Atypical chronic myeloid leukemia: from cytology to molecular characterization

A 68-year-old woman with a history of breast cancer in complete remission presented with absolute leukocytosis (42 × 10⁹/L) and slight thrombocytosis (533 × 10⁹/L). Manual differential revealed 68% neutrophils, 4% band forms, 5% metamyelocytes, 5% myelocytes, 2% blasts, 2% monocytes, and 0% basophils. Marrow aspirate was hypercellular with significant granulocytic proliferation (panel A: Wright-Giemsa stain; 40× lens objective), myeloid dysplasia consistent mainly of abnormal segmentation of the nucleus (panels B and C: Wright-Giemsa stain; 100× lens objective), low blast count (panel C: Wright-Giemsa stain; 100× lens objective), and dysmegakaryopoiesis (panel D: Wright-Giemsa stain; 100× lens objective). Karyotype was normal. Fluorescence in situ hybridization was negative for fusions involving PDGFR-A, PDGFR-B, FGFR1, PCM1-JAK1, or BCR::ABL1. Mutations in JAK2, CALR, MPL, and CSF3R were not identified. Next-generation sequencing identified mutations in EZH2 (variant allele fraction [VAF] 95%), ASXL1 (VAF 48%), and 2 SETBP1 variants (VAF 25% and 13%). Mutations in CBL were absent. A diagnosis of atypical chronic myeloid leukemia (aCML) was rendered.

aCML is manifested by hyperleukocytosis without monocytosis or basophilia, organomegaly, or marked dysgranulopoiesis. Because of its rarity, it remains an exclusion diagnosis, and for this purpose it is essential to combine cytology and molecular features. Frequently mutated genes include SETBP1, ASXL1, NRAS/KRAS, SRSF2, and TET2. The prognosis for individuals with aCML remains poor and SETPB1 mutations have been correlated with worse outcomes.

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