RESUMEN
The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.
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COVID-19 , Leucemia Linfocítica Crónica de Células B , Humanos , Persona de Mediana Edad , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Rituximab/efectos adversos , Neoplasia Residual/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversosRESUMEN
Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with ≥5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter real-life retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, and TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q- /TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (P<0.0001). We herein demonstrate that CK landscape at CLL diagnosis allows the risk of RS transformation to be refined and we recapitulated clinico-biological variables into a prognostic model.
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Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Humanos , Cariotipo , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Estudios RetrospectivosAsunto(s)
Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Piperidinas/uso terapéutico , Rituximab/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aberraciones Cromosómicas/efectos de los fármacos , Femenino , Humanos , Cariotipo , Masculino , Piperidinas/efectos adversos , Rituximab/efectos adversos , Resultado del TratamientoRESUMEN
Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright © 2015 John Wiley & Sons, Ltd.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adulto , Anciano , Ensayos Clínicos Controlados como Asunto , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse.
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Leucemia Linfocítica Crónica de Células B/genética , Mutación , Adulto , Anciano , Biopsia , Evolución Clonal , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/genética , Exoma/genética , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , RecurrenciaRESUMEN
We analysed the long-term outcome of 35 children and adolescents (<20 years at diagnosis) with chronic myeloid leukaemia (CML) in chronic phase: 20 patients had received interferon-alpha and/or tyrosine kinase inhibitors (TKIs), and 15 underwent a haematopoietic stem cell transplant. The 10-year survival probabilities were similar in transplanted and non-transplanted patients (73·3% vs. 72·1%, respectively), whereas the survival probability was significantly lower in patients diagnosed before 1999 compared to those diagnosed afterwards (62·1% vs. 100%, P = 0·0384). The availability of TKIs and the standardized molecular monitoring have significantly improved treatment, management and outcome in children and adolescents with CML.
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Trasplante de Células Madre Hematopoyéticas , Interferón-alfa/uso terapéutico , Leucemia Mieloide de Fase Crónica/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Niño , Preescolar , Manejo de la Enfermedad , Monitoreo de Drogas/métodos , Femenino , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged <18 years at diagnosis. A total of 47 CP-CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91.5% of the evaluable patients at a median time of 6 months. BCR-ABL1 International Scale ≤ 0.1% (major molecular response; MMR) and ≤0.01% (molecular response; MR) at 12 months were 66.6% and 33%, respectively. During follow-up, MMR and MR were achieved in 78.6% and 61% of children, respectively. IM was safely discontinued in 3 long-term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression-free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow-up of 52 months (range 3-146), all patients are alive. High-dose IM is a long-term effective therapy in children and adolescents with CP-CML.
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Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Italia , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Trasplante de Células Madre , Tasa de SupervivenciaAsunto(s)
Leucemia Linfocítica Crónica de Células B , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Rituximab/uso terapéutico , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Sixty-four patients < 20 years of age, investigated for a suspicion of Philadelphia-negative myeloproliferative disease (MPD), were retrospectively evaluated to characterize the different forms and to examine the treatments used and long-term outcome. JAK2 mutations, endogenous erythroid colony growth, and clonality were investigated in 51 children. Mutations of thrombopoietin, the thrombopoietin receptor (MPL), and the erythropoietin receptor and mutations of other genes involved in the pathogenesis of MPD were investigated in JAK2 wild-type patients. Based on our criteria for childhood MPD, we identified 34 patients with sporadic thrombocythemia (ST), 16 with hereditary thrombocytosis (HT), 11 with sporadic polycythemia (SP), and 3 with hereditary polycythemia (HP). JAK2(V617F) mutations were present in 47.5% of ST and in no HT. The MPL(S505A) mutation was detected in 15/16 HT patients and in no ST (P < .00001). The JAK2(V617F) mutation occurred in 27% of SP patients diagnosed according to the Polycythemia Vera Study Group or World Health Organization 2001 criteria. Children with ST received more cytoreductive drugs than those with HT (P = .0006). After a median follow-up of 124 months, no patient had developed leukemia or myelofibrosis and 5% had thrombosis; the miscarriage rate in thrombocythemic patients was 14%. The low complication rate in our population suggests that children with MPD may be managed by tailored approaches.
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Policitemia/tratamiento farmacológico , Trombocitemia Esencial/tratamiento farmacológico , Trombocitosis/tratamiento farmacológico , Adolescente , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Janus Quinasa 2/genética , Masculino , Mutación , Policitemia/complicaciones , Policitemia/genética , Embarazo , Complicaciones Hematológicas del Embarazo , Resultado del Embarazo , Receptores de Trombopoyetina/genética , Estudios Retrospectivos , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/genética , Trombocitosis/complicaciones , Trombocitosis/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin "bivalent domains," hypermethylation, recruitment of polycomb (PcG)-RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.
