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Current issues in CLL
Assessing MRD negativity
- The evolution of highly sensitive assays to detect residual disease has resulted in a reevaluation of the traditional response criteria for this heterogeneous disease67
- MRD is a sensitive, objective measure of disease status following treatment. MRD negativity is defined as having achieved <1 CLL cell in 10,000 leukocytes9
- Techniques used to assess MRD status include flow cytometry and allele-specific oligonucleoside polymerase chain reaction (ASO-PCR).9,45 Both techniques yield data that are highly correlative.15 Although the ASO-PCR method is more sensitive, it may have less specificity, which may result in false positives15
- Flow cytometry measures the number of cells by labeling cell surface antigens with fluorescent antibodies. To identify CLL cells, up to 4 cell surface antigens are labeled to detect malignant cells68
- PCR is a technique used to amplify DNA segments that are unique to the CLL cells (that results from immunoglobulin gene rearrangement). The amplified DNA is then detected and quantified69
- In assessing MRD status, it is important to note the origin of the sample being used to determine MRD status. Patients found to be MRD negative as determined by results from a sample of peripheral blood may not be MRD negative if a sample were taken from the bone marrow.9,15 It has been proposed that assessment of MRD status based on a bone marrow sample should be performed when MRD negativity in peripheral blood has been achieved
MRD as a clinical endpoint
- The concept of MRD negativity is distinct from that of a CR because MRD endpoints have different criteria68
- In a clinical analysis using a sensitive flow cytometric assay, about 25% of 104 patients who were declared to have a CR by NCI-WG criteria were defined as MRD positive since CLL cells represented more than 0.05% of bone marrow leukocytes at 3 months after treatment68
- Achieving MRD negativity after treatment has correlated with longer disease-free intervals when compared to MRD-positive patients70 (Figure 8)
