Axatilimab Plus Ruxolitinib Shows Manageable Safety in Untreated cGVHD

A combination of axatilimab (Niktimvo) and ruxolitinib (Jakafi) demonstrated a safety profile comparable with ruxolitinib alone, with no evidence of additive toxicity in patients with newly diagnosed moderate or severe chronic graft-vs-host disease (cGVHD), according to findings presented at the EBMT Society’s 52nd Annual Meeting.¹

Among treated patients in the ongoing phase 2 trial (NCT06388564), grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 25.0% of patients who received the combination compared with 15.8% who received ruxolitinib alone and 18.8% who received corticosteroids, and no prespecified threshold for stopping due to unacceptable toxicity was met.

“In this ongoing phase 2 trial, the safety analysis shows a continued favorable adverse effect profile, especially in the combination arm, and treatment is ongoing in a majority of the patients,” Amandeep Salhotra, MD, of City of Hope in Duarte, California, stated in his presentation of the data.

Background and Rationale

Chronic GVHD remains a leading cause of morbidity and nonrelapse mortality following allogeneic hematopoietic stem cell transplantation. Its pathogenesis is driven by distinct but interacting mechanisms: colony-stimulating factor (CSF)-1 receptor (CSF-1R)–dependent monocyte and macrophage activation contributes to fibrosis and end-organ damage, whereas JAK1/JAK2-mediated cytokine signaling promotes T-cell activation and systemic inflammation.

Axatilimab is a high-affinity anti–CSF-1R monoclonal antibody that depletes pathogenic monocytes and macrophages, whereas ruxolitinib is a selective JAK1/JAK2 inhibitor; both are approved for steroid-refractory cGVHD and have independently demonstrated clinically meaningful efficacy and acceptable tolerability in previously treated cGVHD.² Given their nonoverlapping mechanisms of action, investigators hypothesized that combining them could enhance efficacy without compounding toxicity.

Study Design

The ongoing, randomized, open-label, multicenter phase 2 study enrolled patients aged at least 12 years with new-onset moderate or severe cGVHD per 2014 National Institutes of Health (NIH) consensus criteria and no prior systemic cGVHD therapy. Patients were randomly assigned 1:1:1 to axatilimab 0.3 mg/kg every 2 weeks plus ruxolitinib 10 mg twice daily, ruxolitinib 10 mg twice daily alone, or corticosteroids (starting dose 1 mg/kg/d prednisone equivalent) for up to 24 months. Randomization was stratified by disease severity and concurrent use of a calcineurin inhibitor or mTOR inhibitor.

The primary end point is overall response, defined as complete or partial response per the 2014 NIH consensus criteria at 6 months (cycle 7, day 1), in the absence of new systemic therapy for cGVHD. Safety and tolerability are secondary end points. A prespecified interim safety analysis was conducted after approximately 30 patients had received at least 1 cycle of treatment, with a stopping criterion for unacceptable toxicity at least 4 patients in any group experiencing a toxic event.

Patient Characteristics

The median age of enrolled patients was 65.0 years (range, 16-77), and 53.0% were male.¹ Baseline demographics and clinical characteristics were well balanced across treatment arms. The median time from transplant to cGVHD diagnosis was 7.6 months (range, 1.7-72.3 months), and 47.0% of patients had severe cGVHD at enrollment. Commonly involved organs included the mouth (71.2%), eyes (65.2%), and skin (62.1%), and the majority of patients had at least 3 organs involved at baseline. Nearly all patients had malignant underlying disease, and the majority received human leukocyte antigen–identical transplants.

Safety Results

As of the October 3, 2025, data cutoff, 66 patients had been randomly assigned across 3 arms, with 56 patients receiving at least 1 dose of treatment. Anemia was the only grade 3 or higher TEAE occurring in 2 or more patients overall, with 1 case each in the combination and ruxolitinib arms. The prespecified stopping criterion for unacceptable toxicity was not met, and none of the treatment arms approached the prespecified stopping thresholds.

TEAEs of any grade occurred in 75.0% of those treated with the combination, 84.2% of those treated with ruxolitinib, and 81.3% of those treated with corticosteroids. In the combination arm, the most common any-grade TEAE was anemia (20.0%), with constipation, elevated alanine aminotransferase (ALT), elevated amylase, fatigue, and diarrhea each occurring in 10.0% of patients. The ruxolitinib arm showed a broader array of frequent TEAEs, including anemia and elevated aspartate aminotransferase (each in 21.1%), and decreased platelet count, diarrhea, fatigue, elevated amylase, elevated ALT, peripheral edema, pyrexia, and upper respiratory tract infection (each 15.8%). In the corticosteroid arm, insomnia (25.0%) and constipation (18.8%) were most common.

One patient in the combination group discontinued treatment due to TEAEs, attributed to concurrent fatigue and anxiety. Median treatment duration was 4.3 months for the combination, 4.7 months for ruxolitinib, and 2.0 months for corticosteroids. Treatment discontinuation was highest in the corticosteroid arm (47.4%), followed by ruxolitinib (25.0%) and axatilimab/ruxolitinib (17.4%), with approximately one-third of patients in the corticosteroid group discontinuing treatment and initiating a new systemic therapy for cGVHD.

Clinical Implications

The updated safety analysis supports continued investigation of the axatilimab/ruxolitinib combination in the frontline cGVHD setting. Salhotra and colleagues concluded that the combination demonstrated manageable safety with no new signals and no evidence of additive toxicity compared with ruxolitinib monotherapy. Treatment remained ongoing in 73.9% of axatilimab/ruxolitinib patients at the data cutoff, compared with 58.3% in the ruxolitinib arm and 31.6% in the corticosteroid arm, suggesting durable treatment tolerability.

“The combination demonstrated manageable safety profile with no new safety signals and no additive toxicity compared to ruxolitinib alone,” said Salhotra.

The primary efficacy end point of overall response at 6 months in the absence of new systemic therapy is anticipated with further follow-up of this ongoing trial.

REFERENCES

1. Zeiser R, Salhotra A, Bonifazi F, et al. Axatilimab in combination with ruxolitinib in patients with newly diagnosed chronic graft-versus-host disease: updated safety analysis of a randomized, phase 2 study. Presented at: 2026 EBMT Annual Meeting; March 22-25, 2026; Madrid, Spain. OS16-04.

2. Lee SJ, Zeiser R. FDA-approved therapies for chronic GVHD. Blood. 2025;145(8):795-800. doi:10.1182/blood.2024026633