JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study

Marco Fischer; Peter Olbrich; Jérôme Hadjadj; Volker Aumann; Shahrzad Bakhtiar; Vincent Barlogis; Philipp von Bismarck; Markéta Bloomfield; Claire Booth; Emmeline P. Buddingh; Deniz Cagdas; Martin Castelle; Alice Y. Chan; Shanmuganathan Chandrakasan; Kritika Chetty; Pierre Cougoul; Etienne Crickx; Jasmeen Dara; Angela Deyà-Martínez; Susan Farmand; Renata Formankova; Andrew R. Gennery; Luis Ignacio Gonzalez-Granado; David Hagin; Leif Gunnar Hanitsch; Jana Hanzlikovà; Fabian Hauck; José Ivorra-Cortés; Kai Kisand; Ayca Kiykim; Julia Körholz; Timothy Ronan Leahy; Joris van Montfrans; Zohreh Nademi; Brigitte Nelken; Suhag Parikh; Silvi Plado; Jan Ramakers; Antje Redlich; Frédéric Rieux-Laucat; Jacques G. Rivière; Yulia Rodina; Pérsio Roxo Júnior; Sarah Salou; Catharina Schuetz; Anna Shcherbina; Mary A. Slatter; Fabien Touzot; Ekrem Unal; Arjan C. Lankester; Siobhan Burns; Mikko R.J. Seppänen; Olaf Neth; Michael H. Albert; Stephan Ehl; Bénédicte Neven; Carsten Speckmann

doi:10.1016/j.jaci.2023.10.018

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study

Marco Fischer, Peter Olbrich, Jérôme Hadjadj, Volker Aumann, Shahrzad Bakhtiar, Vincent Barlogis, Philipp von Bismarck, Markéta Bloomfield, Claire Booth, Emmeline P. Buddingh, Deniz Cagdas, Martin Castelle, Alice Y. Chan, Shanmuganathan Chandrakasan, Kritika Chetty, Pierre Cougoul, Etienne Crickx, Jasmeen Dara, Angela Deyà-Martínez, Susan FarmandRenata Formankova, Andrew R. Gennery, Luis Ignacio Gonzalez-Granado, David Hagin, Leif Gunnar Hanitsch, Jana Hanzlikovà, Fabian Hauck, José Ivorra-Cortés, Kai Kisand, Ayca Kiykim, Julia Körholz, Timothy Ronan Leahy, Joris van Montfrans, Zohreh Nademi, Brigitte Nelken, Suhag Parikh, Silvi Plado, Jan Ramakers, Antje Redlich, Frédéric Rieux-Laucat, Jacques G. Rivière, Yulia Rodina, Pérsio Roxo Júnior, Sarah Salou, Catharina Schuetz, Anna Shcherbina, Mary A. Slatter, Fabien Touzot, Ekrem Unal, Arjan C. Lankester, Siobhan Burns, Mikko R.J. Seppänen, Olaf Neth, Michael H. Albert, Stephan Ehl, Bénédicte Neven, Carsten Speckmann^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Original language	English
Pages (from-to)	275-286.e18
Journal	Journal of Allergy and Clinical Immunology
Volume	153
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2023.10.018
Publication status	Published - Jan 2024

Keywords

autoimmunity
baricitinib
chronic mucocutaneous candidiasis
gain of function
immune dysregulation
inborn error of immunity
JAK inhibitor
JAK/STAT signaling
primary immunodeficiency
ruxolitinib

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10.1016/j.jaci.2023.10.018

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Fischer, M., Olbrich, P., Hadjadj, J., Aumann, V., Bakhtiar, S., Barlogis, V., von Bismarck, P., Bloomfield, M., Booth, C., Buddingh, E. P., Cagdas, D., Castelle, M., Chan, A. Y., Chandrakasan, S., Chetty, K., Cougoul, P., Crickx, E., Dara, J., Deyà-Martínez, A., ... Speckmann, C. (2024). JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study. Journal of Allergy and Clinical Immunology, 153(1), 275-286.e18. https://doi.org/10.1016/j.jaci.2023.10.018

@article{5c4a9505de404c7291cb1752e200cb9c,

title = "JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study",

abstract = "Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.",

keywords = "autoimmunity, baricitinib, chronic mucocutaneous candidiasis, gain of function, immune dysregulation, inborn error of immunity, JAK inhibitor, JAK/STAT signaling, primary immunodeficiency, ruxolitinib",

author = "Marco Fischer and Peter Olbrich and J{\'e}r{\^o}me Hadjadj and Volker Aumann and Shahrzad Bakhtiar and Vincent Barlogis and {von Bismarck}, Philipp and Mark{\'e}ta Bloomfield and Claire Booth and Buddingh, {Emmeline P.} and Deniz Cagdas and Martin Castelle and Chan, {Alice Y.} and Shanmuganathan Chandrakasan and Kritika Chetty and Pierre Cougoul and Etienne Crickx and Jasmeen Dara and Angela Dey{\`a}-Mart{\'i}nez and Susan Farmand and Renata Formankova and Gennery, {Andrew R.} and Gonzalez-Granado, {Luis Ignacio} and David Hagin and Hanitsch, {Leif Gunnar} and Jana Hanzlikov{\`a} and Fabian Hauck and Jos{\'e} Ivorra-Cort{\'e}s and Kai Kisand and Ayca Kiykim and Julia K{\"o}rholz and Leahy, {Timothy Ronan} and {van Montfrans}, Joris and Zohreh Nademi and Brigitte Nelken and Suhag Parikh and Silvi Plado and Jan Ramakers and Antje Redlich and Fr{\'e}d{\'e}ric Rieux-Laucat and Rivi{\`e}re, {Jacques G.} and Yulia Rodina and J{\'u}nior, {P{\'e}rsio Roxo} and Sarah Salou and Catharina Schuetz and Anna Shcherbina and Slatter, {Mary A.} and Fabien Touzot and Ekrem Unal and Lankester, {Arjan C.} and Siobhan Burns and Sepp{\"a}nen, {Mikko R.J.} and Olaf Neth and Albert, {Michael H.} and Stephan Ehl and B{\'e}n{\'e}dicte Neven and Carsten Speckmann",

