Clinical and molecular predictors of interferon-α response in erdheim-chester disease and myeloproliferative neoplasm.

Abstract Background: Erdheim–Chester disease (ECD) is a rare clonal histiocytosis driven by MAPK pathway somatic mutations, causing multi-organ histiocytic infiltration. While kinase inhibitors are effective, their universal availability and long-term tolerability remain challenges. Interferon-alpha (IFN-α) still serves as frontline therapy for selected ECD patients and is employed in other myeloid neoplasms. However, reliable predictors of IFN-α response remain elusive. This study aimed to identify clinical and molecular factors associated with the efficacy of IFN-α in a large international cohort of ECD and myeloproliferative neoplasm (MPN). Methods We retrospectively analyzed 377 patients (ECD n=300; MPN n=77) treated with IFN-α across centers in France, Italy, and the United States. Clinical and molecular data were retrieved from medical records. Clonal hematopoiesis (CH) was defined by the presence of myeloid gene mutations in blood/bone marrow without overt hematological malignancy. Response was assessed by PET–CT (ECD) or standard guidelines (MPN); non-response was defined by progressive disease. Results We analyzed 300 ECD patients (median age 59 years; 87% men; 67% BRAFV600Emutation) treated with interferon as first (n=255), second (n=40), and third line (n=5) therapy. The overall response rate (ORR) was 83% (n=249). Responders were older at diagnosis (median age 59 years vs 54; p=0.0189), at the first symptom onset (56 vs 51; p=0.0231), and at IFN-α initiation (59 vs 54; p=0.0175), with longer disease duration (58 months [44–67] vs 10.8 [4–25]; p<0.0001), and less frequently women (11% vs 19%; p=0.0262). Regarding the prediction of response, the multivariable logistic regression model identified women (OR=0.36, 95% CI 0.14–0.95; p=0.0406), digestive tract involvement (OR=0.20, 95% CI 0.06–0.68; p=0.0109) as negative predictors, whereas ENT involvement (OR=3.99, 95% CI 1.42–11.19; p=0.0089), and CH (OR=2.81, 95% CI 1.13–6.98; p=0.0270) were positive predictors. Among 255 first-line IFN-α patients, the ORR was 76% (n=195). Sixty patients (23%) had disease progression. Responders were older at diagnosis (59 years vs 54; p=0.05), had higher baseline CRP (83% vs 36%; p=0.0448) and more myeloid gene driver mutation on NGS ( median 1 [1–2] vs 0 [0–1]; p=0.0013). In this group, CH was the sole independent predictor of response (OR=20.02, 95% CI 3.2–199; p=0.0009).Within the CH subgroup (n=86; 93% response), women sex (OR=0.15, 95% CI 0.02–0.82; p=0.0288) and digestive tract involvement (OR=0.13, 95% CI 0.02–0.94; p=0.0437) were negative predictors, while ENT lesions (OR=9.09, 95% CI 1.15–227.2; p=0.0345) predicted improved response. Among 77 MPN patients, 79% (n=61) achieved response. The use of IFN-α as first line treatment was frequent in responders (72% vs 43%; p=0.0416) and predicts response (OR=3.328, 95% CI 1.077-10.73, p=0.0368) in univariate analysis. In the pooled cohort (n=377), responders (n=310) more often received IFN-α as first-line therapy (83% vs 70%; p=0.015). Among patients having NGS (predominantly ECD, n=175), responders had higher CH prevalence (53% vs 29%; p=0.0171). Multivariable logistic regression confirmed women's sex (OR=0.35, 95% CI 0.15-0.82, p=0.015) as negative predictors, whereas CH (OR=2.64, 95% CI 1.14-6.56, p=0.02) predicted improved response. Conclusion This multicenter study, the largest to evaluate IFN-α outcomes in ECD, identifies key clinical and molecular predictors of response. Crucially, CH defines a unique subgroup with enhanced IFN-α sensitivity, highlighting the potential for molecular treatment stratification.