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 (HR)||
Complete HR (CHR):
|Cytogenetic response (CyR)||
|Molecular response (MR)||
*Complete HR should be confirmed on 2 subsequent occasions.
↑Complete CyR should be confirmed on 2 subsequent occasions.
?The international scale as proposed by Hughes et al.1
§ Major molecular response should be confirmed on 2 subsequent occasions.
WBC, white blood cell.
Adapted with permission from Baccarani et al.2
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).1-3 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 months.2
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).1,2 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 treatment.2
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 progression.4 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 CCyR.5 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.6,7 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).1,2 Undetectable or unquantifiable levels of BCR-ABL constitute a complete molecular response (CMR)2. 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 occasions.2
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).2
Adapted with permission from Baccarani et al. 2
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 3.2
|3 months||No HR||Any HR < CHR|
|6 months||No CHR or CyR||Any CyR < PCyR|
|12 months||< PCyR||Any CyR > PCyR and < CCyR||Any MR < MMR|
|18 months||Any CyR < CCyR||Any MR < MMR|
HR, haematological response; CHR, complete haematological response; PCyR, partial cytogenetic response; CCyR, complete cytogenetic response; MR, molecular response; MMR, major molecular response.
Reprinted with permission from Baccarani et al.2
1. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28-37.
2. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
3. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in OncologyTM. Available at: http://www.nccn.org/. Accessed July 19, 2006.
5. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432
6. Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia. 2003;17:2401-2409.
7. Paschka P, Muller MC, Merx K, et al. Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission. Leukemia. 2003;17:1687-1694.