Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

Abstract

The distinction between chronic eosinophilic leukemia, not otherwise specified and idiopathic hypereosinophilic syndrome largely relies on clonality assessment. Prior to the advent of next-generation sequencing, clonality was usually determined by cytogenetic analysis. We applied targeted next-generation sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of idiopathic hypereosinophilic syndrome patients (n = 51), and assessed the significance of mutations in conjunction with clinicopathological features. The findings were further compared with those of 17 chronic eosinophilic leukemia, not otherwise specified patients defined by their abnormal cytogenetics and/or increased blasts. Mutations were detected in 14/51 idiopathic hypereosinophilic syndrome patients (idiopathic hypereosinophilic syndrome/next-generation sequencing-positive) (28%), involving single gene in 7 and ≥ 2 in 7 patients. The more frequently mutated genes included ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%). Idiopathic hypereosinophilic syndrome/next-generation sequencing-positive patients showed a number of clinical features and bone marrow findings resembling chronic eosinophilic leukemia, not otherwise specified. Chronic eosinophilic leukemia, not otherwise specified patients showed a disease-specific survival of 14.4 months, markedly inferior to idiopathic hypereosinophilic syndrome/next-generation sequencing-negative (P o0.001), but not significantly different from idiopathic hypereosinophilic syndrome/next-generation sequencing-positive (P = 0.117). These data suggest that targeted next-generation sequencing helps to establish clonality in a subset of patients with hypereosinophilia that would otherwise be classified as idiopathic hypereosinophilic syndrome. In conjunction with other diagnostic features, mutation data can be used to establish a diagnosis of chronic eosinophilic leukemia, not otherwise specified in patients presenting with hypereosinophilia.

Myeloid neoplasms with eosinophilia

“…103 Single gene mutations were found in 7 patients, and 2 or more gene mutations were found in the additional 7 patients. Mutations included ASXL1 (43%), TET2 (36%), EZH2 (29%), CBL (14%), SETBP1 (22%), and NOTCH1 (14%).…”

The Diagnostic Work-Up of Hypereosinophilia

“…In recent years, using NGS technology, somatic mutations associated with myeloid neoplasms have been detected in 25-30% of patients who have a normal karyotype and no increase in blasts and who would otherwise be considered to be idiopathic DOI: 10.1159/000489341 HES. Mutations by NGS have been found mostly in genes involved in DNA methylation and chromatin modification, such as ASXL1, TET2, EZH2, and DNMT3A [81,82]. While a positive mutation provides evidence of clonality, these mutations have been reported in aging individuals lacking evidence of a myeloid neoplasm [83,84].…”

“…There is a male predominance in both disease entities; however, the median age is in the 4th decade for idiopathic HES and in the 6th decade for CEL and NOS [81]. Organ damage due to an eosinophilic infiltrate or eosinophil activation is, by definition, seen in all patients with idiopathic HES and frequently involves skin, lung, and gastrointes- tinal tract [87].…”

“…Patients with CEL, NOS who either have a karyotypic abnormality and/or increased blasts have a median overall survival of 15-22 months [81,88]. Most CEL, NOS patients either die of AML progression or BM failure.…”

“…In the past, clonality had been mainly determined by chromosomal analysis or mutations well known to occur in MPNs, such as JAK2, MPL, CALR, or KIT. However, it has been shown that these mutations are extremely uncommon in CEL, NOS [80,81]. In recent years, using NGS technology, somatic mutations associated with myeloid neoplasms have been detected in 25-30% of patients who have a normal karyotype and no increase in blasts and who would otherwise be considered to be idiopathic DOI: 10.1159/000489341 HES.…”