NPM1-mutated acute myeloid leukemia with marked erythroid and megakaryocytic differentiation Free

A 74-year-old man presented with refractory NPM1-mutated acute myeloid leukemia (AML) after cycle 1 of azacitidine/venetoclax induction. Bone marrow aspirate smears showed 67% blasts. A subset had erythroid differentiation with a deeply basophilic cytoplasm, round nuclei, and prominent nucleoli (red arrow), whereas another suggested a megakaryocytic lineage with pale basophilic cytoplasm with blebs and ovoid nuclei (blue arrow) (panel A, Giemsa stain, original magnification ×1000, scale bar 20 μm). The biopsy showed extensive blast infiltration and dysplastic megakaryocytes (panel B, hematoxylin and eosin stain, original magnification ×400, scale bar 20 μm). The blasts were positive for CD71 and CD61 (subset) (panels C and D, respectively, original magnification ×200, scale bar 50 μm) on immunohistochemistry staining. NPM1 immunohistochemistry showed nuclear and cytoplasmic reactivity (mutant pattern) (panel E, original magnification ×400, scale bar 50 μm). Flow cytometry revealed erythroid blasts (60% subset) with expression of CD71, CD105, and CD235a (small subset) and megakaryocytic blasts (40%) with expression of CD41, CD42b, and CD61. The karyotype was normal. The pretreatment immunophenotype was unknown. Next-generation sequencing detected NPM1 (c.860_863dupTCTG,p.W288fs∗12, type A; variant allelic frequency [VAF] of 40%), FLT3-ITD (VAF, 29%), DNMT3A (p.P709R; VAF, 36%), NRAS (p.G12V; VAF, 3%), PTPN11 (p.D61N; VAF, 12%), WT1 (p.E148∗; VAF, 37%), and RAD21 (p.E428∗; VAF, 33%) mutations.

Erythroid and megakaryocytic differentiation is exceedingly rare in NPM1-mutated AML, which is typically extremely sensitive to BCL2 inhibition with venetoclax. AML with erythroid/megakaryocytic differentiation, however, may be resistant to venetoclax because of the upregulation of BCL2-related antiapoptotic proteins, such as BCL-XL. Notably, RAS-MAPK pathway–activating mutations have also been associated with venetoclax resistance. The presence of NRAS and PTPN11 mutations here also may have contributed to the resistance to venetoclax therapy.

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