Translating Innovation Into Practice: Emerging Treatments and Real-World Data in GVHD - Episode 2
Novel Mechanisms and Emerging Therapies in Chronic GVHD
Panelists discuss how belumosudil works through anti-inflammatory and antifibrotic mechanisms by preventing actin filament polymerization and sequestering transcription factors, while axatilimab-csfr represents a novel approach targeting monocyte and macrophage pathways through CSF-1R blockade to reduce tissue inflammation and fibrosis in patients with chronic GVHD who have failed multiple prior therapies.
Novel Mechanisms and Emerging Therapies in Chronic GVHD
This segment continues the discussion of belumosudil's therapeutic mechanisms, emphasizing its dual anti-inflammatory and antifibrotic properties. Beyond its T-cell modulating effects, belumosudil prevents actin filament polymerization and sequesters transcription factors in the cytoplasm, resulting in reduced production of profibrotic molecules and cytokines. This mechanism provides improvement in sclerotic manifestations of chronic graft-vs-host disease (GVHD), addressing both inflammatory and fibrotic components of the disease. However, similar to other agents, responses are predominantly partial rather than complete, highlighting an ongoing unmet clinical need for achieving complete remissions.
The most recent FDA approval in 2024 introduced axatilimab-csfr, a novel monoclonal antibody targeting monocyte and macrophage pathways in chronic GVHD pathogenesis. This represents a significant mechanistic departure from T-cell-focused therapies, addressing decades of research demonstrating the role of inflammatory macrophages and monocytes in secreting fibrogenic cytokines. The AGAVE-201 phase 2 randomized study evaluated 3 dosing regimens, with patients receiving treatment every two weeks at lower doses or monthly at the higher 3 mg/kg dose, showing high overall response rates even in heavily pretreated patients with multiple prior agent exposures.
Axatilimab-csfr's mechanism involves blocking the CSF-1R pathway, which reduces nonclassical monocytes in circulation and decreases their migration to tissues where they differentiate into inflammatory macrophages. These tissue macrophages normally secrete profibrotic cytokines like TGF-β, leading to collagen formation and fibrosis. By interrupting this pathway, axatilimab-csfr provides a complementary approach to T cell–targeted therapies, explaining why patients previously exposed to T cell–directed treatments still responded effectively. The availability of 4 approved agents with distinct mechanisms of action—targeting BTK, JAK, ROCK2, and CSF-1R pathways—provides clinicians with multiple therapeutic options that address different components of chronic GVHD's complex immunological cascade.
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