Mutational Analyses to Influence Treatment Choices for Imatinib Resistant Chronic Myeloid Leukemia (CML)

Two tyrosine kinase inhibitors – dasatinib and nilotinib – have shown significant clinical activity in imatinibresistant or imatinib-intolerant chronic myeloid leukemia (CML). Choosing the most appropriate therapy in the face of imatinib failure is a matter of some debate.

Imatinib is an important breakthrough drug credited with revolutionizing the treatment of CML. However, resistance to the drug has emerged as a major clinical issue. Further, some patients experience intolerable side effects. Researchers have identified specific mutations in a rogue gene that renders imatinib ineffective. The mechanisms of the resistance are many and include mutations in the kinase domain of BCR-ABL, increased production of BCR-ABL, or activation of BCR-ABL-independent pathways.

Nilotinib and dasatinib are second-line therapeutic agents for patients with resistance or intolerance to imatinib. Nilotinib, an orally bioavailable, selective BCR-ABL tyrosine kinase inhibitor overcomes most imatinib resistant BCR-ABL mutations in preclinical and clinical models. Dasatinib has a wider spectrum of activity against a broader range of BCR-ABL forms than imatinib and has shown clinical benefit and tolerability in patients in all phases of CML. The two drugs work against the same abnormal protein targeted by imatinib, but in slightly different ways. Dasatinib binds both active and inactive conformations of ABL. In contrast, nilotinib binds to the inactive ABL kinase conformation. In least 300-fold more potent than imatinib against unmutated ABL.

The most important factor in determining the choice of second-line therapy is prior therapeutic response. In clinical practice, failure or suboptimal response to imatinib should trigger a search for mutations. There is emerging evidence that approximately one quarter of patients with imatinib resistance have a mutation profile that should influence the choice of nilotinib or dasatinib therapy. There are a large number of mutations associated with imatinib resistance and a small number of specific mutations associated with a lack of response or resistance to nilotinib and dasatinib. A single mutation, T315I, indicates that neither nilotinib nor dasatinib will be effective. Choosing the most appropriate treatment after imatinib failure may be critical in attaining the best possible long-term prognosis.