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

Maria Ilaria Del Principe, Giovanni Del Poeta, Francesco Buccisano, Luca Maurillo, Adriano Venditti, Antonella Zucchetto, Rita Marini, Pasquale Niscola, Maria Antonietta Irno Consalvo, Carla Mazzone, Licia Ottaviani, Paola Panetta, Antonio Bruno, Riccardo Bomben, Giovanna Suppo, Massimo Degan, Valter Gattei, Paolo De Fabritiis, Maria Cantonetti, Francesco Lo CocoDomenico Del Principe, Sergio Amadori

Research output: Contribution to journalArticle

Abstract

The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P <.001), in CD38+ (P <.001) and in sCD23+ patients (P <.001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P <.001) and OS (P <.001 and P <.001, respectively) as compared with ZAP-70-/CD38- or ZAP-70- patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38- or mutated showed a shorter PFS, whereas 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 <.001) and within the poor-risk cytogenetic subset (P = .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 IgV H 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.

Original languageEnglish
Pages (from-to)853-861
Number of pages9
JournalBlood
Volume108
Issue number3
DOIs
Publication statusPublished - Aug 1 2006

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ZAP-70 Protein-Tyrosine Kinase
B-Cell Chronic Lymphocytic Leukemia
Genes
Cells
Flow cytometry
Disease-Free Survival
Set theory
Cytogenetics
Survival
Karyotype
Flow Cytometry
Multivariate Analysis
Observation

ASJC Scopus subject areas

  • Hematology

Cite this

Del Principe, M. I., Del Poeta, G., Buccisano, F., Maurillo, L., Venditti, A., Zucchetto, A., ... Amadori, S. (2006). Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood, 108(3), 853-861. https://doi.org/10.1182/blood-2005-12-4986

Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. / Del Principe, Maria Ilaria; Del Poeta, Giovanni; Buccisano, Francesco; Maurillo, Luca; Venditti, Adriano; Zucchetto, Antonella; Marini, Rita; Niscola, Pasquale; Irno Consalvo, Maria Antonietta; Mazzone, Carla; Ottaviani, Licia; Panetta, Paola; Bruno, Antonio; Bomben, Riccardo; Suppo, Giovanna; Degan, Massimo; Gattei, Valter; De Fabritiis, Paolo; Cantonetti, Maria; Lo Coco, Francesco; Del Principe, Domenico; Amadori, Sergio.

In: Blood, Vol. 108, No. 3, 01.08.2006, p. 853-861.

Research output: Contribution to journalArticle

Del Principe, MI, Del Poeta, G, Buccisano, F, Maurillo, L, Venditti, A, Zucchetto, A, Marini, R, Niscola, P, Irno Consalvo, MA, Mazzone, C, Ottaviani, L, Panetta, P, Bruno, A, Bomben, R, Suppo, G, Degan, M, Gattei, V, De Fabritiis, P, Cantonetti, M, Lo Coco, F, Del Principe, D & Amadori, S 2006, 'Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia', Blood, vol. 108, no. 3, pp. 853-861. https://doi.org/10.1182/blood-2005-12-4986
Del Principe MI, Del Poeta G, Buccisano F, Maurillo L, Venditti A, Zucchetto A et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood. 2006 Aug 1;108(3):853-861. https://doi.org/10.1182/blood-2005-12-4986
Del Principe, Maria Ilaria ; Del Poeta, Giovanni ; Buccisano, Francesco ; Maurillo, Luca ; Venditti, Adriano ; Zucchetto, Antonella ; Marini, Rita ; Niscola, Pasquale ; Irno Consalvo, Maria Antonietta ; Mazzone, Carla ; Ottaviani, Licia ; Panetta, Paola ; Bruno, Antonio ; Bomben, Riccardo ; Suppo, Giovanna ; Degan, Massimo ; Gattei, Valter ; De Fabritiis, Paolo ; Cantonetti, Maria ; Lo Coco, Francesco ; Del Principe, Domenico ; Amadori, Sergio. / Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. In: Blood. 2006 ; Vol. 108, No. 3. pp. 853-861.
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AU - Del Principe, Maria Ilaria

AU - Del Poeta, Giovanni

AU - Buccisano, Francesco

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AU - Venditti, Adriano

AU - Zucchetto, Antonella

AU - Marini, Rita

AU - Niscola, Pasquale

AU - Irno Consalvo, Maria Antonietta

AU - Mazzone, Carla

AU - Ottaviani, Licia

AU - Panetta, Paola

AU - Bruno, Antonio

AU - Bomben, Riccardo

AU - Suppo, Giovanna

AU - Degan, Massimo

AU - Gattei, Valter

AU - De Fabritiis, Paolo

AU - Cantonetti, Maria

AU - Lo Coco, Francesco

AU - Del Principe, Domenico

AU - Amadori, Sergio

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N2 - The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P <.001), in CD38+ (P <.001) and in sCD23+ patients (P <.001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P <.001) and OS (P <.001 and P <.001, respectively) as compared with ZAP-70-/CD38- or ZAP-70- patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38- or mutated showed a shorter PFS, whereas 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 <.001) and within the poor-risk cytogenetic subset (P = .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 IgV H 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.

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