Acute leukemia of ambiguous lineage: the known and the uncertain

Acute leukemia of ambiguous lineage (ALAL) is a rare, high-risk form of acute leukemia. It is characterized by the inability to assign a single lineage of differentiation to the leukemia and can manifest with more than one lineage-defining marker, called mixed phenotype acute leukemia (MPAL), or the complete absence of such markers, defined as acute undifferentiated leukemia (AUL). Recent genetic, epigenetic and metabolic insights refine diagnostic frameworks, inform classification and risk-stratification, and expose potential targetable vulnerabilities. However, the rarity and heterogeneous manifestations of ALAL result in ongoing diagnostic and therapeutic uncertainty. The most recent World Health Organization and International Consensus Classification documents provide a pragmatic framework integrating immunophenotypic and genetic criteria for classification, with recognition of specific somatic genetic alterations that define disease biology. These include rearrangements involving BCR::ABL1, KMT2A, ZNF384, and BCL11B activation. Current evidence supports the use of acute lymphoblastic leukemia-type induction regimens (with the addition of tyrosine kinase inhibitors for Philadelphia chromosome- positive MPAL) over acute myeloid leukemia or hybrid approaches. For AUL the optimal therapeutic approach is uncertain. Incorporation of targeted therapies in combination with intensive, and lower-intensity chemotherapy backbones based on the specific biological and genetic characteristics of ALAL is an appealing approach and is increasingly reported. The use of lineage-specific targeted approaches may result in therapeutic pressure and lineage switch in patients with acute leukemia with multi-phenotypic potential. The role and optimal platform for minimal residual disease surveillance in ALAL to guide therapy, and inform transplantation is unclear, given the paucity of prospective controlled data.