American Association for Cancer Research
ccr-23-0666_supplementary_figure_s3_suppfs3.docx (162.72 kB)

Supplementary Figure S3 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials

Download (162.72 kB)
journal contribution
posted on 2023-10-13, 07:42 authored by Eduardo Rodríguez-Arbolí, Catherine J. Lee, Teresa Caballero-Velázquez, Carmen Martínez, Clara García-Calderón, María Reyes Jiménez-León, María Aránzazu Bermúdez-Rodríguez, Lucía López-Corral, Ana Triguero, Lynn Onstad, Mitchell E. Horwitz, Stefanie Sarantopoulos, Stephanie J. Lee, José Antonio Pérez-Simón

Fold change from baseline in the absolute count of circulating B cells (C1D1: n=13 responders [R], n=6 non-responders [NR]; C2D1: n=13 R, n=6 NR; C4D1: n=12 R, n=4 NR) (A), naive B cells (C1D1: n=11 R, n=6 NR; C2D1: n=11 R, n=5 NR; C4D1: n=11 R, n=4 NR) (B), unswitched memory B cells cells (C1D1: n=12 R, n=5 NR; C2D1: n=12 R, n=4 NR; C4D1: n=11 R, n=3 NR) (C) and switched memory B cells (C1D1: n=13 R, n=6 NR; C2D1: n=13 R, n=5 NR; C4D1: n=12 R, n=4 NR) (D). E) Fold change in CD268 (BAFF) expression on B cells (C1D1: n=13 R, n=6 NR; C2D1: n=13 R, n=5 NR; C4D1: n=12 R, n=3 NR). MFI normalised ratios were used for expression quantification. MFI, median fluorescence intensity; n.s., non-statistically significant.





Sclerotic chronic GVHD (scGVHD) is characterized by progressive skin fibrosis and frequent refractoriness to available therapies. Aberrant activation of Hedgehog signaling in dermal fibroblasts has been implicated in scGVHD. Here, we report the results of two phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) that evaluated glasdegib, a smoothened antagonist, as a novel therapeutic agent in refractory scGVHD. Adult patients with active scGVHD after ≥1 (FHD) or ≥2 (GETH-TC) lines of therapy were enrolled. Primary endpoints were dose-limiting toxicity (DLT) and MTD in the GETH-TC trial, and safety and tolerability measures in the FHD trial. Glasdegib was administered once daily in 28-day cycles. Responses were scored per 2014 NIH cGVHD criteria. Correlative studies were performed to evaluate the role of fibroblast-independent immune mechanisms on clinical activity. Twenty (GETH-TC) and 15 (FHD) patients were recruited. Treatment-emergent grade (G) ≥2 adverse events (AE) in the GETH-TC trial included muscle cramps (85%), alopecia (50%), and dysgeusia (35%). Two patients experienced a DLT (G3 muscle cramps), and the MTD was established at 50 mg. G3 muscle cramps were the most frequently reported AE (33%) in the FHD trial. At 12-months, the skin/joint scGVHD overall response rate was 65% (all partial responses) in the GETH-TC trial and 47% (6 partial responses, 1 complete response) in the FHD cohort. No immune correlates of response were identified. Glasdegib demonstrated promising responses in patients with refractory scGVHD, but tolerability was limited by muscle cramping.

Usage metrics

    Clinical Cancer Research





    Ref. manager