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

[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.
Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the Job Research Foundation (NY, USA); the Consejería de Salud de la Junta de Andalucía (SA0051/2020 to O.N.); Agencia de Innovación y Desarrollo de Andalucía (PI-0184–2018 to P.O); Instituto de Salud Carlos III, Madrid, Spain (Sara Borrell, CD20/00124 to P.B.L, Juan Rodés JR18/00042 to P.O, FIS PI19/01471 to O.N. and P.O); the projects PI18/00223, FI19/00208, and PI21/00211 to LA, integrated in the Plan Nacional de I + D + I and co-financed by the ISCIII—Subdirección General de Evaluación y Fomento de la Investigación Sanitaria—and the Fondo Europeo de Desarrollo Regional (FEDER), by Pla Estratègic de Recerca i Innovació en Salut (PERIS), Departament de Salut, Generalitat de Catalunya (SLT006/17/ 00199 to LA), by a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (IN[17]_BBM_CLI_0357) to LA, by a 2017 Beca de Investigación de la Sociedad Española de Inmunología Clínica Alergología y Asma Pediáatrica to LA, by a 2021 Beca de Investigación de la Sociedad Española de Inmunología Clínica, Alergología y Asma Pediátrica to ADM and by the Ministry of Health, Czech Republic (NV18-05–00162 to M.B and NV19-05–00332 to V.K).