Nilotinib - Tasigna®
Response Criteria in Ph+ CML
As a consequence of the imatinib experience in Ph+ CML, experts worldwide have recommended definitions of response1 (Figure 1) and consensus guidelines for response assessment (Table 1) to standardize optimal Ph+ CML therapy.1-3 A hematologic response to therapy in CML is reflected in a reduction of WBC count accompanied by a decrease in spleen size. A complete hematologic response (CHR) includes a platelet count of <450 × 109/L, a WBC count of <10 × 109/L, <5% basophils, and a nonpalpable spleen.3 Treatment guidelines recommend that a CHR should be achieved within 3-6 months of therapy (Figure 2).2,3
Figure 1. Definitions of Response to Therapy in ph+ CML.4
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| Hematologic Response | Cytogenetic Response | Molecular Respnose | |
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| Methods |
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| BCR-ABL to control gene ratio according to the International Scale | |||
Cytogenetic response refers to a reduction in the presence of the Ph chromosome in the karyotype of cells analyzed in the metaphase stage of the cell cycle. A complete cytogenetic response (CCyR) is defined as the lack of detection of the Ph chromosome.3 Intermediate levels of cytogenetic response are defined in Figure 2. The prognostic significance of achieving a CCyR in CML therapy is well established.4 According to the European LeukemiaNet recommendations and National Comprehensive Cancer Network guidelines, an optimal response during CML therapy includes achievement of a CCyR within 1 year (Figure 2).2,3
Figure 2. Criteria for Satisfactory Response at Landmark Time Points in ph+ CML Therapy 4
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Investigators and clinicians have recently turned to more sensitive methods of detection of minimal residual disease in Ph+ CML. Stringent criteria of response that reflect the disease at the molecular level have been developed.6 Reductions in BCR-ABL messenger RNA transcript levels in patient serum, as measured by the highly sensitive method of quantitative reverse transcription polymerase chain reaction (RQ-PCR), define a molecular response.7 A ³3-log reduction in BCR-ABL transcripts with respect to levels of a control gene such as BCR or ABL, from a standard baseline established from patients with Ph+ CML-CP before therapy, is defined as a major molecular response (MMR). Recently, an International Scale for expressing molecular response has been proposed in which the baseline BCR-ABL to control gene transcript ratio is represented by 100%.1 To harmonize the scale across different laboratories, BCR-ABL gene to control gene transcript ratios known to correspond to a 3-log reduction from a previous baseline established from newly diagnosed patients before therapy are converted to 0.1%. CML treatment recommendations or guidelines suggest that achievement of MMR after 1 year of therapy is optimal (Figure 2).3,8
References:
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. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Chronic Myelogenous Leukemia. 2006;1.
3.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.
4. Dewar AL, Cambareri AC, Zannettino AC, et al. Macrophage colony stimulating factor receptor, c-fms, is a novel target of imatinib. Blood. 2005;105:3127-3132.
5.Rosti G, Testoni N, Martinelli G, Baccarani M. The cytogenetic response as a surrogate marker of survival. Semin Hematol. 2003;40(2 suppl 2):56-61.
6. Mensink E, van de Locht A, Schattenberg A, et al. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol. 1998;102:768-774.
7. 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.
8. Mauro MJ, Deininger MW. Chronic myeloid leukemia in 2006: a perspective. Haematologica. 2006;91:152.