Review Highlights Role of JAK Inhibition in Advancement of GVHD Prevention, Treatment

As research continues to pursue advances in preventing morbidity and mortality from graft-vs-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo ASCT), a group of researchers has compiled the latest advancements in preventing and treating the complication, publishing their review in Frontiers in Immunology.

Recent years have brought to market new treatment approaches to GVHD, for which corticosteroids have been a treatment mainstay. Notably, Janus kinase (JAK) inhibitors have brought a new class of treatment to GVHD. Ruxolitinib first received a nod from the FDA in 2019 for the treatment of steroid-refractory GVHD and has since gained approval for chronic disease and expanded its use to a broader population of patients.

“With multiple recent FDA approvals for both acute and chronic GVHD, the optimal sequence of these therapies is unknown, and certain GVHD manifestations may favor one agent over others,” explained the researchers. “It is also unclear how best to combine JAK inhibitors with existing GVHD therapies. In the real-world setting, ruxolitinib is often combined with other immunosuppressants, such as corticosteroids, calcineurin inhibitors, mycophenolate, belumosudil, and extracorporeal photopheresis, although there is a paucity of prospective clinic trials to guide the use of these combinations. Continued development of novel therapeutics for treatment of GVHD remains essential.”

Experts note that JAK inhibitors may help to improve existing GVHD prophylaxis platforms | Image Credit: dizain - stock.adobe.com

Outside of ruxolitinib, itacitinib has been explored for use in steroid-naïve patients with acute GVHD. After promising data in early-stage trials, the treatment failed to meet its prespecified efficacy end point in the phase 3 GRAVITAS-301 trial (NCT03139604). The trial included approximately 430 patients randomized to receive the JAK inhibitor in combination with steroids, or steroids and placebo. At day 28, overall response rates were 74% for the itacitinib arm and 66% for the placebo arm.

“Given the morbidity associated with both acute and chronic GVHD, improving existing GVHD prophylaxis platforms through the incorporation of JAK inhibitors is a natural next step forward,” noted the researchers. Currently, standard approaches for GVHD prophylaxis include calcineurin inhibitors like tacrolimus, usually in combination with methotrexate (MTX) or mycophenolate mofetil, which inhibit interleukin-2–mediated activation and T-cell proliferation.

Some researchers have explored the use of ruxolitinib in combination with tacrolimus and MTX for acute GVHD prophylaxis. A phase 2 multicenter trial of 43 patients with primary or secondary myelofibrosis showed that the regimen yielded a GVHD-free relapse-free survival rate of 74% at 1 year. Safety findings were similar to those seen in previous studies, with adverse events including thrombocytopenia, neutropenia, and anemia. A separate phase 2 study tested the same combination as maintenance for chronic GVHD in patients with acute myeloid leukemia or a myelodysplastic syndrome, showing a 1-year chronic GVHD incidence of 27% and 1-year disease incidence requiring systemic therapy incidence of 8.4%.

Several pilot studies of ruxolitinib alone have been initiated, with one open-label study of the treatment used in patients with myelofibrosis undergoing allo-HSCT. Given during the peritransplantation period, ruxolitinib at a lower dose was associated with a 17% cumulative incidence of grade 2/3 GVHD and at a higher dose was associated with a 11% cumulative incidence of grade 2/3 disease.

Other JAK inhibitors, including baricitinib, pacritinib, and itacitinib have been and continue to be explored. Following promising results from a phase 1 study in 24 patients undergoing a matched sibling donor (MSD) or a matched unrelated donor (MUD) transplantation, baricitnib is being investigated further. Similarly, a phase 1 study of 12 patients yielded promising results for pacrtinib in combination with sirolimus and low-dose tacrolimus for preventing GVHD in patients undergoing MSD or MUD allo-HSCT.

Reference

Togni E, Cole O, Abboud R. Janus kinase inhibition in the treatment and prevention of graft-versus-host disease. Front Immunol. Published online February 5, 2024. oi:10.3389/fimmu.2024.1304065