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Regulación de la Expresión Génica , Granulocitos/citología , MicroARNs/genética , Factores de Transcripción NFI/genética , Regiones Promotoras Genéticas/genética , Proteínas Represoras/metabolismo , Transcripción Genética , Secuencia de Bases , Western Blotting , Inmunoprecipitación de Cromatina , Epigenómica , Citometría de Flujo , Silenciador del Gen , Hematopoyesis/fisiología , Heterocromatina/genética , Humanos , Inmunoprecipitación , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Luciferasas/metabolismo , MicroARNs/metabolismo , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mielopoyesis/fisiología , Factores de Transcripción NFI/antagonistas & inhibidores , Factores de Transcripción NFI/metabolismo , Proteínas del Grupo Polycomb , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Homología de Secuencia de Ácido NucleicoRESUMEN
Chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor (BCR) belonging to subset #1 (IGHV1-5-7/ IGKV1-39) display a poor outcome. To characterize their genetic and genomic features and BCR function, we selected 20 subset #1 CLL from a series of 579 cases. Subset #1 CLL, all showing unmutated IGHV, were associated with the presence of del(11q) (50%) in comparison with unmutated CLL, unmutated stereotyped CLL other than subset #1 and with cases using the same IGHV genes but a heterogeneous VH CDR3 (non-subset #1 CLL). There were no distinctive features regarding CD38, ZAP-70, and TP53 disruption. NOTCH1, SF3B1, and BIRC3 were mutated in 15%, 0%, and 5% of cases, respectively, while BIRC3 was deleted in 22% of cases. Microarray unsupervised analysis on 80 unmutated/mutated/stereotyped/non-stereotyped CLL showed a tight clustering of subset #1 cases. Their genomic signature exhibited several differentially expressed transcripts involved in BCR signal transduction, apoptosis regulation, cell proliferation, and oxidative processes, regardless of del(11q). Accordingly, BCR ligation with anti-IgM revealed a significant higher proliferation of subset #1 versus unmutated non-subset #1 CLL, both at baseline and after 2448 hr stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function, and patients prognosis.
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Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Receptores de Antígenos de Linfocitos B/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Proliferación Celular , Análisis por Conglomerados , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Receptores de Antígenos de Linfocitos B/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal , TranscriptomaAsunto(s)
Anemia Aplásica , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva , Adolescente , Anemia Aplásica/diagnóstico , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/genética , Suero Antilinfocítico/administración & dosificación , Ciclosporina/administración & dosificación , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Resultado Fatal , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Imidazoles/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Metilprednisolona/administración & dosificación , Prednisolona/administración & dosificación , Piridazinas/administración & dosificaciónRESUMEN
AIM: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable). METHODS: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. RESULTS: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). CONCLUSIONS: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Cromosoma Filadelfia/efectos de los fármacos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Anciano , Benzamidas , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Metafase/efectos de los fármacos , Persona de Mediana Edad , Pronóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidoresRESUMEN
Mantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non-nodal MCL) may have a more indolent course. To gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53-pathway. Furthermore, GEP analysis revealed that non-nodal MCL cases were characterized by the down-modulation of the following gene categories: cell projection, actin cytoskeleton organization, cell adhesion (ITGAE, CELSR1, PCDH9) and tumour invasion/progression (PGF, ST14, ETS1, OCIAD1, EZR). Many down-modulated genes were related to the TP53-pathway and to DNA damage response. IGHV status proved unmutated in all nodal and mutated in all non-nodal MCL. Non-nodal leukaemic MCLs display a peculiar clinical presentation, with distinctive biological features, such as mutated IGHV and a transcriptional profile lacking tumour invasion properties, that might contribute to the absence of nodal involvement and to the less aggressive clinical course.
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Citoesqueleto de Actina/genética , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Genes p53/genética , Leucemia de Mastocitos/genética , Ganglios Linfáticos/patología , ADP-Ribosil Ciclasa 1/metabolismo , Anciano , Anciano de 80 o más Años , Adhesión Celular/genética , ADN de Neoplasias/genética , Regulación hacia Abajo/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Leucemia de Mastocitos/metabolismo , Leucemia de Mastocitos/patología , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Mutación , Invasividad NeoplásicaRESUMEN
BACKGROUND: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. DESIGN AND METHODS: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. RESULTS: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. CONCLUSIONS: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.
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Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/metabolismo , Análisis por Conglomerados , Proteínas de Unión al ADN/metabolismo , Femenino , Duplicación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Reproducibilidad de los Resultados , Análisis de Supervivencia , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Given that TP53 alterations predict prognosis and response to therapy in chronic lymphocytic leukemia (CLL), screening for TP53 mutations has an increasing role in patient management. TP53 direct sequencing is a time-consuming method, while the AmpliChip p53 Research Test is a novel non time-consuming microarray-based resequencing assay and queries Exons 2-11. We evaluated the impact of TP53 mutations on clinical outcome by analyzing 98 untreated CLL using the AmpliChip p53 Research Test and direct sequencing and performed microarrays analysis on TP53 mutated and/or deleted cases. The AmpliChip p53 Research Test detected 17 mutations in 14 patients (17.3%); a significant association between TP53 mutations and del(17p) was recorded. From a clinical standpoint, a higher percentage of mutation was found in CLL with unfavorable outcome (17.2% vs. 7.1% in progressive vs. stable cases). Detection of TP53 mutations by the AmpliChip p53 Research Test was associated with a significantly worse survival (P = 0.0002). Comparison of the array and direct sequencing tests showed that the p53 Research Test detected more mutations, although it failed to identify two microdeletions. Finally, microarrays analysis showed a more distinctive signature associated with del(17p) than with TP53 mutations, likely due to a concomitant gene dosage effect. The AmpliChip p53 Research Test is a straightforward method that bears prognostic value. This study confirms a high percentage of TP53 mutations in CLL with unfavorable outcome and a significant association between TP53 aberrations and del(17p). Finally, specific gene expression profiles are recognized for TP53 alterations.
