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Unit Code 83727:
ZAP-70, Chronic Lymphocytic Leukemia (CLL) Prognosis

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Useful For

As a risk factor for disease progression in patients with B-cell CLL

Clinical Information

B-cell chronic lymphocytic leukemia (CLL) is the most common

leukemia in adults. Its clinical course is highly variable with survival

times ranging from months to decades. The standard procedure

for estimating prognosis are clinical staging systems developed by

Rai and Binet. In these staging systems, most CLL patients have early

stage disease. Genetic prognostic markers such as immunoglobulin

heavy chain gene mutational status and fluorescence in situ hybridization

(FISH) studies for specific chromosomal abnormalities have now been

developed to refine the risk of progressive disease. CD38 and ZAP-70

have been identified as surrogate markers for mutational status and can be

evaluated by flow cytometric immunophenotyping.

 

ZAP-70 (70-kDa zeta-associated protein) is an intracellular tyrosine

kinase discovered initially because of its role in T-cell signaling. It has

also been found to be associated with the B-cell receptor in CLL.

The expression of ZAP-70 (>20% of B-cells) has been associated

with an increased risk for an adverse outcome in B-cell CLL and is

considered an important risk factor in these patients. ZAP-70

expression, if present, is constant throughout the patient's clinical

course and thus is a valid risk marker regardless of when it is

evaluated.

Reference Values

An interpretive report will be provided.

 

Interpretation

ZAP-70 expression is considered to be a risk factor for disease

progression in patients with B cell CLL. The threshold for ZAP70

staining is established by using normal B cells as the negative

cutoff value and comparing with background positive T cell

staining.

 

 - ZAP-70- negative (<20% of monoclonal B cells) CLL patients

   have a median time to treatment of 9.2 years.

 

 - ZAP-70- positive (>20% of monoclonal B cells) CLL patients have

   a median time to treatment of 2.9 years.

 

See "ZAP70 Expression and Overall Survival Among Patients

with B-Cell CLL" in Multimedia for survival curves.

Cautions

ZAP-70 is an intracellular activation marker in CLL cells and

expression can be labile after 24 hours. Failure to follow specimen

processing, transportation, and storage requirements may lead

to false results..

 

Bone marrow, lymph node, and tissue specimens will not be

accepted as these specimen types have not been clinically

validated at Mayo or in literature studies. Since B-cell CLL

is, by definition, a peripheral leukemic process and since blood

specimens can be easily obtained, this should not be a significant

limitation.

 

A ZAP-70 study may be rejected if the histogram pattern indicates

that there has been any cellular changes that could prevent

accurate interpretation of antigen expression.

 

Prior documented flow cytometric diagnosis of CLL is required

before testing for ZAP-70. Specimens submitted for #3287 "Leukemia/

Lymphoma Immunophenotyping by Flow Cytometry" will

not be optimal for ZAP-70 testing due to the time delay and

differences in specimen handling requirements. It is suggested

that a second blood specimen be submitted for ZAP-70.

 

If no immunoglobulin light chain-restricted B cells are identified,

then no ZAP-70 results will be reported.

Clinical Reference

1.     Rassenti LZ, Huynh L, Toy TL, et al:  ZAP-70 compared with

      immunoglobulin heavy-chain gene mutation status as a

      predictor of disease progression in chronic lymphocytic

      leukemia. N Engl J Med 2004 August 26;351(9):893-901

 

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 May 1;

      348(18):1764-1765

 

3.     Orchard JA, Ibbotson RE, Davis Z, et al:  ZAP-70 expression

      and prognosis in chronic lymphocytic leukaemia. Lancet 2004

      January 10;363(9403):105-111

Key