Mixed phenotype acute leukemia across lineage boundaries: from classification to clonal biology and precision therapy

Mixed phenotype acute leukemia (MPAL) is a rare group of acute leukemias in which myeloid and lymphoid differentiation coexist within the same blast population or across clonally related subpopulations, exposing the limitations of phenotype-based classification. The fifth edition of the World Health Organization classification and the International Consensus Classification have refined lineage assignment and genetic exclusions, yet uncertainty persists in cases with borderline myeloperoxidase expression, bilineal architecture, and treatment-associated lineage change. Genomic and single-cell studies show that similar immunophenotypes can arise from distinct clonal trajectories, with lesions such as BCR::ABL1 , KMT2A rearrangements, BCL11B deregulation, and TP53 alterations shaping developmental potential, prognosis, and therapeutic vulnerability. Retrospective evidence supports acute lymphoblastic leukemia-like induction for many children and fit younger adults, whereas treatment in adults requires closer integration of age, fitness, adverse genetics, and early measurable residual disease (MRD) response. Tyrosine kinase inhibitors, venetoclax, menin inhibitors, bispecific antibodies, antibody-drug conjugates, and cellular therapies broaden therapeutic options but can also impose selective pressures that promote antigen loss or lineage switch. This review integrates contemporary classification, clonal biology, diagnostic workflow, and treatment into a lineage-aware, MRD-adaptive framework. Management should track the founding clone across phenotypic states through rapid genomic profiling, broad flow and molecular MRD assessment, and systematic reassessment at relapse. Prospective international studies linking lineage architecture, genomic drivers, target distribution, and MRD kinetics are needed to define durable treatment strategies for MPAL.