RESUMEN
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.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/diagnóstico , Proteína Tirosina Quinasa ZAP-70/análisis , ADP-Ribosil Ciclasa 1/análisis , Adulto , Anciano , Anciano de 80 o más Años , Análisis Citogenético , Femenino , Citometría de Flujo , Humanos , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Pronóstico , Receptores de IgE/análisis , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: p53 status and CD38 antigen are biological factors influencing response to therapy and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). This study tests the hypothesis that soluble p53 alone and in association with CD38 can enucleate B-CLL subsets at worse prognosis. DESIGN AND METHODS: Wild and mutant forms of p53 protein were evaluated in 197 B-CLL patients at diagnosis or before progression by an immunoenzymatic method in plasma using an anti-p53 monoclonal antibody. CD38 expression was analyzed by a multicolor flow cytometric assay. RESULTS: Higher levels of both soluble p53 (sp53) and CD38 were significantly correlated with intermediate and high Rai stages, with higher beta2-microglobulin and soluble CD23 values, determined at diagnosis. Shorter overall survival (OS) and progression-free survival (PFS) were both observed in sp53+ and CD38+ patients (p<0.0001). Simultaneous positivity or negativity for sp53 and CD38 identified two subsets of patients, the former with a worse prognosis and the latter with a better prognosis with regard to PFS (p<0.0001) and OS (p<0.0001). The predictive value of sp53 and CD38 was retained among the patients within the intermediate Rai risk group. INTERPRETATION AND CONCLUSIONS: sp53 and CD38 together with ZAP-70 were confirmed to be independent prognostic factors in multivariate analysis. With regard to PFS, ZAP-70, sp53 and CD38 were confirmed to be independent prognostic factors. Concerning OS, ZAP-70, CD38 and age (< or > 60 years) were independent prognostic factors whereas sp53 showed only a tendency towards statistical significance.
