How to think about acute leukemia of ambiguous lineage

Classification of acute leukemia involves assigning lineage by resemblance of blasts to normal progenitor cells. This approach provides descriptive information that is useful for disease monitoring, provides clues to pathogenesis, and can help to select effective chemotherapeutic regimens. Acute leukemias of ambiguous lineage (ALAL) are those leukemias that either fail to show evidence of myeloid, B-lymphoid, or T-lymphoid lineage commitment or show evidence of commitment to more than 1 lineage, including mixed-phenotype acute leukemia (MPAL). The different treatment regimens for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) make ALAL a challenge both diagnostically and therapeutically. Current classification criteria have reduced the reported incidence of mixed lineage leukemias by emphasizing fewer markers and categorizing some biphenotypic leukemias with recurrent cytogenetic abnormalities as other entities. Several recent studies have explored the genomic and epigenetic landscape of MPAL and emphasize the genomic heterogeneity of MPAL. Two classification proposals of myeloid malignancies recently been published and include International Consensus Classification and fifth edition of the World Health Organization Classification of Haematolymphoid Tumours. Our review aims to discuss the diagnostic challenges in the setting of classification updates, recent genomic studies, and therapeutic strategies in this poorly understood disease.