Phase 2 Trial of Ruxolitinib Cream for Chronic Cutaneous GvHD

Oral ruxolitinib is approved to treat aGvHD and cGvHD, while ruxolitinib cream is approved for atopic dermatitis and vitiligo. Topical corticosteroids are the mainstay of skin-directed therapy but may incompletely treat cutaneous cGvHD.We conducted a phase 2 prospective, randomized, double-blind trial evaluating the efficacy and safety of ruxolitinib 1.5% cream in patients ≥12 years old with cutaneous nonsclerotic and superficially sclerotic cGvHD with ≥2% of body surface area (BSA) affected. Patients were eligible if any systemic therapy was stable for ≥4 weeks and concurrent topical/photo- therapy was not used. Patients were randomly assigned (1:1) to receive ruxolitinib cream to the left or right side of face/body with vehicle cream to contralateral side twice daily for 28 days. Primary endpoint was efficacy at Day 28, as measured by BSA of the GvHD rash on the side of face/body treated with ruxolitinib cream vs contralateral side treated with vehicle. Secondary endpoints: Physician's Global Assessment (PGA), and Composite Assessment of Index Lesion Severity (CAILS) at Days 14 and 28. Exploratory endpoints: (1) tape stripping via the SmartSticker™ and RNA-sequencing was used to investigate gene expression differences between 1) ruxolitinib and vehicle treatments, and 2) responders (R: PGA 0-4) and nonresponders (NR: PGA 5-6) at Day 28; (2) total body 3-D photography (Canfield) was measured at each time point.Between 6/2019 – 9/2022, 24 patients (median 47.5 years; 46% male) were randomized, with a history of acute leukemia (N=16 [67%]) or non-Hodgkin lymphoma (N=4 [16%]). Most patients had cutaneous nonsclerotic cGvHD (87%). Most patients had failed ≥2 topical therapies: 88% failed topical steroids, 42% topical calcineurin inhibitors, and 29% phototherapy. BSA of cGvHD on the treatment side compared to the vehicle side was significantly improved from Day 1 (14.4 vs 14.5% on treatment/vehicle; p=0.12) to Day 14 (7.7 vs 10.4; p=0.002) to Day 28 (6.2 vs 10.4; p=0.003), respectively. Both secondary endpoints were significantly improved with treatment starting on Day 14 into Day 28 (PGA D1: 5 treatment vs 5 vehicle; D14: 2.7 vs 3.8, p=0.002; D28: 1.9 vs 3.7, p=0.0004. CAILS D1: 15 treatment vs 15.3 vehicle, p=0.12; D14: 6.9 vs 11, p=0.0009; D28: 5.8 vs 10.6, p=0.004). One grade 1 headache was possibly attributed to therapy. RNA sequencing identified 288 DEGs (FC>2; p=0.05) between R (n = 17) and NR (n = 5) at Day 28 (Figure) with pathway differences in IL-12 signaling. Treatment response was detected via total body 3-D photography.This is the first prospective study to report that ruxolitinib 1.5% cream was safe and effective compared to placebo in treating cutaneous nonsclerotic and superficially sclerotic GvHD. Responders to ruxolitinib cream had genomic signature differences in IL-12 signaling. Total body imaging may be a helpful tool in monitoring treatment response in cGvHD patients.