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Leucemia linfatica cronica B (linfoma linfocitico) ICD-O code 9823/3
PROGNOSI
Negli ultimi anni l'eterogeneità clinica della CLL è stata collegata ad alcune caratteristiche biologiche delle cellule neoplastiche, ed in particolare alla presenza di mutazioni somatiche dei geni Ig [1]. I casi che presentano mutazioni (post-follicolari) sono caratterizzati da andamento clinico indolente, mentre i casi che non presentano le mutazioni (pre-follicolari) sono più aggressivi. La ricerca di metodi che possano sostituire le complesse indagini molecolari ha evidenziato il significato prognostico di due marcatori immunofenotipici, il CD38 e lo ZAP-70.
N Engl J Med. 2003 May 1;348(18):1764-75. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marce S, Lopez-Guillermo A, Campo E, Montserrat E. Department of Hematology, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain. BACKGROUND: The mutational status of immunoglobulin heavy-chain variable-region (IgVH) genes in the leukemic cells of chronic lymphocytic leukemia (CLL) is an important prognostic factor in the disease. We investigated whether the expression of ZAP-70 by CLL cells correlated with the IgVH mutational status, disease progression, and survival. METHODS: The expression of ZAP-70 was analyzed in T-cell and B-cell lines and in peripheral-blood samples from 56 patients with CLL with the use of flow cytometry, Western blotting, and immunohistochemistry. The results were correlated with the IgVH mutational status and clinical outcome. RESULTS: ZAP-70 was detected by flow-cytometric analysis in cells of T-cell lineage and in leukemic cells from 32 of 56 patients with CLL. In all patients in whom at least 20 percent of the leukemic cells were positive for ZAP-70, IgVH was unmutated, whereas IgVH mutations were found in 21 of 24 patients in whom less than 20 percent of the leukemic cells were positive for ZAP-70 (P<0.001). Concordant results were obtained when ZAP-70 expression was assessed by immunohistochemistry or Western blotting. The level of ZAP-70 expression did not change over time (median, 37 months) in sequential samples from 30 patients with CLL. Patients with Binet stage A CLL who had at least 20 percent ZAP-70-positive leukemic cells had more rapid progression and poorer survival than those with less than 20 percent ZAP-70-positive cells. CONCLUSIONS: Among patients with CLL, expression of ZAP-70, as detected by flow-cytometric analysis, correlated with IgVH mutational status, disease progression, and survival.
Blood. 2003 Jun 15;101(12):4944-51. Epub 2003 Feb 20. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE, Zhao H, Ibbotson RE, Orchard JA, Davis Z, Stetler-Stevenson M, Raffeld M, Arthur DC, Marti GE, Wilson WH, Hamblin TJ, Oscier DG, Staudt LM. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. The presence or absence of somatic mutations in the expressed immunoglobulin heavy chain variable regions (IgVH) of chronic lymphocytic leukemia (CLL) cells provides prognostic information. Patients whose leukemic cells express unmutated IgVH regions (Ig-unmutated CLL) often have progressive disease, whereas patients whose leukemic cells express mutated IgVH regions (Ig-mutated CLL) more often have an indolent disease. Given the difficulty in performing IgVH sequencing in a routine diagnostic laboratory, this prognostic distinction is currently unavailable to most patients. Pilot gene expression profiling studies in patients with CLL identified genes that were differentially expressed between the Ig-unmutated and Ig-mutated CLL subtypes. Here, we have profiled an expanded cohort of 107 patients and show that ZAP-70 is the gene that best distinguishes the CLL subtypes. Ig-unmutated CLL expressed ZAP-70 5.54-fold more highly than Ig-mutated CLL (P < 10(-21)). ZAP-70 expression correctly predicted IgVH mutation status in 93% of patients. ZAP-70 expression and IgVH mutation status were comparable in their ability to predict time to treatment requirement following diagnosis. In 7 patients, ZAP-70 expression and IgVH mutation status were discordant: 4 Ig-mutated CLLs had high ZAP-70 expression and 3 Ig-unmutated CLLs had low ZAP-70 expression. Among these ZAP-70 "outliers," those with Ig-mutated CLL had clinical features that are uncharacteristic of this CLL subtype: 2 required early treatment and 2 used a mutated VH3-21 gene, an IgVH gene that has been associated with progressive disease. We developed reverse transcriptase-polymerase chain reaction and immunohistochemical assays for ZAP-70 expression that can be applied clinically and would yield important prognostic information for patients with CLL.
