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