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. 2024 Jun;99(6):1108-1118.
doi: 10.1002/ajh.27306. Epub 2024 Apr 2.

Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study

Matthieu Groh  1   2 , Laurène Fenwarth  3 , Mathilde Labro  4 , Augustin Boudry  3 , Elise Fournier  3 , Mathieu Wemeau  5 , Alice Marceau-Renaut  3 , Rafael Daltro de Oliveira  6 , Julie Abraham  7 , Marly Barry  8 , Philippe Blanche  9 , Quentin Bodard  10 , Thorsten Braun  11 , Safia Chebrek  12 , Matthieu Decamp  13 , Cécile-Audrey Durel  14 , Edouard Forcade  15 , Mathieu Gerfaud-Valentin  16 , Camille Golfier  17 , Clément Gourguechon  18 , Nathalie Grardel  3 , Olivier Kosmider  19 , Nihal Martis  20 , Sarah Melboucy Belkhir  21 , Fatiha Merabet  22 , Adrien Michon  23 , Stéphane Moreau  7 , Cécile Morice  24 , Antoine Néel  25 , Franck E Nicolini  26 , Laurent Pascal  27 , Florence Pasquier  28 , Andrea Pieragostini  29 , Catherine Roche-Lestienne  30 , Philippe Rousselot  22 , Louis Terriou  31 , Anne Thiebaut-Bertrand  32 , Jean-François Viallard  33 , Claude Preudhomme  3 , Jean-Emmanuel Kahn  34   35 , Guillaume Lefevre  2   36 , Nicolas Duployez  3 ; CEREO Collaborators
Affiliations
Free article

Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study

Matthieu Groh et al. Am J Hematol. 2024 Jun.
Free article

Abstract

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

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