RESUMEN
BCL6 somatic mutations affect normal and tumoral post germinal center B-lymphocytes. Our objective was to analyse expression, mutations and polymorphisms in the BCL6 gene and to correlate those variables with the clinical outcome in early-stage chronic lymphocytic leukemia (CLL). CLL samples were used for characterisation of the mutational status of BCL6/ immunoglobulin variable heavy chain (IGHV) genes, and expression of BCL6 was determined by real time PCR and immunoblot. Out of 68 cases, 29% show somatic mutations on BCL6 which occur exclusively in IGHV mutated cases. They are single nucleotide substitutions located mainly in two short mutational hot spots. CLL cells express different levels of BCL6 regardless of the mutational status, the number of mutations and polymorphisms. CLL cases expressing high levels of BCL6 have significantly shorter treatment-free interval. In conclusion, in early-stage patients with CLL, we found no correlation between expression and the mutations or polymorphism in BCL6, but high levels of BCL6 can discriminate patients with a worse prognosis.
Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Valor Predictivo de las Pruebas , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/análisis , Femenino , Genes de Inmunoglobulinas , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Mutación Puntual , Polimorfismo Genético , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-6 , Resultado del TratamientoRESUMEN
Chronic lymphocytic leukemia is an adult-onset leukemia with a heterogeneous clinical behavior. When chronic lymphocytic leukemia cases were divided on the basis of IgV(H) mutational status, widely differing clinical courses were revealed. Since IgV(H) sequencing is difficult to perform in a routine diagnostic laboratory, finding a surrogate for IgV(H) mutational status seems an important priority. In the present study, we proposed the use of Cryptochrome-1 as a new prognostic marker in early-stage chronic lymphocytic leukemia. Seventy patients (Binet stage A, without treatment) were included in the study. We correlated Cryptochrome-1 mRNA with well established prognostic markers such as IgV(H) mutations, ZAP70, LPL or CD38 expression and chromosomal abnormalities. High Cryptochrome-1 expression correlated with IgV(H) unmutated samples. In addition, Cryptochrome-1 was a valuable predictor of disease progression in early-stage chronic lymphocytic leukemia, therefore it can be introduced in clinical practice with the advantage of a simplified method of quantification.
Asunto(s)
Flavoproteínas/genética , Valor Predictivo de las Pruebas , ARN Mensajero/análisis , Biomarcadores , Criptocromos , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , PronósticoRESUMEN
B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Perfilación de la Expresión Génica , Salud , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas Proto-Oncogénicas c-bcl-6Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Proteína Tirosina Quinasa ZAP-70/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Estadificación de Neoplasias , ARN Mensajero/genética , Tasa de SupervivenciaRESUMEN
The introduction of reduced-intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re-evaluated in Hodgkin lymphoma (HL). While T-cell depletion reduces graft-versus-host disease (GvHD), it potentially abrogates graft-versus-tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF-A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF-A resulted in significantly lower incidences of non-relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF-A and MF groups, respectively. Current progression-free survival (CPFS) was superior with MF-A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0.0356). Disease status at transplantation significantly influenced overall survival (P = 0.0038) and CPFS (P = 0.0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T-cell depletion (P = 0.0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Depleción Linfocítica , Acondicionamiento Pretrasplante/métodos , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped , Enfermedad de Hodgkin/inmunología , Humanos , Transfusión de Linfocitos , Masculino , Melfalán/uso terapéutico , Metotrexato/uso terapéutico , Persona de Mediana Edad , Análisis Multivariante , Agonistas Mieloablativos/uso terapéutico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is a remarkably heterogeneous disorder. Some patients have an indolent disease whereas others undergo a more agressive presentation needing treatment. New therapeutics approaches are necessary for the treatment of B-CLL. Bortezomib (Btz), is a proteasome inhibitor, currently undergoing clinical trials whose function, at least in part, by stabilizing the IkappaBalpha protein and inhibiting NFkappaB activation. OBJECTIVE: The objective of this work was to study the effects of Btz on isolated human B-CLL cells, in vitro, and to correlate the differential rates of apoptosis induction with biological variables. MATERIAL AND METHODS: 31 B-CLL samples, from patients in stage A of Binet