Imatinib-Induced Clinical Response in ETV6::ACSL6 Myeloid Neoplasm with Eosinophilic Pneumonitis: A Case Report

Objective: Unusual or unexpected effect of treatment Background: Myeloid neoplasms with ETV6::ACSL6 fusions are extremely rare entities that are characterized by eosinophilic and/or basophilic leukocytosis. While they clinically mimic myeloid neoplasms with eosinophilia and tyrosine kinase fusions such as ETV6::PDGFRB, they have not been shown to be responsive to imatinib. There are currently no effective treatments available and clinical outcomes are poor. Case Report: We report a rare case of a 71-year-old man with a history of myelodysplastic syndrome/neoplasms (MDS) with mutated SF3B1 and multilineage dysplasia treated with luspatercept followed by azacitidine. However, he developed clonal evolution of disease to MDS with hypereosinophilia. Chromosome analysis identified t(5;12) (q31;p13). Fluorescence in situ hybridization was negative for FIP1L1/PGFFRA or PDGFRB gene rearrangement, but RNA-sequencing identified the ETV6::ACSL6 fusion. He received a hematopoietic cell transplantation with achievement of complete remission but subsequently relapsed, with chromosome analysis again revealing t(5;12)(q31;p13) [ETV6::ACSL6]. He rapidly clinically deteriorated and developed refractory respiratory failure due to acute eosinophilic pneumonitis. He received a prolonged course of high-dose steroids without adequate improvement of the eosinophilia. Based on reports showing good response to tyrosine kinase inhibitors in patients with the ETV6::PDGFRB fusion, treatment was switched to imatinib, leading to rapid normalization of absolute eosinophil counts, with clinical improvement. Conclusions: Our findings suggest that imatinib should be considered for patients with a myeloid neoplasm with an ETV6::ACSL6 fusion who are refractory to corticosteroids. Further molecular investigations are needed to elucidate the underlying mechanism of imatinib sensitivity in ETV6::ASCL6-associated disease, given the absence of genetic in-volvement of a tyrosine kinase.