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Genes p53/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica/métodos , Inestabilidad Genómica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Mutación Puntual , Pronóstico , Eliminación de Secuencia/genéticaRESUMEN
Deletion at 13q14 is detected by fluorescence in situ hybridization (FISH) in about 50% of chronic lymphocytic leukemia (CLL). Although CLL with 13q deletion as the sole cytogenetic abnormality (del13q-only) usually have good prognosis, more aggressive clinical courses are documented for del13q-only CLL carrying higher percentages of 13q deleted nuclei. Moreover, deletion at 13q of different sizes have been described, whose prognostic significance is still unknown. In a multi-institutional cohort of 342 del13q-only cases and in a consecutive unselected cohort of 265 CLL, we investigated the prognostic significance of 13q deletion, using the 13q FISH probes locus-specific identifier (LSI)-D13S319 and LSI-RB1 that detect the DLEU2/MIR15A/MIR16-1 and RB1 loci, respectively. Results indicated that both percentage of deleted nuclei and presence of larger deletions involving the RB1 locus cooperated to refine the prognosis of del13q-only cases. In particular, CLL carrying <70% of 13q deleted nuclei with deletions not comprising the RB1 locus were characterized by particularly long time-to-treatment. Conversely, CLL with 13q deletion in <70% of nuclei but involving the RB1 locus, or CLL carrying 13q deletion in ≥70% of nuclei, with or without RB1 deletions, collectively experienced shorter time-to-treatment. A revised flowchart for the prognostic FISH assessment of del13q-only CLL, implying the usage of both 13q probes, is proposed.
Asunto(s)
Trastornos de los Cromosomas/genética , Leucemia Linfocítica Crónica de Células B/genética , Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Estudios de Cohortes , Humanos , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/patología , Pronóstico , ARN Largo no Codificante , Proteína de Retinoblastoma/genética , Eliminación de Secuencia , Transferasas , Proteínas Supresoras de Tumor/genéticaRESUMEN
In chronic myeloid leukemia, different methods are available to monitor the response to therapy: chromosome banding analysis (CBA), interphase fluorescence in situ hybridization (I-FISH), and real-time quantitative polymerase chain reaction (RT-Q-PCR). The GIMEMA CML WP (Gruppo Italiano Malattie Ematologiche Adulto Chronic Myeloid Leukemia Working Party) has performed a prospective study to compare CBA and I-FISH for the definition of complete cytogenetic response (CCgR). Samples (n = 664) were evaluated simultaneously by CBA and I-FISH. Of 537 cases in CCgR, the number of positive nuclei by I-FISH was less than 1% in 444 cases (82.7%). Of 451 cases with less than 1% positive nuclei by I-FISH, 444 (98.4%) were classified as CCgR by CBA. The major molecular response rate was significantly greater in cases with I-FISH less than 1% than in those with I-FISH 1% to 5% (66.8% vs 51.6%, P < .001) and in cases with CCgR and I-FISH less than 1% than in cases with CCgR and I-FISH 1% to 5% (66.1% vs 49.4%, P = .004). I-FISH is more sensitive than CBA and can be used to monitor CCgR. With appropriate probes, the cutoff value of I-FISH may be established at 1%. These trials are registered at http://www.clinicaltrials.gov as NCT00514488 and NCT00510926.
Asunto(s)
Bandeo Cromosómico , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del TratamientoRESUMEN
A comprehensive panel of clinical-biological parameters was prospectively evaluated at presentation in 112 patients with chronic lymphocytic leukemia (<65 years), to predict the risk of progression in early stage disease. Eighty-one percent were in Binet stage A, 19% in stages B/C. Treatment-free survival was evaluated as the time from diagnosis to first treatment, death or last follow up. In univariate analysis, advanced stage, hemoglobin, platelets, white blood cell, leukemic lymphocyte count, raised beta 2-microglobulin and LDH, unmutated immunoglobulin variable region genes, CD38, del(17p), del(11q) and +12, were significantly associated with a short treatment-free survival; the T/leukemic lymphocyte ratio was associated with a better outcome. Multivariate analysis of treatment-free survival in stage A patients selected a high white blood cell count and unmutated immunoglobulin variable region genes as unfavorable prognostic factors and a high T/leukemic lymphocyte ratio as a favorable one. At diagnosis, these parameters independently predict the risk of progression in stage A chronic lymphocytic leukemia patients.