Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.
Baricitinib
Children
Chronic mucocutaneous candidiasis
Inborn errors of immunity
JAK inhibitors
JAK-STAT pathway
Pediatrics
Primary immunodeficiency disease
Ruxolitinib
STAT1 GOF
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
07
01
2022
accepted:
21
03
2022
pubmed:
30
4
2022
medline:
27
8
2022
entrez:
29
4
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 35486339
doi: 10.1007/s10875-022-01257-x
pii: 10.1007/s10875-022-01257-x
pmc: PMC9402491
doi:
Substances chimiques
Janus Kinase Inhibitors
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
Types de publication
Journal Article
Multicenter Study
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1071-1082Subventions
Organisme : Consejería de Salud, Junta de Andalucía
ID : SA0051/2020
Organisme : Agencia de Innovación y Desarrollo de Andalucía
ID : PI-0184-2018
Organisme : Instituto de Salud Carlos III
ID : CD20/00124
Organisme : Instituto de Salud Carlos III
ID : JR18/00042
Organisme : Instituto de Salud Carlos III
ID : PI19/01471
Organisme : Instituto de Salud Carlos III
ID : PI18/00223
Organisme : Instituto de Salud Carlos III
ID : FI19/00208
Organisme : Instituto de Salud Carlos III
ID : PI21/00211
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
ID : NV18-05-00162
Organisme : Ministerstvo Zdravotnictví Ceské Republiky
ID : NV19-05-00332
Organisme : Departament de Salut, Generalitat de Catalunya
ID : SLT006/17/ 00199
Organisme : Fundación BBVA
ID : IN[17]_BBM_CLI_0357 leonardo grant
Organisme : Fundación de la Sociedad Española de Alergología e Inmunología Clínica
ID : grant 2021
Organisme : Fundación de la Sociedad Española de Alergología e Inmunología Clínica
ID : grant 2017
Informations de copyright
© 2022. The Author(s).
Références
van der Veerdonk FL, Plantinga TS, Hoishchen A, Smeekens SP, Joosten LAB, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61. https://doi.org/10.1056/NEJMoa1100102 .
doi: 10.1056/NEJMoa1100102
pubmed: 21714643
Liu L, Okada S, Hong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutation impair IL-17 immunity and underlie chronic mucocutaneous candidaisis. J Exp Med. 2011;208:1635–48. https://doi.org/10.1084/jem.20110958 .
doi: 10.1084/jem.20110958
pubmed: 21727188
pmcid: 3149226
Al Shehri T, Gilmour K, Gothe F, Loughlin S, Bibi S, Rowan AD, et al. Novel gain-of-function mutation in Stat1 sumoylation site leads to CMC/CID phenotype responsive to ruxolitinib. J Clin Immunol. 2019;39(8):776–85. https://doi.org/10.1007/s10875-019-00687-4 .
doi: 10.1007/s10875-019-00687-4
pubmed: 31512162
Kiu H, Nicholson SE. Biology and significance of the JAK/STAT signaling pathways. Growth Factors. 2012;30(2):88–106. https://doi.org/10.3109/08977194.2012.660936 .
doi: 10.3109/08977194.2012.660936
pubmed: 22339650
pmcid: 3762697
Zimmerman O, Olbrich P, Freeman AF, Rosen LB, Uzel G, Zerbe CS, et al. STAT1 gain-of-function mutations cause high total STAT1 levels with normal dephosphorylation. Front Immunol. 2019;10(10):1433. https://doi.org/10.3389/fimmu.2019.01433 .
doi: 10.3389/fimmu.2019.01433
pubmed: 31354696
pmcid: 6635460
Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al.. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016; ;127(25):3154–64. https://doi.org/10.1182/blood-2015-11-679902 .
Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, et al. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2018;141(2):704-717.e5. https://doi.org/10.1016/j.jaci.2017.03.049 .
doi: 10.1016/j.jaci.2017.03.049
pubmed: 28601685
Forbes LR, Vogel TP, Cooper MA, Castro-Wagner J, Schussler E, Weinacht KG, et al. JAKinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. 2018;142(5):1665–9. https://doi.org/10.1016/j.jaci.2018.07.020 .
doi: 10.1016/j.jaci.2018.07.020
pubmed: 30092289
pmcid: 6322659
Moriya K, Suzuki T, Uchida N, Nakano T, Katayama S, Irie M, Rikiishi T, Niizuma H, Okada S, Imai K, Sasahara Y, Kure S. Ruxolitinib treatment of a patient with steroid-dependent severe autoimmunity due to STAT1 gain-of-function mutation. Int J Hematol. 2020;112(2):258–62. https://doi.org/10.1007/s12185-020-02860-7 .
doi: 10.1007/s12185-020-02860-7
pubmed: 32180118
Chaimowitz NS, Ebenezer SJ, Hanson IC, Anderson M, Forbes LR. STAT1 gain of function, type 1 diabetes, and reversal with JAK inhibition. N Engl J Med. 2020t 8;383(15):1494–1496. https://doi.org/10.1056/NEJMc2022226 .
