ZAP-70 May Be Better Predictor of CLL Progression than CD38, Mutational Status

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Blood First Edition Paper, prepublished online April 6, 2006

Submitted December 19, 2005

Accepted March 18, 2006

Clinical significance of ZAP-70 protein expression in B-cell chronic

lymphocytic leukemia

Ilaria Del Principe, Giovanni Del Poeta*, Francesco Buccisano,

Luca Maurillo, o Venditti, Antonella Zucchetto, Rita Marini,

Pasquale Niscola, Antonietta Irno Consalvo, Carla Mazzone,

Licia Ottaviani, Paola Panetta, Bruno, Riccardo Bomben,

Giovanna Suppo, Massimo Degan, Valter Gattei, Paolo de Fabritiis,

Cantonetti, Francesco Lo Coco, Domenico Del Principe, and

Amadori

Cattedra di Ematologia, University Tor Vergata, Rome, Italy

Clinical and Experimental Hematology Research Unit, Centro di

Riferimento Oncologico, Aviano (PN), Italy

Clinica Pediatrica, University Tor Vergata, Rome, Italy

The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is

variable, and novel biological parameters need to be added to the

clinical staging systems to predict an indolent or aggressive

outcome.

We investigated the 70-kD zeta-associated protein (ZAP-70), CD38,

soluble CD23 (sCD23) and cytogenetics in 289 B-CLL patients.

Both a shorter progression free survival (PFS) and overall survival

(OS) were observed in ZAP-70+ (P<0.00001), in CD38+ (P<0.00001) and

in sCD23+ patients (P<0.00001 and P=0.013, respectively). ZAP-

70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed

both a shorter PFS (P<0.00001) and OS (P=0.00002 and P=0.00004,

respectively) as compared to ZAP-70-/CD38- or ZAP-70- patients with

mutated IgVH genes. Discordant patients showed an intermediate

outcome.

Noteworthy, ZAP-70+ patients even if CD38- or mutated showed a

shorter PFS, while ZAP-70- patients even if CD38+ or unmutated had a

longer PFS. Furthermore, ZAP-70 positivity was associated with a

shorter PFS both within normal karyotype (P=0.00006) and within the

poor risk cytogenetic subset (P=0.02). The predictive value of ZAP-70

expression was confirmed in multivariate analysis.

Thus, ZAP-70 protein determined by flow cytometry improves the

prognostic significance of cytogenetics and appears to be a better

predictor of outcomes than IgVH gene mutational status. On this line,

we recommend and are also interested in conducting a prospective

randomized trial of early intervention versus observation for ZAP-70+

patients.