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Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Test Guide

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Laboratory Evaluation

  

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are white blood cell cancers characterized by the expansion of small, monoclonal B lymphocytes that are functionally impaired.1 CLL and SLL are histologically and immunophenotypically similar and are considered to be different forms of the same disease.1,2 In CLL, the functionally impaired lymphocytes are mainly found in the blood and bone marrow, although the spleen, liver, and lymph nodes may also be involved; in SLL, abnormal lymphocytes are mainly found in the lymph nodes.2 CLL and SLL have a heterogeneous clinical course, ranging from indolent to aggressive.

CLL diagnosis requires a CBC (with differential and platelet count) and immunophenotyping tests performed on blood specimens to detect and quantify B lymphocytes with the CLL/SLL immunophenotype (Appendix 1). A threshold of ≥5x109/L abnormal B lymphocytes is used for diagnosis of CLL, and a bone marrow biopsy is generally not required. SLL diagnosis involves identifying B lymphocytes with the CLL/SLL immunophenotype in the lymph nodes.

Once CLL or SLL is diagnosed, prognosis can be assessed with the help of chromosomal, gene mutation, immunophenotyping, and cell turnover analyses.1,2 Disease severity staging can be performed using either the Ann Arbor system for SLL or the Rai and Binet systems for CLL, which are based on clinical factors such as the number of involved tissues and cell counts in the blood and bone marrow (Appendix 2).2,3 Rai stage, along with additional factors such as beta-2-microglobulin and lactate dehydrogenase levels, may in turn be used in prognostic models to estimate survival probability and survival time.4 Asymptomatic individuals with early-stage CLL or SLL do not require treatment and can be managed with a “watch and wait” approach. This approach involves regular monitoring; if signs of symptomatic disease are found, therapy should be considered.5,6 Disease progression in symptomatic individuals can be monitored by assessing changes in blood cell counts, bone marrow and/or lymph node morphology, chromosomal abnormalities, and serum markers.2

The accompanying flowcharts show how laboratory tests may be used in the diagnosis and prognostic assessment of CLL/SLL (Figure 1), as well as in the monitoring of disease progression (Figure 2). Technical details and ordering information are provided in Tables 1 and 2.
Figure 1. Use of laboratory testing to diagnose CLL/SLL and assess prognosis.

Figure 2. Use of laboratory testing to monitor CLL/SLL disease progression in individuals with early-stage disease and in symptomatic patients with treatment indications.

The tables and appendices are provided for informational purposes only and are 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.
Table 1. Core Laboratory Tests Useful for CLL/SLL Diagnosis, Classification, Prognosis, and Management
Test
Code		 Test Name

Clinical Use

Comments
Diagnosis Prognosis Monitoring

Morphology and Comprehensive Tests

6399

CBC (Includes Differential and Platelets)

X

X

X

 

17734(X)a

Comprehensive Hematopathology Report

Includes morphology evaluation and immunophenotyping for CLL/SLL; at the discretion of the hematopathologist, it may also include detection of chromosomal abnormalities

X

X

X

 

Flow Cytometry Tests

17817(X)b

Chronic Lymphocytic Leukemia (CLL)/Lymphoma Diagnostic Panel

Includes CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, CD56, CD64, FMC7, Kappa, and Lambda

X

 

X

Includes diagnostic markers for CLL/SLL
and other non-Hodgkin lymphomas2

16000b

ZAP-70

X

Molecular Test

15480(X)c

Chronic Lymphocytic Leukemia, IgVH Mutation Status, Cell-based

 

X

 

 

Cytogenetic and FISH Tests

14600(X)

Chromosome Analysis, Hematologic Malignancy

X

X

X

Alternative to FISH testing; evaluates abnormalities in all chromosomes in metaphase cells

16864b

FISH, B-Cell Chronic Lymphocytic Leukemia Panel

Includes FISH analysis of abnormalities in chromosomes 6, 11, 12, 13, and 17

 

X

X

Standard of care for determining CLL/SLL chromosomal abnormalities7

Multi-Technology Panel

17240

CLL Prognostic Panel, Limited

Includes IgVH mutation analysis; ZAP-70; and FISH, B-Cell Chronic Lymphocytic Leukemia Panel

X

The tests listed in this table are applicable for both CLL and SLL.
CBC, complete blood count; CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; FISH, fluorescence in situ hybridization.
a Test results are reviewed by a hematopathologist and, if deemed medically necessary for evaluation, additional tests are performed at an additional charge. CPT codes vary depending on the specific tests ordered. Test code 17734(X) includes an interpretive report issued by a hematopathologist.
b This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.
c This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Table 2. Other Laboratory Tests Useful for CLL/SLL Diagnosis, Classification, Prognosis, and Management
Test
Code		 Test Name

