KITD816V and JAK2V617F mutations are seen recurrently in hypereosinophilia of unknown significance

Abstract

Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP1 in 55 (12%), KIT D816V1 in 14 (3%), and JAK2 V617F1 in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V1 eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP1 cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 lg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V1 SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP1 cases but was only 26 and 41 months for KIT D816V1 SM and JAK2 V617F1 MPN-eo, respectively. Eosinophilia of 2 3 10 9 /l was identified as discriminator for inferior survival in KIT D816V1 and/or JAK2 V617F1 patients (median survival 20 months vs. not reached, P 5 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.

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

“…KIT M541L mutations were recently reported in four of five chronic eosinophilic leukemia, not otherwise specified patients who did not have PDGFRA/B lesions but responded to tyrosine kinase inhibitor treatment. 18 Schwaab and colleagues 19 reported KIT 816 V mutations in 3% (14 patients) and JAK2 V617F mutations in 4% (17 patients) of patients who presented with hypereosinophilia of unknown significance. Notably, with the mutation information and upon review of the slides, the authors reclassified the cases with KIT D816V as systemic mastocytosis with eosinophilia (systemic mastocytosis-eo) and cases with JAK2 V617F mutation as myeloproliferative neoplasm with eosinophilia (myeloproliferative neoplasm-eo).…”

The Diagnostic Work-Up of Hypereosinophilia

“…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.…”

Routine Screening for <b><i>KIT</i></b> M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia

“…Most commonly, translocations or other genomic rearrangements generate TK fusion genes, e.g., FIP1L1-PDGFRA , ETV6-PDGFRB , ZMYM2-FGFR1 , PCM1-JAK2 , and many others [2], but some cases test positive for activating TK point mutations such as KIT D816V or JAK2 V617F [4]. Identifying driver fusion genes is critical for clinical management, e.g., patients with PDGFRA or PDGFRB rearrangements have excellent responses to imatinib, with most cases achieving sustained hematological and molecular remission [5,6,7].…”