Análisis de tp53 y caracterización citogenética y molecular de 54 pacientes con leucemia linfática crónica en estadios iii y iv tratados en 1ª línea con fludarabina

Zusammenfassung

TITULO: ANÁLISIS DE TP53 Y CARACTERIZACIÓN CITOGENETICA Y MOLECULAR DE 54 PACIENTES CON LEUCEMIA LINFÁTICA CRÓNICA EN ESTADIOS III Y IV TRATADOS EN Ia LINEA CON FLUDARABINA RESUMEN: ANALYSIS OF TP53 AND GENETIC CHARACTERIZATION OF 54 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN III/IV STAGES TREATED IN FIRST LINE WITH FLUDARABINE Mikel Valgañón Petrizan. School of Science, University of Navarra (Spain), 2005. B-cel1 chronic lymphocytic leukemia (CLL), the most common leukemia in the Western countries, is characterized by the accumulation of clonal mature B lymphocytes in blood, bone marrow and secondary lymphoid tissues. CLL patients have a variable natural history with regard to time to progression and response to standard cytotoxic therapies. Genetic factors have been established in the recent years as important predictors of disease progression and survival in this disease, and they have implications for the risk-adapted clinical management of CLL. we have evaluated the rate of response to fludarabine as first line therapy in 54 patients with CLL in advanced stages, analyzing the cytogenetic profile, aberrations in TP53, including the methylation status of its promoter, and the IGVH mutation status. According to the advanced stage of the disease in our series, 75% of patients had genetic aberrations associated with poor prognosis: del (17p) and/or del (llq), and no-mutated IGVH genes. Ten patients (18.5%) had methylation in the promoter región of TP53. 83% of patients treated achieved response, with a high rate of complete remission (47.6%). Although we found a significative correlation between failures and the presence of TP53 aberrations (p=0.0065), either methylation (p=0.018) or deletion (p=0.015), 64% of the patients with aberrations in this gene responded to treatment (11/17), suggesting that fludarabine induces high remission rates, even in these patients. This is the first time that the significance of TP53 promoter methylation status is described in this pathology, and our data support that this epigenetic phenomenon could be involved in the pathogenesis and clinical evolution of CLL. Deletions on 13ql4 occur in more than 50% of CLL cases. The frequency and early appearance of the 13ql4 deletions suggest a causative role in the pathogenesis of B-CLL. We analyzed the 13ql4 deleted region on 33 CLL patients, defining the locus D13S25 as the minimal common region deleted. We confirmed the molecular heterogeneity of 13ql4 deletions. Our results suggest the occurrence of a possible genetic subgroup, characterized by the presence of a small deletion (< 2Mb) and a greater proportion of cytogenetic aberrations; although in our series we did not find a significative association with the outcome of the patients