Acute leukemia therapy at a crossroads: from conventional chemotherapy to the era of precision medicine.
Since the discovery of cytotoxic agents in the mid-20th century, acute leukemia has consistently served as a model for oncology research. As the Human Genome Project and subsequent genomic profiling elucidated the landscape of somatic mutations and cytogenetic aberrations driving leukemogenesis, the development of molecularly targeted therapies has dramatically accelerated, yielding significant improvements in patient outcomes. In acute myeloid leukemia (AML), the emergence of selective inhibitors targeting high-frequency alterations such as FLT3, NPM1, and IDH1/2 has redefined the standard of care, demonstrating superior efficacy when combined with conventional intensive chemotherapy or hypomethylating agents. Simultaneously, for acute lymphoblastic leukemia (ALL), in addition to the significant improvements achieved by tyrosine kinase inhibitors (TKIs) for BCR-ABL-positive ALL, the advent of CD19- or CD22-targeted monoclonal antibodies and CAR-T cell therapies has marked an epoch-making milestone, representing a major paradigm shift in the management of relapsed or refractory cases. Bridging these two distinct lineages, menin inhibitors have emerged as a novel class of agents targeting a common pathogenic mechanism in KMT2A-rearranged AML/ALL and NPM1-mutated AML, exhibiting promising antileukemic activity across these subtypes. In this review, we describe the evolution of leukemia therapy-highlighting historical trajectory across AML, APL, and ALL from uniform cytotoxic chemotherapy to molecularly targeted agents, antibody-based therapies, and chemo-free paradigms, while outlining future perspectives for precision hematology.