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Chronic Lymphocytic Leukemia (CLL) - Diagnostic and Prognostic Testing

Test code(s) 16000, 17817[X], 17239

Question 1. What testing does Quest Diagnostics offer for patients with chronic lymphocytic leukemia (CLL)?

The CLL/Lymphoma Diagnostic Panel (test code 17817[X]) is a flow cytometry test that can be performed using blood, bone marrow aspirate, or fresh tissue. In addition to standard B-cell and T-cell markers, it includes CD38 and FMC7, which assist in the differential diagnosis of other B-cell lymphoproliferative disorders.

The CLL Prognostic Panel, Comprehensive (test code 17239) can be used for determining prognosis and risk stratification. It includes chromosome analysis, a 6-marker FISH panel, IgVH gene mutation analysis, ZAP-70, CD38, and serum ß2-microglobulin. This test code includes a patient-specific overall risk categorization based on all the test results.

Each of these markers can also be ordered individually. Please refer to our Directory of Services for ordering information.

Question 2. Why is the prognostic panel important in the management of CLL?

CLL can have widely variable outcomes, and clinical management is dependent on the presenting features and disease course. Molecular and immunophenotypic markers can help identify those patients with a higher risk for aggressive disease.1-4 This can help physicians select the optimal treatment and surveillance program at time of initial diagnosis.3,4

The most important predictor of adverse outcome and a need for treatment is deletion/loss of the TP53 gene.3 Other strong predictors of more aggressive disease include unmutated IgVH status, ZAP-70 expression, and deletion/loss of the ATM gene.1 Less significant predictors of poor outcome include elevated ß2-microglobulin and increased CD38 expression (≥30% of CD5+/CD19+ cells).

Note that the presence of del13q14 and/or trisomy (+)12, which may be detected by chromosome analysis or FISH, is not associated with an unfavorable prognosis but can be helpful in establishing a diagnosis of CLL in cases with atypical features.

Question 3. What is the benefit of testing multiple prognostic markers simultaneously?

Many cases of high-risk CLL have abnormal results for several prognostic markers. Few cases, however, demonstrate presence of all the unfavorable markers. Furthermore, multiple, large studies have shown that although some unfavorable markers are closely correlated to each other, most still have independent prognostic power in multivariate models.1 Consideration of favorable and unfavorable markers and their relative prognostic power provides the most complete picture of a patient’s risk for aggressive disease. In the comprehensive prognostic panel (test code 17239), a patient-specific interpretation that considers the relative prognostic power of the markers detected is provided.

Question 4. What sample types are appropriate for the CLL Prognostic Panel, Comprehensive test?

Either blood or bone marrow aspirate samples from a patient with CLL can be tested. This panel should NOT be ordered if the sample shows minimal involvement by CLL. Consider ordering test code 17817[X] instead for workup of patients with possible low-levels of residual CLL. 

Question 5. What is the clinical significance of ZAP-70 in CLL?

ZAP-70 is a membrane-associated, intracellular protein kinase that is critical for signal transduction in T-cells and natural killer (NK)-cells. It is not normally present in B-cells.

Aberrant ZAP-70 expression in ≥10% of CD5+/CD19+ cells has been shown to be an unfavorable CLL prognostic indicator.2 Patients with CLL and a positive ZAP-70 test result tend to have an unmutated IgVH gene, unfavorable cytogenetic features, and a shorter time interval from diagnosis to treatment. In contrast, a negative result, indicated by ZAP-70 expression in <10% of CD5+/CD19+ cells, is associated with more favorable features, such as mutated IgVH and no evidence of ATM and TP53 genetic loss. 

Question 6. Is the measurement of ZAP-70 by flow cytometry reliable?

Flow cytometric measurement of intracellular ZAP-70 requires a robust technique.5 In our assay, the expected levels of ZAP-70 positivity in T-cells and NK-cells and the absence of staining in non-neoplastic B lymphocytes (when present) are used as internal controls. ZAP-70 expression is reported only in the CD5+/CD19+ cells. 

Question 7. Can ZAP-70 be tested using bone marrow sections?

If only formalin-fixed, paraffin-embedded (FFPE) bone marrow tissue is available, we can test for ZAP-70 expression using immunohistochemistry (ZAP-70, IHC with Interpretation, test code 90192). Our studies using parallel FFPE tissue and bone marrow aspirate material show that IHC results correlate well with flow cytometry results. Other prognostic factors, such as karyotype, FISH markers, CD38 and ß2-microglobulin levels, are not available on FFPE material.

 

References

  1. Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nature Rev Cancer. 2010;10:37-50.
  2. Crespo M, Bosch F, Villamor N, et al., ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775.
  3. Pospisilova S, et al. ERIC recommendations onTP53 mutation analysis in chronic lymphocyticleukemia. Leukemia. 2012;26(7):1458–1461.
  4. Hallek M, et al. Guidelines for the diagnosis andtreatment of chronic lymphocytic leukemia: a report from the International Workshop on ChronicLymphocytic Leukemia updating the NationalCancer Institute-Working Group 1996 guidelines.Blood. 2008;111(12):5446–5456.
  5. Shankey, TV, Forman M, Scibelli P, et al. An Optimized Whole Blood Method for Flow Cytometric Measurement of ZAP-70 Protein Expression in Chronic Lymphocytic leukemia. Cytometry B Clin Cytom. 2006;70B:259-269.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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