Midostaurin plus chemotherapy is standard of care inFLT3-ITD AML for young patients who can tolerate intensive chemotherapy. Resistance to this combination occurs in three distinct patterns: 1) acquired mutations in separate signaling pathways in a FLT3-ITD–negative clone, 2) selection of resistant subclones that express an FLT3 mutation, or 3) persistence of the dominant FLT3-ITD clone.