Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia.
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 IgV(H) 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 IgV(H) 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.
Del Principe
Maria Ilaria
MI
Cattedra di Ematologia, Università Tor Vergata, Ospedale S Eugenio, Via Fiume Giallo, 430 MA, 00144 Roma, Rome, Italy.
Del Poeta
Giovanni
G
Buccisano
Francesco
F
Maurillo
Luca
L
Venditti
Adriano
A
Zucchetto
Antonella
A
Marini
Rita
R
Niscola
Pasquale
P
Consalvo
Maria Antonietta Irno
MA
Mazzone
Carla
C
Ottaviani
Licia
L
Panetta
Paola
P
Bruno
Antonio
A
Bomben
Riccardo
R
Suppo
Giovanna
G
Degan
Massimo
M
Gattei
Valter
V
de Fabritiis
Paolo
P
Cantonetti
Maria
M
Lo Coco
Francesco
F
Del Principe
Domenico
D
Amadori
Sergio
S
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020732:Cytogenetic Analysis; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D017455:Receptors, IgE / Q000032:analysis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis* / Q000235:genetics
D007135:Immunoglobulin Variable Region; D017455:Receptors, IgE; D051746:ZAP-70 Protein-Tyrosine Kinase; D051997:ADP-ribosyl Cyclase 1