Introduction: Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and non-relapse mortality in patients who undergo allogeneic hematopoietic stem cell transplantation. Pathogenesis of cGVHD involves macrophage and monocyte activation, which contribute to multiorgan inflammation and fibrosis. Axatilimab (AXA), a high-affinity monoclonal antibody targeting colony stimulating factor 1 receptor (CSF-1R), depletes CSF-1R–dependent monocytes and macrophages, which mediate fibrosis and end-organ damage in cGVHD. Ruxolitinib (RUX) is a selective inhibitor of Janus kinase (JAK)1/JAK2, which mediate cytokine signaling, T-cell activation, and inflammation in cGVHD. Both AXA and RUX have demonstrated clinically meaningful efficacy and were generally well tolerated as single agents in previously treated cGVHD. Due to their distinct mechanisms of action, combining AXA and RUX may improve efficacy without overlapping safety concerns.

Aims: To report an interim safety analysis of AXA in combination with RUX in patients with newly diagnosed cGVHD.

Methods: In this ongoing, randomized, open-label, multicenter, phase 2 study (NCT06388564), eligible patients were aged ≥12 years with new onset, moderate or severe cGVHD and had not received previous systemic cGVHD treatment. Patients were randomized 1:1:1 to receive AXA 0.3 mg/kg every 2 weeks in combination with RUX 10 mg twice daily (BID; AXA+RUX), RUX 10 mg BID alone, or corticosteroids alone for up to 24 months. The primary endpoint is overall response (including complete or partial response) at 6 months in the absence of a new systemic cGVHD therapy. Safety assessments include treatment-emergent adverse events (TEAEs), physical examinations, and laboratory assessments. A pre-specified interim safety analysis was planned to occur after approximately 30 patients receive ≥1 cycle of study treatment.

Results: As of the interim analysis, 44 patients have enrolled (AXA+RUX, n=15; RUX, n=15; corticosteroids, n=14), and 43 patients have received study treatment. The median (range) age of enrolled patients was 65.0 (19–77) years, and 21 patients (47.7%) were women. The median (range) time from transplant to diagnosis of cGVHD was 7.9 (3.4–72.3) months, and 24 patients (54.5%) had severe disease at enrollment. Peripheral blood stem cells were the most common stem cell source (n=41, 93.2%); 3 patients (6.8%) received bone marrow. Most stem cell donors were unrelated to the patient (n=28, 63.6%); siblings (n=11, 25.0%) or other family members (n=5, 11.4%) were also donors. Eight patients discontinued treatment (AXA+RUX, n=1 [relapse or progression of underlying hematologic disease; patient was considered to be at high risk of relapse, and relapse was not considered to be related to study treatment]; RUX, n=1 [death due to bronchospastic crisis, which was considered by the investigator as unrelated to RUX]; corticosteroids, n=6 [received a new systemic therapy due to insufficient response to treatment, n=5; withdrawal by patient, n=1]). Among all treated patients, a total of 32 experienced TEAEs (AXA+RUX, n=11 [73.3%]; RUX, n=12 [80.0%]; corticosteroids, n=9 [69.2%]). TEAEs occurring in >1 patient in a group were diarrhea, fatigue, hyperkalemia, increased amylase, and decreased neutrophil count (all n=2) in the AXA+RUX group; anemia (n=3), increased amylase (n=3), upper respiratory tract infection (n=3), diarrhea (n=2), fatigue (n=2), increased blood alkaline phosphatase (n=2), peripheral edema (n=2), pollakiuria (n=2), and vertigo (n=2) in the RUX group; and constipation and insomnia (both n=3) in the corticosteroid group. Five patients experienced a grade ≥3 TEAE (AXA+RUX, n=2 [13.3%]; RUX, n=2 [13.3%]; corticosteroids, n=1 [7.7%]).

Conclusion: In this interim analysis of a randomized phase 2 trial, the combination of AXA+RUX was well tolerated with no evidence of additive toxicity.

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2025
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