• Daniel Wolff, Corey Cutler, Stephanie J Lee, Iskra Pusic, Henrique Bittencourt, Jennifer White, Mehdi Hamadani, Sally Arai, Amandeep Salhotra, Jose A Perez-Simon, Amin Alousi, Hannah Choe, Mi Kwon, Arancha Bermúdez, Inho Kim, Gerard Socié, Saurabh Chhabra, Vedran Radojcic, Timothy O'Toole, Chuan Tian, Peter Ordentlich, Zachariah DeFilipp, Carrie L Kitko, and AGAVE-201 Investigators.
• From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.).
• N. Engl. J. Med. 2024 Sep 19; 391 (11): 100210141002-1014.

BackgroundColony-stimulating factor 1 receptor (CSF1R)-dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.MethodsIn this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.ResultsA total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.ConclusionsTargeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).Copyright © 2024 Massachusetts Medical Society.

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