Ustekinumab Shows Greatest GVHD Reduction in MAC Subgroup

Adding ustekinumab (Stelara) to standard prophylaxis did not significantly reduce acute graft-vs-host disease (GVHD) in patients receiving hematopoietic cell transplant (HCT) from matched unrelated donors (MUDs), but it did show greater benefit in patients receiving high-intensity conditioning, according to results presented at the 2026 Transplantation & Cellular Therapy Meetings.¹

The primary end point of 6-month grade 2 to 4 acute GVHD-free survival (GFS) was not met in the overall population; however, ustekinumab showed benefit in a subgroup analysis of patients who received myeloablative conditioning (MAC) rather than reduced-intensity conditioning (RIC).

“We found confirmatory evidence of benefit in this multicenter, randomized, blinded study that manifested with improved GFS, reduced acute GVHD, and reduced nonrelapse mortality [NRM],” Joseph A. Pidala, MD, PhD, said during his presentation.¹ “The effects are most apparent in the myeloablative setting, and we saw no negative impact on other transplant outcomes.” Pidala is a medical oncologist in the Blood and Marrow Transplant Department at Moffitt Cancer Center and an associate professor of oncology in the Department of Oncologic Sciences at the University of South Florida in Tampa.

The pathophysiology of acute GVHD is heavily influenced by donor Th1 and Th17 cell responses, which are dependent on IL-12 and IL-23 signaling. Preclinical models have highlighted IL-12 as a primary driver of alloantigen presentation, particularly within the gastrointestinal (GI) tract following MAC.¹

Ustekinumab, a monoclonal antibody targeting the p40 subunit shared by IL-12 and IL-23 that is used in Crohn disease and ulcerative colitis, has previously shown clinical promise in early translational studies.²

This multicenter, randomized, placebo-controlled, double-blind phase 2 trial (NCT04572815) evaluated whether adding ustekinumab to standard tacrolimus/methotrexate prophylaxis could improve outcomes in patients receiving MUD-HCT.

Study Design and Patient Population

The trial enrolled 116 adult patients (range, 56-58 years) with hematologic malignancies, predominantly acute myeloid leukemia or acute lymphoblastic leukemia (62%), undergoing 8/8 MUD peripheral blood stem cell transplantation. Participants were randomly assigned 1:1 to receive either ustekinumab with intravenous induction followed by subcutaneous doses on days 50, 100, and 160 or placebo. Randomization was stratified by site and conditioning intensity, with 48% receiving MAC and 52% receiving RIC.

Tacrolimus and methotrexate were given according to institutional standards. Use of posttransplantation cyclophosphamide and antithymocyte globulin was excluded.

Efficacy Outcomes and MAC Subgroup Analysis

The study did not meet its primary end point of a statistically significant improvement in 6-month grade 2 to 4 GFS. The 6-month GFS rate was 44.8% in the placebo arm vs 55.2% in the ustekinumab arm (OR for failure of placebo vs ustekinumab, 1.48; 80% CI, 0.91-2.40; 1-sided P =.15).

Despite the primary end point result, several secondary outcomes suggested a clinical benefit, particularly in the early posttransplant period and within the MAC subgroup. At 100 days, the grade 2 to 4 GFS was significantly higher in the ustekinumab group (63.8% vs 44.8%; OR for failure of placebo vs ustekinumab, 2.17; 80% CI, 1.31-3.59). Similarly, the 100-day grade 3 to 4 GFS rate favored the intervention (86.2% vs 74.1%).

Subgroup analysis revealed a pronounced effect among patients receiving MAC. In this cohort, 6-month grade 2 to 4 GFS was 35.7% with placebo vs 60.7% with ustekinumab (OR for failure, 2.78; 80% CI, 1.19-6.41). Conversely, no benefit was observed in the RIC subgroup: 53.3% for placebo vs 50.0% for ustekinumab (OR, 0.87; 80% CI, 0.40-1.92).

The investigators also looked at GVHD by organ staging and observed differences, particularly in the MAC subgroup. “What this shows is there was a reduced burden and a reduced organ severity, especially in the skin, upper GI, and lower GI for the ustekinumab-treated patients,” Pidala said.

“However, we saw no difference in [National Institutes of Health criteria for] moderate to severe chronic GVHD,” he added. “The 12-month estimates were 19% for both groups, and at 24 months, the estimate was 33% for the ustekinumab and 38% for placebo.”

Ustekinumab was associated with 6-month NRM rates of 7.2% vs 16.3% with placebo (OR, 2.33; 80% CI, 1.11-5.29), and these grew to 22% vs 7%, respectively, at longer follow-up. In the MAC group, NRM was 12% with placebo vs 7% with ustekinumab. The overall survival estimate was 80% with ustekinumab vs 63% with placebo at 24 months. At this time point, discontinuation of immune suppression was similar at 12% for placebo vs 15% for ustekinumab.

Effects on Engraftment

Engraftment of neutrophils and platelets appeared similar. Rates of 6-month relapse were nearly identical between the 2 arms (7.2% vs 7.3%), suggesting that IL-12/23 inhibition did not compromise the graft-vs-leukemia effect.

Biologic correlative studies in 39 patients who had received MAC at Fred Hutch Cancer Center in Seattle, Washington, were presented. “What this demonstrates is that it is effective in selective IL-12 inhibition and inhibition of downstream Th1 responses from IL-12,” Pidala said.

Next Steps

Although this phase 2 trial did not reach its primary end point for the entire cohort at 6 months, the data provide a compelling signal for ustekinumab's efficacy in the early posttransplant phase and specifically within the MAC setting.

“We think reviewing these data that this is most impressive in the myeloablative setting, and there's some kind of rationale as to why that may be. I think future studies probably would focus on that,” Pidala said.

REFERENCES

1. Pidala JA, Nakamura R, Chen G, et al. Randomized phase II trial of ustekinumab for GVHD prevention in matched unrelated donor transplants: primary trial results. Presented at: 2026 Transplantation & Cellular Therapy Meetings; February 4-7, 2026; Salt Lake City, UT. Abstract 9.

2. Pidala J, Beato F, Kim J, et al. In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation. Haematologica. 2018;103(3):531-539. doi:10.3324/haematol.2017.171199