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An 80-year-old man with recently diagnosed chronic eosinophilic leukemia (CEL) presented with progressive constitutional symptoms and concern for leukemic transformation after failing tyrosine kinase inhibitor therapy. Laboratory studies revealed leukocytosis with profound eosinophilia (70%; absolute eosinophil count, 36.8 × 10⁹/L), accompanied by anemia and thrombocytopenia. His course was rapidly complicated by tumor lysis syndrome requiring hemodialysis. Imaging showed diffuse marrow involvement without organomegaly. Peripheral blood smear demonstrated striking eosinophilia with uneven granule distribution, cytoplasmic hypogranulation, and vacuolation (panel A, Giemsa stain, 100× lens objective), without monocytosis or increased blasts (3%). Bone marrow aspirate showed numerous eosinophilic precursors and mature eosinophils (panel B, Giemsa stain, 20× lens objective), whereas biopsy revealed a markedly hypercellular marrow (panel C, hematoxylin and eosin stain, 5× lens objective) with sheets of eosinophils and extensive Charcot-Leyden crystal deposition (panel D, hematoxylin and eosin stain, 100× lens objective). Flow cytometry did not identify an abnormal lymphoid or immature myeloid population. Fluorescence in situ hybridization and RNA sequencing did not detect eosinophilia-associated fusions or rearrangements. However, next-generation sequencing revealed pathogenic mutations involving NPM1, SRSF2, DNMT3A, and biallelic TET2. The patient showed minimal response to azacitidine and venetoclax and died of organ dysfunction.

NPM1 mutations in CEL are exceedingly rare. This case highlights the aggressiveness of NPM1-mutated myeloid neoplasms and the need to consider acute myeloid leukemia in eosinophilic presentations with NPM1 mutations.

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