Bloomfield M, Kanderová V, Paračková Z, Vrabcová P, Svatoň M, Froňková E, et al. A. Utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation. J Clin Immunol. 2018;38(5):589–601. https://doi.org/10.1007/s10875-018-0519-6
Vargas-Hernández A, Mace EM, Zimmerman O, Zerbe CS, Freeman AF, Rosenzweig S, Leiding JW, Torgerson T, Altman MC, Schussler E, Cunningham-Rundles C, Chinn IK, Carisey AF, Hanson IC, Rider NL, Holland SM, Orange JS, Forbes LR. Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2018 Jun;141(6):2142–2155.e5. https://doi.org/10.1016/j.jaci.2017.08.040 .
Neven B, Al Adba B, Hully M, Desguerre I, Pressiat C, Boddaert N, et al. JAK inhibition in the Aicardi-Goutières syndrome. N Engl J Med Mass Med Soc. 2020;383(22):2190–3. https://doi.org/10.1056/NEJMc2031081 .
doi: 10.1056/NEJMc2031081
Hadjadj J, Frémond ML, Neven B. Emerging place of JAK inhibitors in the treatment of inborn errors of immunity. Front Immunol. 2021;17(12): 717388. https://doi.org/10.3389/fimmu.2021.717388 .
doi: 10.3389/fimmu.2021.717388
Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, et al. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol. 2020;145(5):1452–63. https://doi.org/10.1016/j.jaci.2019.12.896 .
doi: 10.1016/j.jaci.2019.12.896
pubmed: 31887391
Seidel MG, Tesch VK, Yang L, Hauck F, Horn AL, Smolle MA, et al The immune deficiency and dysregulation activity (IDDA2.1 ‘kaleidoscope’) score and other clinical measures in inborn errors of immunity. J Clin Immunol. 2021 Nov 19. https://doi.org/10.1007/s10875-021-01177-2 . Epub ahead of print
Kayaoglu B, Kasap N, Yilmaz NS, Charbonnier LM, Geckin B, Akcay A, et al. Stepwise reversal of immune dysregulation due to STAT1 gain-of-function mutation following ruxolitinib bridge therapy and transplantation. J Clin Immunol. 2021;41(4):769–79. https://doi.org/10.1007/s10875-020-00943-y .
doi: 10.1007/s10875-020-00943-y
pubmed: 33475942
Acker KP, Borlack R, Iuga A, Remotti HE, Soderquist CR, Okada S, et al. Ruxolitinib response in an infant with very-early-onset inflammatory bowel disease and gain-of-function STAT1 mutation. J Pediatr Gastroenterol Nutr. 2020;71(4):e132–3. https://doi.org/10.1097/MPG.0000000000002854 .
doi: 10.1097/MPG.0000000000002854
pubmed: 32732635
Full prescribing information JAKAVI EMA. https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_es.pdf . Accessed 04/08/2021.
Full prescribing information FDA: JAKAVI https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202192s017lbl.pdf . Accessed 04/08/2021.
Loh ML, Tasian SK, Rabin KR, Brown P, Magoon D, Reid JM, et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: a Children’s Oncology Group phase 1 consortium study (ADVL1011). Pediatr Blood Cancer. 2015;62(10):1717–24. https://doi.org/10.1002/pbc.25575 .
doi: 10.1002/pbc.25575
pubmed: 25976292
pmcid: 4546537
Wegehaupt O., Muckenhaupt T., Johnson M.B. et al. Ruxolitinib controls lymphoproliferation and diabetes in a STAT3-GOF patient. J Clin Immunol 40, 1207–1210 (2020). https://doi.org/10.1007/s10875-020-00864-w
Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128(7):3041–52. https://doi.org/10.1172/JCI98814 .
doi: 10.1172/JCI98814
pubmed: 29649002
pmcid: 6026004
Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, et al. Janus kinase inhibition in the Aicardi-Goutières syndrome. N Engl J Med. 2020;383(10):986–9. https://doi.org/10.1056/NEJMc2001362 .
