Test ID: ZAP70    
ZAP-70, Chronic Lymphocytic Leukemia (CLL) Prognosis

A risk factor for disease progression in patients with B-cell chronic lymphocytic leukemia

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 is 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 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 mutation 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.

An interpretive report will be provided.

ZAP-70 expression is considered to be a risk factor for disease progression in patients with B cell chronic lymphocytic leukemia (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.

ZAP-70 is an intracellular activation marker in chronic lymphocytic leukemia (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 LCMS/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.

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