Genomic Landscape of Mixed Phenotype Acute Leukemia Associated With Immunophenotypic Lineage Predominance: Impact on Diagnosis and Treatment

ABSTRACT Objectives Mixed phenotype acute leukemia ( MPAL ) often poses challenges in diagnosis and clinical management. This is the first study to assess the lineage/immunophenotype‐genotype association and the significance of AML ‐myelodysplasia‐related changes ( MR , cytogenetic abnormalities and gene mutations, AML ‐ MR ‐ CG ‐Gene) in MPAL classification. Methods We conducted a clinicopathologic and genomic evaluation of 25 MPAL cases by the WHO ‐ HEM5 / ICC classification criteria, except for retaining those MPAL cases with AML ‐ MR ‐ CG ‐Gene ( Conditional ‐ MPAL ). Results The majority of MPAL cases (22/25, 88%) showed distinct genotypes that overlapped with those of lymphoblastic leukemia ( ALL ) and acute myeloid leukemia ( AML ). The genomic profile of ALL ‐like and AML ‐like was associated with immunophenotypically lymphoid and myeloid lineage predominance, respectively. The lineage/immunophenotype‐genotype association may provide a rationale to develop a lineage‐immunophenotypically/biologically guided therapy selection. Additionally, 64% of MPAL cases carried AML ‐ MR ‐ CG ‐Gene, half of which were MPAL with lymphoid‐lineage predominance and had ALL ‐like molecular signatures, and most of these patients responded well to the ALL ‐based induction regimens. These results support that Conditional‐ MPAL with AML ‐ MR ‐ CG ‐Gene may be better diagnosed as MPAL rather than AML ‐ MR . Conclusion Genomic landscape of AML‐like or ALL‐like MPAL is associated with the immunophenotypic lineage predominance, and such association could impact treatment decisions and provide supporting evidence to refine MPAL diagnostic criteria in future studies.