In this issue of Blood, Nagel et al provide evidence supporting the presence of premalignant leukemic clones in nonlymphoid compartments of patients with BCR-ABL1–positive B-cell precursor acute lymphoblastic leukemia (ALL) as a cause of lineage switch after CD19 immunotherapy, extending the lineage switch mechanism beyond mixed-lineage leukemia (MLL)-rearranged ALL. 1 This observation suggests that CD19-targeted therapies alone may not suffice in the eradication of underlying disease in BCR-ABL1 p210-and p190-positive patients, and that strategies to target the stem cell compartment may be needed for durable remissions in this high-risk population.