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

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.