Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by a reciprocal translocation between the long arms of chromosomes 9 and 22 that results in expression of the oncoprotein BCR-ABL1. An optimal response to tyrosine kinase inhibitors (TKIs) requires a
BCR-ABL
transcript level ≤ 10% at 3 months, ≤ 1% at 6 months, ≤ 0.1% at 1 year, and ≤ 0.01% onwards. Complex scenarios like P190
BCR-ABL
CML, unusual
BCR-ABL
transcripts, primary refractory CML, and detection of TKI-resistance mutations during treatment frequently pose a therapeutic challenge. In this article we present some of these clinical scenarios using a case-based approach.