What is the role of second-generation TKIs in the treatment of chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

The second-generation TKIs dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) are more potent inhibitors of BCR/ABL than imatinib. Moreover, they exhibit significant activity against all resistant mutations except BCR/ABL/T315I . All three have been approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed Philadelphia chromosome–positive (Ph1+) chronic-phase CML, as well as for chronic-phase CML resistant or intolerant to prior therapy that included imatinib. [33, 34, 35]  Dasatinib and bosutinib are also FDA-approved for blast-phase Ph1+ CML in patients resistant to or intolerant of other therapies, including imatinib.

Jabbour and colleagues found that second-generation TKIs induced higher rates of early complete cytogenic response (CCyR) and major molecular response than imatinib. The authors also state that CCyR is a major determinant of CML outcome, regardless of whether major molecular response is achieved or not. [36]

Compared with these second-generation agents, imatinib has relatively low potency and inhibits its target at micromolecular rather than nanomolar concentrations. In addition, imatinib has increased susceptibility to resistance through a number of mutations in the BCR-ABL target. [37]

That said, these new TKIs are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension, [38] while nilotinib has been linked to biochemical changes in liver function and QT-interval prolongation. Development of resistance may also occur with these agents.

Moreover, imatinib is still very effective. It is also less expensive than the new TKIs, and will go out of patent in the near future. Consequently, it may survive the challenge posed by newer agents because of a favorable balance of cost and efficacy. [39] Using the MD Anderson prognostic factors scoring may help in identifying the few patients requiring the more expensive second-generation agents for first-line use. [40]

A study by Verma et al found that second malignancies occur in a small percentage of patients receiving TKI treatment for hematologic malignancies, mostly CML. No evidence suggests, however, that exposure to these inhibitors increases the risk of developing second malignancies. [41]


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