ZAP-70 May be More Reliable Indicator than Mutational Status

[Guest guest]

[As many researchers have been indicating, the prognositic value of

ZAP-70 in CLL needs to be clarified, and its use as an indicator

remains controversial.

Here is another piece of the puzzle. Note that there is only a 71%

concordance between ZAP-70 (of a certain, undefined (here) value) and

mutational status.

This would suggest there is a strong, but not conclusive indication

of mutational status in ZAP-70 positives. The use of ZAP-70 as a

surrogate is (in this study) not seen as a fool-proof stand-in for

mutational status.

On the other hand, the researchers in this paper conclude that it is

the ZAP-70 status itself which is the more reliable prognostic

indicator of progression and treatment.]

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

ZAP-70 compared with immunoglobulin heavy-chain gene mutation status

as a predictor of disease progression in chronic lymphocytic leukemia.

Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg

DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ.

Chronic Lymphocytic Leukemia Research Consortium, University of

California, San Diego, La Jolla 92093, USA.

BACKGROUND: The course of chronic lymphocytic leukemia (CLL) is

variable. In aggressive disease, the CLL cells usually express an

unmutated immunoglobulin heavy-chain variable-region gene (IgV(H))

and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent

disease, the CLL cells usually express mutated IgV(H) but lack

expression of ZAP-70.

METHODS: We evaluated the CLL B cells from 307 patients with CLL for

ZAP-70 and mutations in the rearranged IgV(H) gene. We then

investigated the association between the results and the time from

diagnosis to initial therapy.

RESULTS: We found that ZAP-70 was expressed above a defined threshold

level in 117 of the 164 patients with an unmutated IgV(H) gene (71

percent), but in only 24 of the 143 patients with a mutated IgV(H)

gene (17 percent, P<0.001). Among the patients with ZAP-70-positive

CLL cells, the median time from diagnosis to initial therapy in those

who had an unmutated IgV(H) gene (2.8 years) was not significantly

different from the median time in those who had a mutated IgV(H) gene

(4.2 years, P=0.07). However, the median time from diagnosis to

initial treatment in each of these groups was significantly shorter

than the time in patients with ZAP-70-negative CLL cells who had

either mutated or unmutated IgV(H) genes (P<0.001). The median time

from diagnosis to initial therapy among patients who did not have ZAP-

70 was 11.0 years in those with a mutated IgV(H) gene and 7.1 years

in those with an unmutated IgV(H) gene (P<0.001).

CONCLUSIONS: Although the presence of an unmutated IgV(H) gene is

strongly associated with the expression of ZAP-70, ZAP-70 is a

stronger predictor of the need for treatment in B-cell CLL. Copyright

2004 Massachusetts Medical Society

PMID: 15329427 [PubMed - in process]