinical efficacy.
Methods
See Online Supplementary Appendix for full details.
Inclusion criteria
Patients were aged 18-70 years with adequate vital organ func- tion and Karnofsky performance status. Exclusion criteria were: uncontrolled infection, active HIV, hepatitis B or C infection, or
Variable
Patient age (median, range)
Donor age (median, range)
Ustekinumab
53 (22-69) 33 (22-72)
Placebo
59 (38-69) 29 (22-66)
P
P=0.16 P=0.64
P=0.88
P=0.22
P=0.67
P=0.18
P=0.22
P=0.57
P=1
P=0.12
Donor:recipient sex
F:M 4 4 Others 11 11
Donor:recipient CMV
N:N 3
N:P 7 2 P:N 2 2 P:P 3 6
Disease
ALL 3
AML 6 6 CLL 1 2 HD 2 1 MDS 2 1 MPN 0 2 NHL 1 2
Remission status
CR 9
PIF 1 0 PR 3 0 REL 0 2 SD 2 4
Disease risk index29
Low 2
Intermediate 12 12 High 1 3
5
1
9
Graft type PBSC BM
Conditioning regimen FluBu (6.4 mg/kg) FluBu (AUC 3500) FluBu (AUC 5300) FluMel
Donor relation MRD
MUD
0
15 15 0 0
3 1 1 3 8 9 3 2
7 6 8 9
532
DQB1-mismatch No1315 Yes 2 0
F: female; M: male; CMV: cytomegalovirus; N: negative; P: positive; ALL: acute lymphoblastic leukemia; AML: acute myelogenous leukemia; CLL: chronic lymphocytic leukemia; HD: Hodgkin lymphoma; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; NHL: non-Hodgkin lymphoma; CR: complete remission; PIF: primary induction failure; PR: partial response; REL: relapsed/refractory disease; SD: stable disease. PBSC: peripheral blood mobilized stem cells; BM: bone marrow; Flu: fludarabine; Bu: busulfan; Mel: melphalan; AUC: average daily exposure of busulfan in μMol*minute (min); MRD: matched related donor; MUD: matched unrelated donor.
haematologica | 2018; 103(3)