Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.