Clinical Use

Comments
Diagnosis Prognosis Monitoring

Morphology Test

3542

Tissue, Pathology Report

X

X

X

Used to evaluate lymph node morphology for SLL diagnosis and bone marrow morphology for CLL/SLL prognosis and monitoring

Molecular Tests

14868(X)a

B-Cell Gene Rearrangement, Qualitative PCR, Cell-based

X

Useful for assessing B-cell clonality if flow cytometry results are inconclusive

16515(X)a

P53 Mutation Analysis,

Plasma-based, Leumeta®

 

X

 

Detects >90% of mutations in the P53 gene; does not detect 17p deletion or other large deletions

Cytogenetic and FISH Tests

14501b,c

FISH, P53, Deletion 17p13.1

 

X

 

Detects only the 17p deletion in the P53 gene

17348(X)

FISH, B-Cell Malignancy, IGH, 14q32 Rearrangement

 

X

 

 

Serum Marker Tests

852(X)

Beta-2-Microglobulin, Serum

X

X

593

Lactate Dehydrogenase (LD)

X

X

Multi-Technology Panels

X

17239b

CLL Prognostic Panel, Comprehensive

Includes IgVH Mutation Analysis; ZAP-70; CD38+/CD19+; FISH, B-Cell Chronic Lymphocytic Leukemia Panel; Beta-2-Microglobulin, Serum; Chromosome Analysis, CLL/LPD

      

 

17312b

CLL Prognostic Panel, Comprehensive w/o Karyotype

Includes IgVH Mutation Analysis; ZAP-70; CD38+/CD19+; FISH, B-Cell Chronic Lymphocytic Leukemia Panel; Beta-2-Microglobulin, Serum

   X  

 

The tests listed in this table are applicable for both CLL and SLL.
SLL, small lymphocytic lymphoma; CLL, chronic lymphocytic leukemia; PCR, polymerase chain reaction; FISH, fluorescence in situ hybridization; LPD, lymphoproliferative disorders.
a This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.
b This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.
c Test code 14501 is specific to the performing laboratory. When ordering through your regional business unit, please indicate that the test code is specific for Quest Diagnostics Nichols Institute, Chantilly, VA.

Appendix 1. CLL/SLL Immunophenotype as Determined by Flow Cytometry
Guidelines CLL/SLL Immunophenotype

National Comprehensive Cancer Network (NCCN)2

CD5+, CD10-, CD19+, CD20 dim, CD23+, kappa dim, lambda dim

World Health Organization (WHO)1

CD5+, CD10-, CD11c weak, CD19+, CD20 dim, CD22+, CD23+, CD43+, CD79a+, CD79b -/weak, FMC7 -/weak, IgM dim, IgD dim
Appendix 2. The Rai System and the Binet System for CLL Staging2,3,5
Stage Description Clinical Implication

Rai System

0

Lymphocytosis (PB lymphocytes ≥15,000/μL and ≥40% lymphocytes in BM)

Low riska

Median survival >10 y

I

Lymphocytosis with enlarged lymph node(s)

Intermediate riska

II

Lymphocytosis with enlarged spleen and/or liver, with or
without enlarged lymph nodes

Median survival 7 y

III

Lymphocytosis with anemia (Hb <11 g/dL), with or without enlarged lymph nodes, liver, or spleen

High riska

Median survival 1.5–3 y

IV

Lymphocytosis with thrombocytopenia (platelets <1011/L), with

or without anemia or enlarged lymph nodes, liver, or spleen

Binet System

A

Hb ≥10 g/dL, platelets ≥1011/L, and <3 enlarged areas

Median survival >10 y

B

Hb ≥10 g/dL, platelets ≥1011/L, and ≥3 enlarged areas

Median survival 7 y

C

Hb <10 g/dL and/or platelets <1011/L, and any number of enlarged areas

Median survival 1.5–2.5 y

PB, peripheral blood; BM, bone marrow; Hb, hemoglobin.
a Risk classifications in the Rai system are based on median survival time, with lower risk being associated with
higher median survival time.

References

  1. Muller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:180-182.

  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin’s Lymphomas. Version 3.2011. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Updated May 18, 2011. Accessed March 15, 2012.

  3. Rai KR. A critical analysis of staging in CLL. In: Gale RP, Rai KR, eds. Chronic Lymphocytic Leukemia: Recent Progress and Future Direction. New York, NY: Alan R Liss; 1987:253-264.

  4. Wierda WG, O’Brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109:4679-4685.

  5. Eichhorst B, Hallek M, Dreyling M; on behalf of the ESMO Guidelines Working Group. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(suppl 5):162-164.

  6. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456.

  7. Maddocks KJ, Lin TS. Update in the management of chronic lymphocytic leukemia. J Hematol Oncol. 2009;2:29.
     

 Content reviewed 12/2012
 

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