Clinical Considerations for Axatilimab Use in Steroid-Refractory cGVHD
A panelist discusses how axatilimab demonstrated efficacy in a heavily pretreated patient population with predominantly severe chronic graft-vs-host disease (cGVHD) in the AGAVE-201 trial, with manageable adverse effects including infusion reactions and enzyme elevations that rarely required discontinuation of treatment.
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The AGAVE-201 trial enrolled a challenging patient population with advanced chronic graft-vs-host disease (cGVHD) in the FDA-approved 0.3 mg/kg biweekly axatilimab arm. Among the 79 patients enrolled, the median age was approximately 50 years, with 60% men and one-third of patients older than 65 years. Most patients had longstanding disease with a median GVHD duration of 4 years and multiple organ involvement. Approximately 70% had previously received ibrutinib, and 80% had severe cGVHD that was progressing despite prior treatments. Despite this difficult-to-treat population with both fibrotic and inflammatory manifestations, the approved dose demonstrated high overall response rates.
Axatilimab administration protocols included 30-minute infusions without mandatory premedication. For patients developing infusion reactions (approximately 2% experienced severe reactions), recommendations included slowing the infusion rate by 50% and administering antipyretics and antihistamines for grade 1/2 reactions, with premedication for subsequent cycles. The safety profile was generally favorable, with infections being the most common adverse effect (50%), though only 15% experienced grade 3/4 infections requiring hospitalization and intravenous antibiotics. Constitutional symptoms (fever, myalgia, fatigue), gastrointestinal effects (diarrhea), and headaches were common but rarely severe.
A unique mechanism-related adverse effect of axatilimab is enzyme elevation, particularly affecting amylase, lipase, creatine phosphokinase, and gamma-glutamyl transferase levels. This on-target effect occurs because macrophages and Kupffer cells in the liver, which are inhibited by the drug, normally clear these enzymes from circulation. Enzyme elevations typically appear after the first treatment dose and are expected. Monitoring recommendations include assessing for evidence of organ damage if grade 3 or higher elevations occur, with dose interruptions recommended for 20-fold enzyme increases. At the approved dose level, only 10% of patients discontinued treatment due to adverse effects, while dose interruptions were more common, allowing patients to resume treatment after resolving issues. Approximately 8% required dose reduction to 0.2 mg/kg every 2 weeks.
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