Managing imatinib resistance in chronic myeloid leukaemia.
OBJECTIVE
Imatinib mesylate has proven to be an extremely effective and generally well tolerated drug, producing durable responses in most patients with chronic phase chronic myeloid leukaemia. Nonetheless, a minority of patients are resistant or intolerant to imatinib; proposed alternative strategies include imatinib dose escalation, switching to a second-generation tyrosine kinase inhibitor or, in rare instances, allogeneic stem cell transplantation. The aim of this review is to aid clinicians in the recognition, investigation and appropriate treatment of imatinib resistance.


RESULTS
Although response definitions are still being refined, there is emerging evidence that earlier intervention with next-line therapy is associated with better outcomes, reinforcing the importance of careful monitoring in all patients and mutation analysis in those losing response. Imatinib dose escalation can produce sustained responses in patients resistant to standard dosing, but is frequently poorly tolerated. Dasatinib and nilotinib are both effective next-line therapies, with clinical studies confirming a small number of BCR-ABL kinase domain mutations that confer insensitivity to one or both of these agents.


CONCLUSIONS
The development of imatinib resistance, as defined by the revised European LeukemiaNet criteria, should trigger a careful review of drug adherence or recent interruptions, a repeat bone marrow aspirate and mutation analysis. In the absence of clinically relevant mutations, the choice between dasatinib and nilotinib should be guided by the potential adverse effects specific to each drug and relevant comorbidities.
Osborn
Michael
M
Directorate of Haematology, Australia, SA Pathology, Adelaide, South Australia, Australia.
Hughes
Timothy
T
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib