Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous
leukemia (CML) patients for all stages of the disease and is
endorsed by international treatment guidelines as the first line
option. Although imatinib is highly effective and well tolerated,
the development of resistance represents a clinical challenge.
Since the most frequently identified mechanism of acquired imatinib
resistance is bcr-abl kinase domain point mutations, periodic
hematologic, cytogenetic, and molecular monitoring is critical
throughout imatinib therapy. Once cytogenetic remission is
achieved, residual disease can be monitored by bcr-abl transcript
levels as assayed by reverse transcription polymerase chain
reaction (RT-PCR). Detection of bcr-abl mutants prior to and during
imatinib therapy can aid in risk stratification as well as in
determining therapeutic strategies. Thus, mutation screening is
indicated in patients lacking or losing hematologic response.
Moreover, search for mutations should also be performed when a
3-log reduction of bcr-abl transcripts is not achieved or there is
a reproducible increase of transcript levels. In patients harboring
mutations which confer imatinib resistance, novel second line
tyrosine kinase inhibitors have demonstrated encouraging efficacy
with low toxicity. Only the T315I bcr-abl mutant has proved totally
resistant to all clinically available bcr-abl inhibitors.
Strategies to further increase the rates of complete molecular
remissions represent the next frontier in the targeted therapy of
CML patients.