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Interpretive Handbook

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

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 (> or =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.

Useful For Suggests clinical disorders or settings where the test may be helpful

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


Interpretation Provides information to assist in interpretation of the test results

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 ZAP-70 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 (> or =20% of monoclonal B cells) CLL patients have a median time to treatment of 2.9 years.


See ZAP-70 Expression and Overall Survival Among Patients with B-Cell CLL in Multimedia for survival curves.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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 have been any cellular changes that could prevent accurate interpretation of antigen expression.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

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

4. Chen L, Widhopf G, Huynh L, et al: Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2002;100(13):4609-4614

5. Qian D, Lev S, van Oers NS, et al: Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. J Exp Med 1997;185(7):1253-1259

6. Shanafelt TD, Kay NE, Jenkins G, et al: B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009;113:4188-4196