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78 Involvement of the JAK-STAT Pathway in the Molecular Landscape of Fusion-Free Myeloid Neoplasms with EosinophiliaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Rare Myeloproliferative Neoplasms: Unveiling Promising Pathways and Novel Therapies
Hematology Disease Topics & Pathways:
Research, Biological therapies, Translational Research, epidemiology, MPN, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, Immunotherapy, survivorship, Myeloid Malignancies
Saturday, December 9, 2023: 10:45 AM

Matthieu Groh, MD, MSc1*, Laurène Fenwarth, MD, MSc2*, Augustin Boudry2*, Elise Fournier3*, Alice Marceau-Renaut, PharmD4*, Julie Abraham5*, Marly Barry6,7*, Philippe Blanche, MD8*, Quentin Bodard9*, Thorsten Braun, MD, PhD10,11, Safia Chebrek12*, Rafael Daltro De Oliveira, MD13*, Matthieu Decamp, MD, PhD14*, Cécile Audrey Durel15*, Edouard Forcade, MD, PhD16*, Mathieu Gerfaud-Valentin17*, Camille Golfier18*, Clement Gourguechon19*, Nathalie Grardel20*, Olivier Kosmider, MD, PhD21*, Mathilde Labro22*, Sarah Melboucy Belkhir23*, Fatiha Merabet24*, Adrien Michon25*, Nihal Martis26*, Cécile Morice27*, Stephane Moreau28*, Antoine Néel29*, Franck E. Nicolini, MD, PhD30, Laurent Pascal31*, Florence Pasquier, MD, PhD32*, Andrea Pieragostini33*, Catherine Roche-Lestienne34*, Philippe Rousselot, MD, PhD35*, Anne Thiebaut, MD36*, Jean-Francois Viallard, MD PhD37*, Mathieu Wemeau38*, Claude Preudhomme, PharmD, PhD39*, Jean-Emmanuel Kahn40*, Guillaume Lefèvre41* and Nicolas Duployez, PharmD, PhD39,42*

1French National Reference Center for Hypereosinophilic Syndromes (CEREO), Departement of Internal Medicine, Hôpital Foch, Suresnes, France
2Hematology Laboratory, CHU Lille, Lille, France
3University Hospital, Lille, LILLE, FRA
4Hematology Laboratory, CHU Lille, Lille Cedex, FRA
6CH de Boulogne sur Mer, Boulogne-sur-Mer, TX, FRA
7CH Du Docteur Duchenne, Boulogne Sur Mer Cedex, FRA
8Department of Internal Medicine, CHU Cochin, Paris, France
9CH d'Angoulême, Angoulême, France
10Clinical Hematology, Avicenne University Hospital, Assistance Publique – Hôpitaux de Paris, Bobigny, France
11Hematology Department, Avicenne Hospital, Bobigny, France
12CH d'Avignon, Avignon, FRA
13Centre d'Investigation Clinique, Hôpital St Louis, Paris, France
15Hôpital St Joseph St Luc, Lyon, FRA
16Service d'Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, Pessac, France
17Hôpital de la Croix Rousse, Lyon, France
18Hôpital Lyon Sud, Lyon, France
19Amiens University Hospital, Amiens, France
21Cochin Hospital, Paris, FRA
22Department of Clinical Research and Innovation, Hôpital Foch, Suresnes, France
23CH de St Quentin, St Quentin, France
24andre mignot hospital, LE CHESNAY, FRA
25Hôpital Européen Georges Pompidou, Paris, FRA
26CHU De Nice, Nice, FRA
27Dermatology, CHU de Caen, Caen, France
28Hématologie Clinique, CHU Limoges, Limoges, FRA
29CHU Hôtel-Dieu, Nantes, FRA
30Hematology Department, Centre Leon Berard, Lyon, France
31Faculté Catholique De Lille, Lille, FRA
32INSERM U790, PR1, IGR, Villejuif, FRA
33Hematology, CHU Dijon, Dijon, France
34CHU Lille, Lille, France
35Centre Hospitalier de Verailles, UMR1184, University Versailles Paris-Saclay, Versailles, France
36CHU Grenoble, Grenoble, France
37Service Médecine Interne, Haut-Leveque Hospital, Pessac, France
38CH Valenciennes, Valenciennes, FRA
39Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France
40CHU Ambroise Paré, Boulogne Billancourt, FRA
41Laboratoire d'Immunologie, CHU de Lille, Lille, France
42Hôpital Claude Huriez, Lille, France

Introduction. Gene fusions leading to the constitutive activation of tyrosine kinases (TK) such as PDGFRA, PDGFRB or FGFR1 have been the first recurrent genetic defects involved in myeloid hypereosinophilic syndromes (HES). Although activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is critical for eosinophil production and survival, genes involved in the JAK/STAT pathway are not included in most next-generation sequencing (NGS) panels used for the etiological workup of hypereosinophilia (HE).

