Antigen Pressure, Clonal Evolution, and Lineage Plasticity in B-Cell Acute Lymphoblastic Leukemia: Resistance Biology...

Targeted immunotherapies have transformed the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), yet their efficacy depends on sustained expression of lineage-associated surface antigens. This review examines how antigen-directed pressure reshapes the biology of resistance, distinguishes canonical antigen escape from lineage plasticity, and clarifies the genomic contexts, diagnostic challenges, and therapeutic implications of these distinct escape routes.

Under antigen-directed pressure, leukemia may escape through antigen downregulation, alternative splicing, acquired genetic alteration, or epitope disruption - mechanisms that generally preserve B-lineage identity and often remain addressable with alternative lineage-directed therapy. A biologically distinct route is lineage plasticity, in which cells destabilize lineage commitment or undergo overt lineage switch; clinical outcomes are poor, with a median overall survival of approximately 4.8 months in the largest reported series. Lineage switch is enriched within permissive genomic contexts, most notably KMT2A-rearranged leukemia, which accounted for the majority of B-ALL-to-acute myeloid leukemia or mixed-phenotype switches in a large international cohort. By contrast, CD19-negative antigen escape is more strongly associated with TP53 mutations and preserves B-lineage identity. Whether switching reflects selection of pre-existing subclones, active epigenetic reprogramming, or both remains unresolved. As antigen-directed therapies move into frontline use, distinguishing antigen escape from true lineage transformation is becoming essential for relapse surveillance, disease classification, therapeutic sequencing, and the design of strategies to prevent resistance.