Hedgehog Pathway Inhibitor for Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD)

Background: Sclerodermatous chronic GVHD (scGVHD) is a unique form of cutaneous GVHD that predominantly involves the skin, subcutaneous tissue, fascia and joints. Steroid-refractory scGVHD is especially challenging to manage since it is usually a progressive condition with devastating effects on the quality of life of affected patients. Inhibition of hedgehog signaling has been shown to be effective in the treatment of murine scGVHD. Here, we report a retrospective review of patients with scGVHD who were treated with hedgehog pathway inhibitor, Vismodegib, at Stanford University.

Results: A total of n=8 patients with steroid-refractory scGVHD were treated with Vismodegib 150 mg daily as an off-label use since 2016. The male:female ratio is 5:3 and median age was 49 (range 39-62) at time of start of Vismodegib. The median time from transplant to diagnosis of scGVHD was 26.9 months (range 8.9-37.5) and the median time from diagnosis of scGVHD to Vismodegib treatment was 14.4 months (range 2.7-45.2). All patients had GVHD involvement of other organ besides scGVHD and have received multiple lines of therapy prior to Vismodegib.

Hair thinning/alopecia and muscle cramps were noted in 100% of the patients. 75% (6/8) had dysgeusia, 88% (7/8) had fatigue (gr 2) and 1 patient had an asymptomatic elevated lipase level. All patients required dose reduction or drug holiday due to side effects (mainly muscle cramps). Four patients (50%) stopped the drug due to side effects (2/4) or lack of response (2/4). All Vismodegib-related side effects resolved after discontinuation of the drug. The median duration of Vismodegib treatment was 6.1 months (range 2.3-17.1) for the entire group. One patient received multiple courses of Vismodegib with benefit noted with each course.

Five patients (63%) had partial response including 1 patient responded to multiple courses of Vismodegib and 1 patient had subjective symptom improvement. The median time to clinical response was 103 days (range 24-145) and the duration of response was 7.8 months (range 1.6-13.4). Three patients had experienced prolonged clinical response off the Vismodegib. At the last follow-up visit, all patients were alive and 4 patients continued to take Vismodegib including 1 patient who had been tapered off systemic steroid.

Conclusion: Steroid-refractory scGVHD is an extremely difficult disease to manage with a high rate of morbidity. Our experience with hedgehog pathway inhibitor, Vismodegib, is very encouraging. Additional study to evaluate the optimal dosing, side effects and its efficacy is under way.