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Invited Review

Current and emerging tests for the laboratory monitoring of chronic myeloid leukaemia and related disorders

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Pages 231-246 | Received 03 Dec 2007, Accepted 14 Jan 2008, Published online: 06 Jul 2009
 

Summary

Chronic myeloid leukaemia (CML) is a molecularly defined disease. The BCR-ABL fusion occurs in all cases of classical CML and leukaemic cells express a constitutively activated BCR-ABL tyrosine kinase. Other fusion oncogenes involving tyrosine kinases, including ABL and PDGFRA/B, have been identified, and are associated with leukaemic syndromes that may resemble CML. The discovery and treatment of these related disorders has been facilitated by our detailed understanding of CML. Imatinib mesylate has significantly improved the outcome of patients with CML, but there remains a significant minority of chronic phase CML patients for whom the response to treatment with standard dose imatinib is suboptimal. Cytogenetic and molecular monitoring of the response to treatment provides important prognostic information. Achievement of a major molecular response (MMR) in chronic phase patients treated de novo with imatinib confers near 100% freedom from progression to advanced phase, and MMR is now an important goal of therapy. Standardisation of BCR-ABL molecular monitoring is under way and should enable the accurate and reproducible identification of MMR in laboratories around the world. Point mutations in the kinase domain of BCR-ABL are the most common cause of acquired resistance to imatinib treatment. The susceptibility of a mutation to imatinib, nilotinib, or dasatinib may help to guide changes in therapy in a patient with resistance. In addition to these established methods of monitoring, there are new tests in development that may assist in determining prognosis and optimising therapy. Among patients receiving the same dose of imatinib, the plasma level of imatinib shows considerable inter-patient variation, and there is emerging evidence that higher levels may be associated with improved response to treatment. The intracellular concentration of imatinib also shows considerable variation, most likely related to differences in influx and efflux transport mechanisms. We discuss how these established and emerging assays might be used to optimise the treatment of CML patients.

Abbreviations
ACA=

additional cytogenetic abnormality

ALL=

acute lymphoblastic leukaemia

AML=

acute myeloid leukaemia

AP=

accelerated phase

BC=

blast crisis

CCR=

complete cytogenetic response

CEL=

chronic eosinophilic leukaemia

CHR=

complete haematological response

CML=

chronic myeloid leukaemia

CMR=

complete molecular response

CP=

chronic phase

FISH=

fluorescence in situ hybridisation

KD=

kinase domain

MCR=

major cytogenetic response

MMR=

major molecular response

Ph=

Philadelphia

RQ-PCR=

reverse transcriptase quantitative real-time PCR.

Abbreviations
ACA=

additional cytogenetic abnormality

ALL=

acute lymphoblastic leukaemia

AML=

acute myeloid leukaemia

AP=

accelerated phase

BC=

blast crisis

CCR=

complete cytogenetic response

CEL=

chronic eosinophilic leukaemia

CHR=

complete haematological response

CML=

chronic myeloid leukaemia

CMR=

complete molecular response

CP=

chronic phase

FISH=

fluorescence in situ hybridisation

KD=

kinase domain

MCR=

major cytogenetic response

MMR=

major molecular response

Ph=

Philadelphia

RQ-PCR=

reverse transcriptase quantitative real-time PCR.

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