note = "Publisher Copyright: {\textcopyright} 2023 American Academy of Allergy, Asthma & Immunology",

year = "2024",

month = jan,

doi = "10.1016/j.jaci.2023.10.018",

language = "English",

volume = "153",

pages = "275--286.e18",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "1",

}

Fischer, M, Olbrich, P, Hadjadj, J, Aumann, V, Bakhtiar, S, Barlogis, V, von Bismarck, P, Bloomfield, M, Booth, C, Buddingh, EP, Cagdas, D, Castelle, M, Chan, AY, Chandrakasan, S, Chetty, K, Cougoul, P, Crickx, E, Dara, J, Deyà-Martínez, A, Farmand, S, Formankova, R, Gennery, AR, Gonzalez-Granado, LI, Hagin, D, Hanitsch, LG, Hanzlikovà, J, Hauck, F, Ivorra-Cortés, J, Kisand, K, Kiykim, A, Körholz, J, Leahy, TR, van Montfrans, J, Nademi, Z, Nelken, B, Parikh, S, Plado, S, Ramakers, J, Redlich, A, Rieux-Laucat, F, Rivière, JG, Rodina, Y, Júnior, PR, Salou, S, Schuetz, C, Shcherbina, A, Slatter, MA, Touzot, F, Unal, E, Lankester, AC, Burns, S, Seppänen, MRJ, Neth, O, Albert, MH, Ehl, S, Neven, B & Speckmann, C 2024, 'JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study', Journal of Allergy and Clinical Immunology, vol. 153, no. 1, pp. 275-286.e18. https://doi.org/10.1016/j.jaci.2023.10.018

TY - JOUR

T1 - JAK inhibitor treatment for inborn errors of JAK/STAT signaling

T2 - An ESID/EBMT-IEWP retrospective study

AU - Fischer, Marco

AU - Olbrich, Peter

AU - Hadjadj, Jérôme

AU - Aumann, Volker

AU - Bakhtiar, Shahrzad

AU - Barlogis, Vincent

AU - von Bismarck, Philipp

AU - Bloomfield, Markéta

AU - Booth, Claire

AU - Buddingh, Emmeline P.

AU - Cagdas, Deniz

AU - Castelle, Martin

AU - Chan, Alice Y.

AU - Chandrakasan, Shanmuganathan

AU - Chetty, Kritika

AU - Cougoul, Pierre

AU - Crickx, Etienne

AU - Dara, Jasmeen

AU - Deyà-Martínez, Angela

AU - Farmand, Susan

AU - Formankova, Renata

AU - Gennery, Andrew R.

AU - Gonzalez-Granado, Luis Ignacio

AU - Hagin, David

AU - Hanitsch, Leif Gunnar

AU - Hanzlikovà, Jana

AU - Hauck, Fabian

AU - Ivorra-Cortés, José

AU - Kisand, Kai

AU - Kiykim, Ayca

AU - Körholz, Julia

AU - Leahy, Timothy Ronan

AU - van Montfrans, Joris

AU - Nademi, Zohreh

AU - Nelken, Brigitte

AU - Parikh, Suhag

AU - Plado, Silvi

AU - Ramakers, Jan

AU - Redlich, Antje

AU - Rieux-Laucat, Frédéric

AU - Rivière, Jacques G.

AU - Rodina, Yulia

AU - Júnior, Pérsio Roxo

AU - Salou, Sarah

AU - Schuetz, Catharina

AU - Shcherbina, Anna

AU - Slatter, Mary A.

AU - Touzot, Fabien

AU - Unal, Ekrem

AU - Lankester, Arjan C.

AU - Burns, Siobhan

AU - Seppänen, Mikko R.J.

AU - Neth, Olaf

AU - Albert, Michael H.

AU - Ehl, Stephan

AU - Neven, Bénédicte

AU - Speckmann, Carsten

PY - 2024/1

Y1 - 2024/1

N2 - Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

AB - Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

KW - autoimmunity

KW - baricitinib

KW - chronic mucocutaneous candidiasis

KW - gain of function

KW - immune dysregulation

KW - inborn error of immunity

KW - JAK inhibitor

KW - JAK/STAT signaling

KW - primary immunodeficiency

KW - ruxolitinib

UR - http://www.scopus.com/inward/record.url?scp=85178371751&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2023.10.018

DO - 10.1016/j.jaci.2023.10.018

M3 - Article

C2 - 37935260

AN - SCOPUS:85178371751

SN - 0091-6749

VL - 153

SP - 275-286.e18

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study

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