The development of
imatinib has changed the management of chronic
myeloid leukemia (CML), producing high response rates in most patients. However, most individuals treated with
imatinib, 400 mg, have residual molecular disease, and both intrinsic and acquired resistance can occur. The newer
tyrosine kinase inhibitors,
dasatinib and
nilotinib, are effective in patients with
imatinib-resistant CML, In patients with relapse or resistance, current guidelines recommend escalating the dose of
imatinib or switching to new
tyrosine kinase inhibitors.
Dasatinib has been investigated in patients who were resistant or intolerant to
imatinib. Switching to
dasatinib, 70 mg, twice daily has been shown to be more effective than high-dose
imatinib. Another study found that
dasatinib, 100 mg, once daily was just as effective as the twice-daily regimen but was better tolerated.
Nilotinib is also effective in most patients with resistance or intolerance to
imatinib and is associated with minimal toxicity. Other inhibitors, such as
bosutinib and
INNO-406, are being developed with favorable early results. New drugs are still needed, particularly for individuals who are resistant to
tyrosine kinase inhibitors or those with the T3151 mutation. Emerging CML
therapies, some of which have different mechanisms of action from those of
tyrosine kinase inhibitors, have shown promising results and could offer an alternative to these patients as monotherapy or in combination.