Blood. 2003 Apr 3 [Epub ahead of print]. Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. Guarini A, Gaidano G, Mauro FR, Capello D, Mancini F, De Propris MS, Mancini M, Orsini E, Gentile M, Breccia M, Cuneo A, Castoldi G, Foa R. Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita 'La Sapienza', Rome, Italy. Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10-23 years and who never required treatment have been extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be utilized to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated IgVH pattern, the absence of p53 mutations, a CD4/CD8 ratio >1, the lack of 17p and 11q deletions, as well as of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene that has been linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage from diagnosis to the time of this study, lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently being utilized in the management of CLL, the distinctive features of patients with long- lived stable disease should be prospectically identified at presentation.
Blood. 2003 Feb 15;101(4):1262-9. Epub 2002 Oct 24. The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Ghia P, Guida G, Stella S, Gottardi D, Geuna M, Strola G, Scielzo C, Caligaris-Cappio F. Department of Oncological Sciences, University of Torino, Italy. Chronic lymphocytic leukemia (CLL) has a variable clinical course. CD38 expression and IgV(H) gene mutational status are independent predictors of prognosis, but their relationships and the CD38 cutoff level are unknown. Using cytofluorography, we analyzed CD38 in 148 patients, in 108 of whom we were able to evaluate IgV(H) mutations, make correlations with disease history, and assess cumulative survival. Three different patient groups were identified by the CD38 expression pattern: a group homogeneously CD38(-), a group homogeneously CD38(+), and a group characterized by a bimodal profile, because of the concomitant presence of variable proportions of 2 distinct populations, one CD38(+) and one CD38(-). In CD38 bimodal expression patients the CD38(+) subset was significantly more represented in the bone marrow than in the peripheral blood. For IgV(H) mutations, 11.4% of CD38(-), 84.6% of CD38(+), and 68.0% of CD38 bimodal expression patients had no mutation. CD38 expression, IgV(H) mutational status, and traditional prognostic factors were concordant. The progression rate was 12.9% for CD38(-), 75.0% for CD38(+), and 63.3% for CD38 bimodal expression patients. Only 25.8% of the CD38(-) patients but 63.3% of the bimodal and 75.0% of CD38(+) patients were treated. The presence of a CD38(+) population, albeit small, correlated with the development of autoimmune manifestations. The CD38(-) group has not yet reached the median survival, which is 183 months in the CD38(+) group and 156 months in the CD38 bimodal expression group, regardless of the size of the CD38(+) population. The presence of a distinct CD38(+) population within the leukemic clone, rather than a numerical cutoff definition, correlates with IgV(H) gene mutational status and, irrespective of its size, identifies CLL patients who will have progressive disease.
Blood. 2002 Aug 15;100(4):1410-6. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Krober A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P, Dohner H, Stilgenbauer S. Abteilung Innere Medizin III, University of Ulm, Germany. In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (V(H)) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V(H) mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q-, +8q, 11q-, +12q, 13q-, t(14q), 17p-) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V(H) mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (P(cor)) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% V(H) homology (95% confidence interval [CI], 96%-98% homology, P(cor) <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, P(cor) =.02). In univariate analyses, unmutated V(H) genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in the V(H) unmutated and V(H) mutated subgroups. High-risk genomic aberrations such as 17p- and 11q- occurred almost exclusively in the V(H) unmutated subgroup, whereas favorable aberrations such as 13q- and 13q- as single abnormalities were overrepresented in the V(H) mutated subgroup. In multivariate analysis, unmutated V(H), 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of V(H) mutation status and genomic aberrations to predict outcome in CLL.
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