A general treatment algorithm for CML blast crisis occurring during imatinib therapy. Options include clinical trials studying alternate ABL tyrosine kinase inhibitors (TKI) or other novel agents, more traditional chemotherapeutic regimens tailored to the lineage of acute leukemic transformation, and/or allogeneic stem cell transplantation. Some potential chemotherapeutic regimens include HIDAC (high-dose Ara-C); FLAG-Ida (fludarabine, Ara-C, G-CSF, idarubicin) with or without gemtuzumab ozogamicin (GO); APO (adriamycin, prednisone, vincristine)-like regimens; or Hyper-CVAD (hyperfractionated cytoxan, vincristine, adriamycin, decadron). Because of the limited penetration of imatinib into the central nervous system, the risk of concomitant leukemic meningitis should be strongly considered, particularly in lymphoid blast crisis. (As discussed in the text, some patients with BCR-ABL mutations might respond temporarily to imatinib dose escalation.)