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| Guidelines for CML Patient & Disease Monitoring |
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| (1) Why should I monitor my CML patients? |
Monitoring BCR-ABL levels in patients with CML gives you critical insight into response to therapy so you can make well-informed treatment decisions that maximize patient outcomes.
The National Comprehensive Cancer Network (NCCN) Guidelines recommend serial monitoring every three months to provide trend data for BCR-ABL levels.1
1. NCCN Clinical Practice Guidelines in Oncology, V.1.2006, Chronic Myelogenous Leukemia (http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf)
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| (2) Should I measure BCR-ABL levels in all my CML patients? |
| Yes, all patients with CML should be monitored. The National Comprehensive Cancer Network (NCCN) Guidelines recommend serial monitoring every three months to provide trend data for BCR-ABL levels. |
| (3) How often should I measure BCR-ABL levels? |
| You should measure BCR-ABL levels every 3 months, if the patient’s disease state is stable. If the patient appears to be relapsing, we recommend that you measure BCR-ABL levels every month and include mutation analysis. |
| (4) At what BCR-ABL level is the disease considered controlled? |
The goal of treatment is for the patient to attain Major Molecular Response (MMR) within a 12-18 month time frame. Attaining MMR means a patient is likely to live without disease progression for at least 5 years.1
MMR is defined as greater than or equal to a 3-log reduction in the ratio of BCR-ABL to control gene from a standardized median baseline value.2
Taking into account assay variability, if a patient’s value is maintained within a 3-fold range at or below MMR, the disease may be considered controlled.
1. Druker et al., NEJM 2006; 355: 2408-17
2. Hughes et al., NEJM 2003; 349: 1423-32 |
| (5) What factors can affect BCR-ABL levels? |
Several factors including disease progression and sample processing can affect BCR-ABL levels.
CML can progress due to:
• Patient noncompliance with treatment
• Therapy resistance due to:
Secondary mutations in BCR-ABL
BCR-ABL duplication
Secondary genetic aberrations independent of BCR-ABL
• Progression from chronic to accelerated phase or blast crisis due to therapy relapse.
In addition, BCR-ABL levels can be affected if blood RNA quality is degraded from improper blood collection or sample shipment, or if the patient has myelodysplasia. |
| (6) What is Major Molecular Response (MMR)? Why is it important? |
Attaining major molecular response (MMR) means a patient is likely to live without disease progression for at least 5 years.1
MMR is defined as greater than or equal to a 3-log reduction in the ratio of BCR-ABL to control gene expression levels from a standardized median baseline value.2
Taking into account assay variability, if a patient’s value is maintained within a 3-fold range at or below MMR, the disease may be considered controlled.
In the International Randomized Interferon versus STI571 (IRIS) study, patients with a ratio at or below MMR within 12-18 months of starting imatinib (Gleevec©) treatment were 100% free from progressing to the accelerated phase or blast crisis at 5 years.1
MolecularMD is the only commercial laboratory to offer QRT-PCR BCR-ABL testing with international reference standards defining MMR, thanks to an exclusive agreement with the lead investigators of the IRIS study. To ensure the reliability and reproducibility of every assay, every sample is run against the standards including MMR, for the most accurate BCR-ABL quantification available today.
1. Druker et al., NEJM 2006; 355: 2408-17
2. Hughes et al., NEJM 2003; 349: 1423-32 |
| (7) What is Minimal Residual Disease (MRD)? |
| Minimal residual disease is characterized by a low level of disease, an absence of clinical symptoms and negative BCR-ABL levels as detected by most tests. |
| (8) What is complete cytogenic response (CCR)? |
Complete cytogenetic response (CCR) is defined as the absence of Philadelphia positive chromosomes in the analysis of a bone marrow aspirate of at least 20 chromosome metaphase spreads. CCR is characterized by BCR-ABL levels that are generally 2 logs below the median baseline.
CCR is 2-3 logs less sensitive a measurement of CML disease than BCR-ABL RQ-PCR analysis. It is also much more invasive, requiring a bone marrow aspirate rather than a simple blood draw.
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| (9) What is the advantage of PCR over FISH? |
FISH (fluorescence in situ hybridization) is a cytogenetic technique that looks at 200-500 blood cells attained through a bone marrow biopsy. Because of the small sample size, it is not as sensitive a technique as PCR.
PCR (polymerase chain reaction) is a technique that exponentially amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic techniques such as FISH. PCR measurement requires a simple blood draw, which is much less invasive and less time-consuming than the bone marrow biopsy FISH requires.
In many patients responding well to treatment, cytogenetic techniques such as FISH are not sensitive enough to detect MRD. Low BCR-ABL levels that may not be detectable by FISH can be detected by quantitative PCR.
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