The goals of therapy in patients with chronic myeloid leukaemia (CML) are to:

• Stabilise blood counts
• Achieve haematological, cytogenetic, and molecular responses.

The management of CML is based on meeting certain therapeutic milestones within a specified period of time (Table 1).

Haematological Response

A haematological response (HR) includes reducing platelet counts to < 450 × 10⁹/L and WBC counts to < 10 × 10⁹/L, decreasing the basophil level to < 5%, eliminating immature granulocytes from the peripheral blood, and eradicating the signs and symptoms of disease (Table 1)^{8, 33, 34}. It is recommended that HR be evaluated every 2 weeks until a complete HR has been achieved and confirmed in 2 subsequent occasions, followed by monitoring every 3 months⁸.

Cytogenetic Response

Cytogenetic response (CyR) is an important goal of therapy, with progression-free survival benefits for patients. CyR is based on analysis of bone-marrow aspirates and the reduction or elimination of Philadelphia chromosome-positive (Ph+) cells. A complete cytogenetic response (CCyR) is defined by the absence of Ph+ cells from bone marrow; a partial CyR by the presence of 1%-35% Ph+ cells; a minor CyR by the presence of 36%-65% Ph+ cells; a minimal CyR by the presence of 66%-95% Ph+ cells; and no CyR by the presence of >95% Ph+ cells in bone marrow (Table 1)^{8, 34}. A cytogenetic examination is recommended before treatment, and at least every 6 months until a CCyR has been achieved and confirmed in 2 subsequent occasions, followed by monitoring every 12 months during treatment⁸.

Molecular analytic techniques, such as fluorescence in situ hybridisation (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR), also may be used to detect the presence or absence of BCR-ABL and monitor disease progression³⁵. Although the prognostic role of these techniques continues to be clarified, there is substantial evidence that major reductions in the level of BCR-ABL transcripts correlate with progression-free survival in patients with CML who achieve a CCyR²⁸. For patients receiving therapy for CML, the magnitude of reduction in tumour burden is a key prognostic indicator. Moreover, most patients treated with Glivec^® (imatinib) achieve a CCyR, thus increasing the importance of molecular monitoring of residual disease to further stratify response to treatment and to promptly detect risk of loss of response^{36, 37}. Major molecular response (MMR) has been defined as a ≥3-log decrease in BCR-ABL:BCR mRNA transcripts as measured by quantitative RT-PCR, or a BCR-ABL:ABL ratio <0.10% (Table 1)^{8, 34}. Undetectable or unquantifiable levels of BCR-ABL constitute a complete molecular response (CMR)⁸. The definition of response, however, is evolving based on differences in prognostic value. Molecular response should be evaluated every 3 months once CCyR has been achieved, and an MMR should be confirmed on 2 subsequent occasions. Mutational analysis is highly recommended in case of failure, suboptimal response, or BCR-ABL transcript level increase on at least 2 subsequent occasions⁸.

Response Definition and Monitoring

For the minority of patents with CML who do not respond to Glivec therapy, lack of response to treatment at different time points can be defined as failure, suboptimal, or warnings (Table 2)⁸.

A response is defined as failure when treatment at the current dose is no longer appropriate for the patient and dose escalation or other treatments are required. Suboptimal response indicates that the patient may still have substantial benefit from treatment continuation; however, long-term outcome of the treatment would not likely be as favourable. Dose escalation or other treatment is recommended for patients with a suboptimal response. Warning is indicated when the standard dose of the treatment may not be the best option. Although warnings are flexible and do not necessarily mean that action needs to be taken, a more careful monitoring and dose escalation or other treatments are highly recommended. The criteria proposed by the European LeukemiaNet for failure, suboptimal response, and warning are listed in Table 3⁸.

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