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

Abstract

Introduction: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (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 benefits in several reported cases, their indications, 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 profile 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 deficiency 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 beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Keywords: Baricitinib; Children; Chronic mucocutaneous candidiasis; Inborn errors of immunity; JAK inhibitors; JAK-STAT pathway; Pediatrics; Primary immunodeficiency disease; Ruxolitinib; STAT1 GOF.

Fig. 1

Response to JAK inhibitor treatment. AI, autoimmune; CMC, chronic mucocutaneous candidiasis; DM, diabetes mellitus; LFT, liver function tests; m, month; ND, no detailed information was available for this variable. *Overall response rate was defined as sustained improvement of symptoms (when present) stated by the investigators. **4 months after ruxolitinib and 8 years post hematopoietic stem cell transplantation. ^&Numbers appearing in the colored squares indicate the time to obtain a clinical response to JAKinibs in weeks. ^#Onychomycosis: P9: 8–12 weeks; P10: 24 weeks

Fig. 2

Effect of JAKinibs on Immune deficiency and dysregulation activity (IDDA) score