Plasticity under pressure: biology and detection of lineage switch in acute leukemia

Relapsed acute leukemia can be difficult to salvage. An uncommon but increasingly recognized and aggressive mechanism of relapse involves lineage switch. In lineage switch, the immunophenotype of the leukemia at relapse differs from the immunophenotype at initial diagnosis, with the underlying genetic driver(s) conserved, confirming a clonal relationship. Lineage switch is most common—and was first recognized—in B-cell acute lymphoblastic leukemia with KMT2A rearrangement, which often relapses as acute myeloid leukemia. In an era where antigen-targeted therapies, including chimeric antigen receptor T-cells and bispecific T-cell engagers, are increasingly utilized and thus apply selective antigen pressure, this may increase the incidence of lineage switch across different leukemia subtypes. Patients with lineage switch have dismal outcomes and optimal therapies remain unknown, thus there is a large unmet need to better understand the biology, define the diagnosis, and determine the therapeutic approaches to lineage switch. Here, we address these needs providing a review of the current biology of lineage switch, the relationship to different genetic subtypes and present definitions and recommendations for immunophenotypic and molecular monitoring.