Postimmunotherapy lineage switch. In the international Project EVOLVE cohort, postimmunotherapy lineage switch (LS) occurred primarily in KMT2A-rearranged B-ALL; however, multiple other B-ALL subtypes were represented. LS occurred after CD19 and/or CD22 targeting CAR-T therapy, blinatumomab and inotuzumab ozogamicin---it remains unclear whether immunotherapy directly induces LS or selects for preexisting myeloid or less differentiated clones. B-cell receptor sequencing of pre- and post-LS leukemia suggests that LS may occur via direct B-ALL to myeloid transdifferentiation, but it has also been proposed to arise from primitive precursor populations. LS occurs rapidly, and post-LS treatment outcomes are dismal. Structured collaborative translational research to address the mechanisms that drive LS will likely lead to improved outcomes. ALAL, acute leukemia of ambiguous lineage; AML, acute myeloid leukemia; B-ALL, B-cell acute lymphoblastic leukemia; Blin, blinatumomab; CAR-T, chimeric antigen receptor T cell; HSC, hematopoietic stem cell; Ino, inotuzumab ozogamicin; LS, lineage switch; NOS, not otherwise specified; mOS, median overall survival; MPP, multipotent progenitor cell.