Ustekinumab Plus Standard Prophylaxis Reduces GVHD in MAC Subgroup

Ustekinumab (Stelara) in combination with standard prophylaxis did not significantly reduce the incidence of acute graft-vs-host disease (GVHD) in patients who underwent hematopoietic cell transplant (HCT) from matched unrelated donors (MUD), according to data from a phase 2 trial (NCT04572815) presented during the 2026 Transplantation & Cellular Therapies Meetings.¹

The primary end point of 6-month grade 2-4 acute GVHD-free survival (GFS) was not met in the overall population; however, benefit was shown with ustekinumab in subgroup analysis of those 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],” said Joseph A. Pidala, MD, PhD, associate professor of oncology at the Moffitt Cancer Center in Tampa, Florida, in his presentation. “The effects are most apparent in the myeloablative setting, and we saw no negative impact on other transplant outcomes.”

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.

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

This multicenter, randomized, placebo-controlled, double-blind study sought to evaluate whether the addition of ustekinumab to standard tacrolimus/methotrexate prophylaxis could improve outcomes in patients receiving MUD-HCT.

What were the key study design and patient population characteristics?

The trial enrolled 116 adult patients (median age, 56–58 years) with hematologic malignancies, predominantly acute myeloid leukemia and acute lymphoblastic leukemia (62%), undergoing 8/8 MUD peripheral blood stem cell transplantation. Participants were randomly assigned on a 1:1 basis 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 post-transplantation cyclophosphamide and anti-thymocyte globulin was excluded.

What were the efficacy outcomes and findings from the MAC subgroup analysis?

The study did not meet its primary end point of a statistically significant improvement in 6-month grade 2-4 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 post-transplant period and within the MAC subgroup. At 100 days, the grade 2-4 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 rate of 100-day grade 3-4 GFS favored the intervention (86.2% vs 74.1%).

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

“However, we saw no difference in NIH 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 ostekinumab and 38% for placebo.”

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

What were the 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 were presented. “What this demonstrates is that it is effective in selective IL-12 inhibition and also inhibition of downstream Th1 responses from IL-12,” Pidala said.

What are the 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 post-transplant 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,” said Pidala.

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. Tandem Meetings: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, 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