Cortes JE, Kantarjian H, Shah NP et al.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
N Engl J Med 2012;367:2075–88.
Adam Mead’s review: Despite the success of imatinib for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), between 20% and 30% of patients develop primary or secondary resistance to this agent. Resistance is often caused by acquired mutations in the tyrosine kinase domain of the BCR–ABL fusion oncogene. With the use of the second-generation tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib, approximately half of patients with imatinib-resistant CML will achieve cytogenetic remissions. However, some mutations also confer resistance to second-generation TKIs, particularly the “gatekeeper” T315I mutation. Ponatinib is a third-generation TKI that was rationally designed to target and inhibit T315I-mutated BCR–ABL.