Subject(s)
Clonal Evolution/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mutation , Nuclear Proteins/genetics , Phenotype , Biomarkers, Tumor , DNA Mutational Analysis , Genetic Association Studies , Genome-Wide Association Study , Humans , Leukemia, Myeloid, Acute/mortality , Nucleophosmin , Prognosis , RecurrenceABSTRACT
Introduction: Multiparametric flow cytometry immunophenotype (MFCI) plays a crucial role in the diagnosis of acute leukemia (AL). Through the comprehensive assessment of surface and intracellular antigens expressed by blasts, MFCI permits to distinguish myeloid or B/T lymphoid AL, or AL of ambiguous lineages. By means of MFCI, the blasts can be characterized in bone marrow, peripheral blood, and body fluids, such as cerebrospinal fluid.Area covered: This review discusses how MFCI is currently applied in the diagnostic evaluation of AL; it also focuses on 'peculiar' issues such as the role of MFCI for the diagnosis of central nervous system leukemic involvement.Expert commentary: Despite the improved knowledge about the biology of AL, MFCI remains a fundamental tool to make a prompt and accurate diagnosis. MFCI also provides prognostic information for some antigens are associated with specific cytogenetic/genetic abnormalities and, recently, it became a powerful tool to evaluate the quality and depth of response (the so called 'measurable residual disease'). Its role as an efficient detector of residual disease paved the way to the investigation of tissues other than bone marrow and peripheral blood, demonstrating that even small amounts of AL appear to have a prognostic impact and may require personalized intervention.
Subject(s)
Flow Cytometry/methods , Immunophenotyping/methods , Leukemia/diagnosis , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Flow Cytometry/standards , Humans , Immunophenotyping/standards , Leukemia/cerebrospinal fluid , Leukemia/genetics , Leukemia/immunology , Sensitivity and SpecificityABSTRACT
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.
Subject(s)
Gene Expression Regulation, Leukemic , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , ZAP-70 Protein-Tyrosine Kinase/analysis , ADP-ribosyl Cyclase 1/analysis , Adult , Aged , Aged, 80 and over , Cytogenetic Analysis , Female , Flow Cytometry , Humans , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Mutation , Predictive Value of Tests , Prognosis , Receptors, IgE/analysis , ZAP-70 Protein-Tyrosine Kinase/geneticsABSTRACT
BACKGROUND: Clinical trials of monoclonal antibodies in combination with chemotherapy have reported previously unattained response rates in patients with B-cell chronic lymphocytic leukemia (B-CLL); however, the analysis of ZAP-70 protein and/or CD38 may explain better the discordant outcomes independent of treatment. METHODS: The authors conducted a Phase II study, in which rituximab was added to fludarabine for patients with symptomatic, untreated CLL, to evaluate clinical outcomes. Sixty patients with B-CLL received 6 monthly courses of fludarabine (25 mg/m(2) for 5 days) followed by 4 weekly doses of rituximab (375 mg/m(2)). RESULTS: On the basis of National Cancer Institute criteria, 47 of 60 patients (78%) achieved a complete remission, 9 of 60 patients (15%) achieved a partial remission, and 4 of 60 patients (7%) had no response or progressive disease. It is noteworthy that the patients experienced a long progression-free survival (PFS) from treatment (68% at 3 yrs). A significantly shorter PFS was observed in ZAP-70-positive patients (25% vs. 100% at 3 yrs; P = 0.00005), in CD38-positive patients (18% vs. 91% at 3 yrs; P = 0.0002), and in patients who had more minimal residual disease (36% vs. 77% at 2.5 yrs; P = 0.001). CONCLUSIONS: With the addition of rituximab to fludarabine, improved clinical outcomes were obtained, and the stratification of patients by using ZAP-70 and CD38 may help clinicians offer more aggressive and/or experimental approaches to the treatment of patients with high-risk B-CLL subtypes.