Second-Line Therapy Selection and Disease Phenotype of cGVHD

Dr. Shune continues the case discussion by describing disease progression following second-line therapy and outlining her approach to third-line treatment selection in cGVHD. After initiating systemic corticosteroids in combination with ruxolitinib, along with physical therapy and supportive dermatologic care, the patient experienced meaningful improvement over 6 months. Skin pliability and shoulder range of motion improved, gastrointestinal symptoms stabilized, and corticosteroids were successfully tapered. However, by month 7, the patient developed new erythematous plaques with progressive sclerosis of the lower extremities, worsening dyspnea, and declining pulmonary function, with FEV1 falling to 76%, consistent with evolving pulmonary cGVHD. This progression prompted the need for third-line therapy.

Dr. Shune explains that 2 FDA-approved options are available in the third-line setting: belumosudil and axatilimab. Belumosudil, approved in July 2021 based on the ROCKstar trial, inhibits ROCK2 and modulates STAT signaling, leading to increased regulatory T cells and reduced proinflammatory T-cell subsets, thereby restoring immune balance. Axatilimab, approved in 2024 based on the AGAVE-201 trial, targets the CSF1 receptor, blocking monocyte–macrophage-driven inflammatory pathways that are central to fibrosis and sclerosis.

She highlights key differences in the clinical trial populations and mechanisms of action when selecting therapy. The AGAVE-201 trial included patients with significant pulmonary involvement, including those with severe FEV1 reductions, and demonstrated meaningful responses in both sclerotic skin disease and pulmonary cGVHD. Dr. Shune shares real-world experience from an expanded access program, noting that axatilimab’s efficacy and tolerability closely mirrored trial results. Importantly, axatilimab was safely combined with other agents such as ruxolitinib or belumosudil without major drug–drug interactions.

Based on its favorable safety profile, durability of response, and activity in sclerotic and pulmonary disease, Dr. Shune describes axatilimab as a valuable option for patients with advanced, treatment-refractory cGVHD, with clinical improvement often observed within 2–3 months of initiation.