doi: 10.1056/NEJMc2001362
pubmed: 32877590
pmcid: 7495410
Meesilpavikkai K, Dik WA, Schrijver B, Nagtzaam NMA, Posthumus-van Sluijs SJ, van Hagen PM, et al. Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1). J Allergy Clin Immunol. 2018;142(1):328-330.e2. https://doi.org/10.1016/j.jaci.2018.02.045 .
doi: 10.1016/j.jaci.2018.02.045
pubmed: 29729898
Registry Working Party. Immune deficiency and dysregulation activity (IDDA) score. https://esid.org/Working-Parties/Registry-Working-Party/Studies/IDDA-Score . Accessed: 20 December 2021
Przepiorka D, Luo L, Subramaniam S, Qiu J, Gudi R, Cunningham LC, et al. FDA approval summary: ruxolitinib for treatment of steroid-refractory acute graft-versus-host disease. Oncologist. 2020;25(2):e328–34. https://doi.org/10.1634/theoncologist.2019-0627 .
doi: 10.1634/theoncologist.2019-0627
pubmed: 32043777
Saeed I, McLornan D, Harrison CN. Managing side effects of JAK inhibitors for myelofibrosis in clinical practice. Expert Rev Hematol. 2017;10(7):617–25. https://doi.org/10.1080/17474086.2017.1337507 .
doi: 10.1080/17474086.2017.1337507
pubmed: 28571503
Sant’Antonio E, Bonifacio M, Breccia M, Rumi E. A journey through infectious risk associated with ruxolitinib. Br J Haematol. 2019;187(3):286–295. https://doi.org/10.1111/bjh.16174 .
Ballesta B, González H, Martín V, Ballesta JJ. Fatal ruxolitinib-related JC virus meningitis. J Neurovirol. 2017;23(5):783–78. https://doi.org/10.1007/s13365-017-0558-4 .
Nakayama K, Nakamura M, Konishi A, Kaneko S, Nakamichi K, Saijo M, Yakushiji Y, Kusaka H. JC virus granule cell neuronopathy associated with ruxolitinib: a case report and review of the literature. eNeurologicalSci. 2020;21:100269 . https://doi.org/10.1016/j.ensci.2020.100269
Reoma LB, Trindade CJ, Monaco MC, Solis J, Montojo MG, Vu P, et al A. Fatal encephalopathy with wild-type JC virus and ruxolitinib therapy. Ann Neurol. 2019;86(6):878–884. https://doi.org/10.1002/ana.25608
Wathes R, Moule S, Milojkovic D. Progressive multifocal leucoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369:197–8. https://doi.org/10.1056/NEJMc1302135 .
doi: 10.1056/NEJMc1302135
pubmed: 23841743
Lee SC, Feenstra J, Georghiou PR. Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. BMJ Case Rep. 2014;2014. pii: bcr2014204950. https://doi.org/10.1136/bcr-2014-204950
Gill H, Leung GMK, Seto WK, Kwong YL. Risk of viral reactivation in patients with occult hepatitis B virus infection during ruxolitinib treatment. Ann Hematol. 2019;98(1):215–8. https://doi.org/10.1007/s00277-018-3405-7 .
doi: 10.1007/s00277-018-3405-7
pubmed: 29946910
Caocci G, Murgia F, Podda L, Solinas A, Atzeni S, La Nasa G. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia. 2014;28(1):225–7. https://doi.org/10.1038/leu.2013.235 .
doi: 10.1038/leu.2013.235
pubmed: 23929216
Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013;369:681–3. https://doi.org/10.1056/NEJMc1302895 .
doi: 10.1056/NEJMc1302895
pubmed: 23944322
Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629-1640.e2. https://doi.org/10.1016/j.jaci.2016.11.022 .
doi: 10.1016/j.jaci.2016.11.022
pubmed: 28139313
pmcid: 5482293
Cordero E, Goycochea-Valdivia W, Mendez-Echevarria A, Allende LM, Alsina L, Bravo García-Morato M, et al. Executive summary of the Consensus Document on the diagnosis and management of patients with primary immunodeficiencies. J Allergy Clin Immunol Pract. 2020;8(10):3342–7. https://doi.org/10.1016/j.jaip.2020.05.008 .
doi: 10.1016/j.jaip.2020.05.008
pubmed: 33161963
Registry Working Party. Resources. https://esid.org/Working-Parties/Inborn-Errors-Working-Party-IEWP/Studies/Multicentric-retrospective-study-on-JAKinib-treatment-of-patients-with-IEI-of-the-JAK-STAT-pathway . Accessed 21 December 2021