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Clinical Outcomes of Treatment-Refractory Sclerodermatous Chronic Gvhd Patients Treated with IL-4/IL-13 Inhibition

Year: 2025

Type: article

Abstract: Despite novel agents for the treatment of chronic graft versus host disease (cGVHD), complete responses remain elusive. The sclerotic manifestations of cGVHD can be particularly resistant to traditional therapy. Preclinical data suggests a role for interleukin-4 (IL-4) in skin fibrosis . There is also evidence that overactive IL-4 and IL-13 signaling, mediated by TGF-β, perpetuates fibrosis. Given preclinical data implicating IL-4 and IL-13 in fibrosis and case reports of refractory fibrotic manifestations of cGVHD responsive to dupilumab , we report our experience with dupilumab treatment for sclerotic cGVHD. This is a single center, retrospective analysis of patients (pts) with sclerotic cGVHD treated with dupilumab between 1/1/2020 - 5/31/2024. Data was collected via EMR and included demographics, disease characteristics, treatment response, and clinical outcomes. The primary endpoint was overall response rate (ORR) measured by NIH 2014 Consensus Criteria and Clinically Significant Symptomatic Improvement (CSSI) as deemed by provider. Data outcome measures extended for up to 12 months from initiation of dupilumab. A total of 5 pts were evaluable (See Table 1 for pt demographics). 4 pts had severe sclerotic involvement, 1 had moderate. 2 pts had severe musculoskeletal involvement, 2 had moderate. Pts received a median of 11 prior lines of therapy. No pts had improvement by NIH Consensus Criteria grading, but all had CSSI with improved erythema, scaling, ulcerations , pain, pruritus, and/or softening of sclerosis (See example figures of skin changes). Measurements collected by Rehabilitation Services on 3 pts showed an increase in ROM by 5-10 degrees in affected joints. Serum cytokine levels prior to initiation and after clinical response were available on 4 pts. None had baseline elevation in IL-4 or IL-13, but all had decrease or normalization of IL-2R, IL-6, and IL-10 if baseline elevations present (See Figure 1). Median time to clinical response was 80 days. 2 pts had relapsed disease prior to initiating dupilumab. Prednisone was tapered in 1 pt, tacrolimus and imatinib discontinued in 1 pt respectively. 1 pt was not on other immune suppression due to refractoriness. 2 pts developed pneumonia, no pts developed CMV or EBV reactivation, or bacteremia . Cytopenias were not exacerbated. No pts discontinued due to intolerance. 2 pts expired while on dupilumab, 1 from relapsed disease and 1 from complications of cGVHD. Despite no response by NIH grading, CSSI were observed in 5/5 heavily pre-treated refractory patients treated with dupilumab, therefore its use may be a consideration for patients with refractory sclerotic cGVHD. Cytokine data reflects improved immune regulation after treatment with dupilumab. Further, it may serve as treatment option in patients with relapsed disease in whom other immunosuppressive agents may be contraindicated.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.434