Real-World Clinical Outcomes of Severe, Treatment-Refractory Chronic Gvhd Patients Treated with Axatilimab Combination Therapies
Authors: Peddireddi Ayush V , Caputo Jean , Wall Sarah A. , Vasu Sumithira , Penza Sam , Ho Kevin , Esguerra Vincent , Kaffenberger Benjamin , Choe Hannah 
Published: December 2024

Background: Chronic graft versus host disease (cGVHD) is a major late complication of allogeneic hematopoietic cell transplants (HCT), affecting up to 50% of HCT recipients. GVHD is associated with significant transplant-related morbidity, mortality, infections, and decreased quality of life. Current FDA approved agents for the treatment of refractory cGVHD include ibrutinib, ruxolitinib (rux) and belumosudil (bel). Both rux and bel have been shown to be effective steroid-sparing agents in the treatment of cGVHD, with overall response rates (ORR) of 76% and 65%, respectively. However, patients commonly progress after median 15.5 months (12.4-18.6),indicating a need for additional therapies or combinations. Furthermore, patients with fibrotic manifestations have significantly worse response rates. Axatilimab (axa) targets Colony-Stimulating Factor 1 Receptor (CSF-1R) signaling in macrophages, with recently reported Phase II trial (AGAVE-201) results that demonstrated a 74% ORR in its its lowest dosing level of 0.3 mg/kg q2 weeks. Here we report real-world outcomes of patients with severe cGVHD treated with axa (via compassionate use/single patient IND program) in combination with rux and/or bel.
Methods: This single-center, retrospective study evaluated patients with severe, treatment-refractory cGVHD treated with axa 0.3 mg/kg q2 weeks between 01/01/2022-07/04/2024. The primary endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks), measured by both the NIH 2014 consensus criteria and clinically significant symptomatic improvement (CSSI) as deemed by provider. Other key measurements included time to first response from initiation of axa and duration of response. Responses were also stratified by organ system. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs).
Results: 8 patients were evaluated, with a median time from cGVHD diagnosis to initiation of axa of 1.8 years. All patients had previously progressed through rux and bel as monotherapies, with 4/8 patients subsequently progressing through combination rux/bel prior to receiving axa. All 8 patients were classified as having severe cGVHD as defined by NIH consensus criteria- 5/8 patients had sclerodermatous skin involvement (3 &gt;19-50%, 2 &gt;50% BSA) and 1/8 patients had severe BOS.Patients had received median 5 (range 4-9) previous lines of therapy. When evaluated per NIH Criteria, the ORR including CR and PR at any time was 2/8 (25%). When evaluated per CSSI, ORR was 6/8 (75%). Of the 6 responding patients, 4 were on combination rux/bel/axa while 1 patient was on combo rux/axa and 1 patient was on combo bel/axa. All 4 patients on rux/bel/axa achieved PR; three later discontinued axa due to progression, with one patient continuing the triple combination.
Median time to response was 71 days and 103 days per NIH criteria and CSSI, respectively. Average duration of response was 294.5 and 218 days, respectively. Per organ system measured per CSSI, the highest response rate was in the mouth, lung, and skin,with ORR of 75% (PR 3/4), 50% (PR 1/2), and 42% (PR 3/7). Two patients tapered steroids while on axa. No patients discontinued axa due to intolerance. There were 3 grade 3 SAEs, from osteomyelitis, septic arthritis, and elevated GGT levels. There were 5 AEs attributable to anemia (three grade 1, one grade 2, and one grade 3). There were no SAEs attributable to thrombocytopenia. Drug discontinuation owing to TEAEs occurred in 1 patient, who developed a significantly elevated GGT level.
Discussion: In this heavily pre-treated, severe chronic GVHD patient cohort receiving compassionate use axatilimab, ORR by NIH criteria was 25%, though ORR per CSSI was 75%. While ORR in this study was less than that reported in AGAVE-201, the patients analyzed here had more severe disease comparatively; patients were refractory to mono and combo rux-bel prior to axa initiation, and the majority (6/8) had aggressive fibrotic manifestations of cGVHDnotoriously resistant to treatment. Patients tolerated combination axa with rux and/or bel with 4/8 patients receiving rux-bel-axa. This is the first report of the combination of axa with rux and/or bel, demonstrating that a combination approach with CSF1R/JAK2/ROCK2 inhibition is feasible, tolerable, and may yield clinical benefit in highly refractory cases of cGVHD with fibrotic manifestations.