Methods. A custom 149-gene NGS panel including subunits of the IL3/IL5/GM-CSF receptors, TK (PDGFRA/B, FGFR1, ABL1, FLT3, KIT), intracellular proteins of the JAK-STAT and RAS-MAPK pathways was performed in 64 consecutive adult patients (experimental group) referred between March 2012 to June 2023 to the French Reference Center for Hypereosinophilic Syndromes (CEREO) for HE/HES displaying at least one clinic-biological feature suggestive of myeloid neoplasm (i.e., splenomegaly, other unexplained CBC abnormality besides HE, increased serum tryptase and/or vitamin B12 levels, corticosteroid-refractory HE and/or sensitivity to either TK inhibitors or JAK inhibitors). All of them were negative by PCR and/or FISH analyses for gene rearrangements involving PDGFRA, PDGFRB or FGFR1. Patients with lymphocytic HES (n=7), idiopathic HES (n=26) and HE of undetermined significance (n=11) were used as controls (total, n=44).

Results. Concordant with the latest recommendations of the international cooperative working group on eosinophil-associated disorders, at least one mutation was reported in 50/64 (78%) patients of the experimental group versus 8/44 (18%) patients in the control group (p<0.001) when applying a threshold of at least 3% of variant allele frequency (VAF). Mutations in the control group implied genes involved in age-related clonal hematopoiesis (e.g. DNMT3A, TET2), with low VAF in almost all cases. All 35 patients with at least one mutation involving the JAK/STAT pathway belonged to the experimental group, among whom all 22 patients treated with steroids were refractory to therapy. Eighteen patients had STAT5B mutations, including 13 (72%) with the somatic N642H mutational hotspot. Two patients harbored JAK2Ex13InDel mutations, including one with eosinophilia and erythrocytosis. Previously unreported molecular alterations were also evidenced, including seven patients with JAK1 mutations and three STAT5A-mutated patients who shared common features i.e., the co-occurrence of BCOR mutations, high hemoglobin levels and eosinophil hyperplasia. Of note, the latter mutations were not reported both in a public database (GnomAD) as well as in a second cohort of 613 samples referred for suspicion of myeloid malignancies (yet without HE) studied with the same NGS workflow, thereby strongly supporting their association with myeloid HES. Deciphering the data from bulk sequencing also suggests that JAK-STAT mutations were frequently preceded by (or associated with) myelodysplasia-related gene mutations, with SF3B1 (12/36) and ASXL1 (10/36) mutations being the most common. Overall, both KIT D816V (n=2) and RAS/MAPK pathway activation mutations (n=3) were rare. No mutation of either PDGFRA/B, FGFR1 or IL3/IL5/GM-CSF-receptor genes was evidenced. In the experimental group, 17/18 (94%) patients (including 12 with JAK-STAT mutations) treated with ruxolitinib and with > 3 months of follow-up responded to treatment (12 complete and 5 partial hematological responses).

Discussion. These data emphasize the usefulness of NGS in daily practice for the workup of fusion-free HES patients harboring features suggestive of myeloid neoplasms. In such patients, druggable mutations involving the JAK-STAT pathway (including yet unidentified STAT5A mutations) are frequent. Most JAK/STAT mutations occur in the setting of a preexisting myelodysplastic or myelodysplastic/myeloproliferative disease harboring mutations in RNA-splicing genes or chromatin modifiers. These findings provide a rationale for refining treatment algorithms in fusion-free myeloid HES patients, supporting the use of JAK inhibitors as frontline therapy. More data are warranted to assess whether JAK inhibition enables sustained molecular remission in all disease subtypes.

Disclosures: Groh: AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy, Honoraria. Forcade: Astellas: Speakers Bureau; Alexion: Other: Travel support, Speakers Bureau; Novartis: Consultancy, Other: Travel support, Speakers Bureau; Gilead Sciences: Other: Travel support, Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; MSD: Other: Travel support. Nicolini: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; SUN pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; INCYTE BIOSCIENCES: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rousselot: Incyte: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Viallard: EUSAPHARMA: Consultancy. Kahn: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lefèvre: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

OffLabel Disclosure: Ruxolitinib in fusion-free patients with features of myeloid neoplasms and eosinophilia, harbouring mutations of the JAK-STAT pathway.

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