Selective JAK1 Inhibition Shows Promise as GVHD Prophylaxis

A phase 1 clinical trial combining the selective JAK1 inhibitor itacitinib with standard graft-vs-host disease (GVHD) prophylaxis produced strikingly low rates of both acute and chronic GVHD and zero cases of nonrelapse mortality (NRM) at 1 year in patients undergoing reduced-intensity matched donor hematopoietic stem cell transplantation, according to results presented during an oral presentation at the 52nd Annual Meeting of the European Blood and Marrow Transplantation (EBMT) Society in Madrid, Spain.¹

In the single-center study (NCT05364762), at a median follow-up of 366 days, no patients developed grade 3 to 4 acute GVHD and only 5% had moderate-to-severe chronic GVHD.

“Adding itacitinib to posttransplant cyclophosphamide [PTCy] and tacrolimus-based GVHD prophylaxis was safe, well tolerated, and it may have allowed us to shorten exposure to tacrolimus, which could have impacted the rate of relapse and infection in this small cohort. There was no NRM reported at 1 year, and survival outcome were promising, including GVHD,” Monzr Al Malki, MD, professor at City of Hope in Duarte, California, stated in his presentation.

Background and Study Design

Itacitinib is a selective JAK1 inhibitor that was previously investigated as treatment for patients who developed acute GVHD; however, in the phase 3 GRAVITAS-301 trial (NCT03139604), it failed to meet the primary end point of improving overall response rate compared with corticosteroids alone.² As itacitinib causes less cytopenia than ruxolitinib (Jakafi), which is currently approved to treat acute GVHD, investigators hypothesized that itacitinib could be given safely in combination with PTCy and tacrolimus.

The primary objective of the phase 1 trial was to assess the safety of adding itacitinib.¹ The trial enrolled 20 patients, predominantly older adults with a median age of 63, who received itacitinib, PTCy, and tacrolimus. Most patients (80%) had matched unrelated donors, and diagnoses spanned acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic lymphoma, chronic myelomonocytic leukemia, and myelofibrosis, reflecting a medically complex population. Half had a HCT Comorbidity Index of 3 or higher.

Survival and GVHD Outcomes

GVHD rates were notably low. Grade 2 to 4 acute GVHD at day 180 was just 10% and no patient developed grade 3 to 4 acute GVHD. Moderate-to-severe chronic GVHD at 1 year was 5%, and no patients required immunosuppression at the 1-year mark.

Among 18 survivors, 1-year overall survival was 90% (95% CI, 66%–97%) and relapse-free survival was 85% (95% CI, 60%–95%). One-year GVHD-free, relapse-free survival, a composite end point, stood at 75% (95% CI, 50%-89%). Crucially, NRM was 0% at 1 year, and the 1-year relapse rate was 15%.

The trial tested 2 durations of tacrolimus, 90 days in cohort 1 and 60 days in cohort 2, and found no unexpected safety signals or primary safety events with either schedule. Al Malki noted that 4 of the 5 chronic GVHD events occurred in the 90-day cohort.

Additionally, Al Malki said that because only a small number of patients developed GVHD and they responded to steroids, it is not known whether patients who received itacitinib would be responsive to ruxolitinib or another JAK inhibitor indicated for steroid-refractory GVHD.

Safety Profile

All 20 patients achieved engraftment, with median neutrophil recovery at 16 days and platelet recovery at 27 days. The most common grade 3 or higher adverse event at least possibly related to itacitinib was anemia, occurring in 14 patients (70%), though all were grade 3 with no grade 4 cases. Grade 3 or higher thrombocytopenia occurred in 18 patients, predominantly within 6 weeks of transplant, with a median duration of 16 days, and resolved without significant bleeding. Febrile neutropenia and sepsis each occurred in 3 patients (15%).

Cytokine release syndrome was observed in 3 patients (15%), all grade 1 to 2, with no severe cases. Infections during the first 100 days were mostly bacterial (64% of all infections) and grade 1 to 2; no grade 3 infections were reported. Al Malki compared this favorably with the infection rate reported in the phase 3 BMT CTN 1703 trial (NCT03959241) that established the benefit of PTCy-based GVHD prophylaxis.³

Pharmacokinetics and Quality of Life

An exploratory pharmacokinetic analysis revealed a significant drug-drug interaction between itacitinib and tacrolimus: median itacitinib C_max and area under the curve were more than 2-fold higher on day +10 (when tacrolimus had been added) compared with day +5 (itacitinib alone), a difference with P-values below 0.001.¹ Investigators attributed this likely to tacrolimus inhibiting CYP3A, the enzyme responsible for itacitinib metabolism, noting that elimination half-life was unchanged between the 2 time points.

Patient-reported quality of life outcomes, measured using the FACT-BMT instrument across multiple domains including physical, emotional, functional, and social/family well-being, showed consistent improvement from baseline through 1 year posttransplant.

Context and Next Steps

PTCy-based GVHD prophylaxis has become increasingly central to matched donor transplantation, but there remains room for improvement of infection rates and cumulative incidence of GVHD. Malki concluded that itacitinib is safe and well tolerated when added to this standard, and despite the current lack of availability of itacitinib, the favorable efficacy warrants further investigation to further improve outcomes and avoid excessive immunosuppression.

“Even though the drug is not available now for further study, this proof-of-concept study supports further work in combining JAK inhibition with [PTCy] to optimize immune tolerance posttransplant,” said Al Malki.

REFERENCES

1. Al Malki MM, Yang D, Mokhtari S, et al. Itacitinib in combination with post-transplant cyclophosphamide and tacrolimus (ICT) as GVHD prophylaxis for reduced intensity matched donor hematopoietic cell transplantation (HCT): Final analysis. Presented at: 2026 EBMT Annual Meeting; March 22-25, 2026; Madrid, Spain.OS12-03.

2. Zeiser R, Socié G, Schroeder MA, et al. Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial. Lancet Haematol. 2022;9(1):e14-e25. doi:10.1016/S2352-3026(21)00367-7

3. Bolaños-Meade J, Hamadani M, Wu J, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943