Chronic myeloid leukemia (CML) is well suited to molecular monitoring as rising and falling levels of BCR-ABL transcript, measured by RQ-PCR (real time quantitative polymerase chain reaction) from venous peripheral blood (PB) correlate well with disease progression and remission (1). Fluorescence in situ hybridization (FISH) and classical cytogenetics performed on bone marrow (BM) may have a role (2,3) but neither are as sensitive and reproducible for disease monitoring as RQ-PCR, especially when RQ-PCR is performed within a standardized laboratory with an optimized system(4).

The development of the tyrosine kinase inhibitor imatinib has significantly altered the management of CML with far fewer patients currently exposed to the toxicities of chemotherapy or the hazards of stem-cell transplantation. However resistance to imatinib is well documented, particularly in patients who commence imatinib in the advanced phases and may indicate a need for therapy change (1,5-10). The major mechanism of resistance is mutation within the BCR-ABl kinase domain. A greater than two-fold rising level of BCR-ABL transcript has been shown to be associated with the detection of mutations (1). This chapter will discuss molecular monitoring in the imatinib era, focusing on treatment that began in early chronic phase disease.


The discovery of the Philadelphia (Ph) chromosome (11) and its molecular counterpart, the BCR-ABL fusion gene, gave CML a unique genetic marker of malignancy and, since then, much has been established about its role in cell physiology, signal transduction, and the regulation of hematopoiesis. After allogeneic BM transplant the detection of the BCR-ABL oncogene in patients with CML is significantly associated with disease relapse compared with patients in whom BCR-ABL is either not detectable or who have significantly reduced levels of transcript (12). Patients treated with interferon alpha who achieved CCyR, had prolonged disease remissions if they had undetectable levels of transcript or significantly reduced levels of transcript, compared to patients without significantly reduced levels of transcript (13). This correlation is also seen in imatinib therapy where a reduction in measurable BCR-ABL to the level of a major molecular response (MMR) is associated with a lack of disease progression, first documented in the IRIS trial (14). Table 1 defines treatment response as determined by cytogenetic and molecular analysis.

TABLE 1 Defining Response: Levels of Detectable Disease Using Different Methods and Correlation with BCR-ABL Ratio According to the Proposed International Scale

Level of response


Equivalent BCR-ABL ratio

Diagnosis in chronic phase

Complete hematological response (CHR)

Minimal cytogenetic response Minor cytogenetic response Partial cytogenetic response (PCyR) Major cytogenetic response (MCyR) Complete cytogenetic response (CCyR)

Major molecular response (MMR) Complete molecular response (CMR)

Peripheral blood: leucocytosis, peaks of myelocytes and neutrophils, blasts generally <2% basophils <20%, platelets normal or increased. Bone marrow blasts <5%

Platelet <450 x 109 Wcc <10 x 109 Differential without immature granulocytes and with <5% basophils. Non palpable spleen. 66-95% Ph positive metaphases 36-65% Ph positive metaphases 1 -35% Ph positive metaphases 0-35% Ph positive metaphases 0% Ph positive metaphases

Range 30-300%

>3 log reduction BCR-ABL mRNA

from a standardized baseline Undetectable BCR-ABL mRNA by RT- 0% PCR at a defined level of sensitivity

Source: From Ref. 4.

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