were used for this study, and the apoptotic effect of Btz on these cells was measured. RESULTS: Our data show that Btz treatment of B-CLL cells induces apoptosis in a time and dose-dependent manner. The apoptosis induction is mediated in part by inhibition of NFkappaB and is dependent on caspases activation. Interesting, in IgVH mutated cells, Btz have statistically significant differences in their in vitro activity on B-CLL cells according to their BCL-6 mutational status. CONCLUSIONS: Btz is a promising pharmacologic agent for the treatment of B-CLL, but its efficacy seems to be related to IgVH and BCL-6 mutational status, therefore, it could be interesting to further investigate the mechanisms involved in the different behavior of the cells in response to apoptosis induction by this drug.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ácidos Borónicos/farmacología , Reordenamiento Génico de Cadena Pesada de Linfocito B , Leucemia Linfocítica Crónica de Células B/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-6/genética , Pirazinas/farmacología , ADP-Ribosil Ciclasa 1/biosíntesis , ADP-Ribosil Ciclasa 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Clorometilcetonas de Aminoácidos/farmacología , Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Inhibidores de Caspasas , Caspasas/fisiología , Inhibidores de Cisteína Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Genes de Inmunoglobulinas , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Proteínas I-kappa B/metabolismo , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , FN-kappa B/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Nitrilos/farmacología , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Tirosina Quinasas/fisiología , Pirazinas/administración & dosificación , Sulfonas/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo , Proteína Tirosina Quinasa ZAP-70/biosíntesis , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.
Asunto(s)
Supervivencia de Injerto , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad de Hodgkin/mortalidad , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad de Hodgkin/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , España , Trasplante de Células Madre/mortalidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/mortalidad , Trasplante HomólogoRESUMEN
BACKGROUND: The HER-2 receptor undergoes a proteolytic cleavage generating an NH(2)-terminally truncated fragment, p95HER-2, that is membrane-associated and tyrosine-phosphorylated. We have reported that p95HER-2, but not the full-length receptor, p185HER-2, correlated with the extent of lymph node involvement in patients with breast cancer and its expression was significantly enhanced in nodal metastatic tissue. These facts suggested an important role for p95HER-2 either as a marker or cause of metastasis and poor outcome in breast cancer. In this work, we have studied the prognostic value of p95HER-2 in breast cancer. METHODS: Primary breast tumor tissues (n = 483) were from surgical resections conducted in hospitals in two different countries: the U.S. (n = 334) and Spain (n = 149). HER-2 protein forms, including p185HER-2 and p95HER-2, were examined in extracts of primary breast tumors by Western blot analysis. The levels of the two forms (high or low) were tested for association with other clinicopathologic factors and for correlation with disease-free survival. RESULTS: The median follow-up was 46 months. A high level of p95HER-2 in primary tumor tissue correlated with reduced 5-year disease-free survival (hazard ratio, 2.55; 95% confidence interval, 2.13-8.01; P < 0.0001). The median time for disease-free survival was 32 versus 139 months in patients with low levels of p95HER-2. In comparison, high levels of the full-length p185HER-2 did not significantly correlate with poor outcome (P > 0.1). Multivariate analysis revealed that high p95HER-2 was an independent predictor of disease-free survival (hazard ratio, 1.59; 95% confidence interval, 1.246-1.990; P = 0.0004). CONCLUSIONS: p95HER-2 expression is an independent prognostic factor in breast cancer and defines a group of patients with HER-2-positive breast cancer with significantly worse outcome.
Asunto(s)
Neoplasias de la Mama/metabolismo , Ganglios Linfáticos/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Factores de Riesgo , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
BACKGROUND: The majority of patients with breast carcinoma with > or = 10 metastatic axillary lymph nodes (ALNs) develop recurrent disease within 5 years from diagnosis. The purpose of the current study, performed retrospectively, was to characterize the natural history of this subset of patients, both before and after the advent of adjuvant anthracycline-based chemotherapy and tamoxifen. METHODS: Retrospectively, patients with primary breast carcinoma (N = 882) with > or = 10 metastatic ALNs, treated between 1954 and 1998, were selected from 3 institutions: The University of Texas M. D. Anderson Cancer Center (Houston, TX); the Institut Gustave Roussy (Villejuif, France); and Hospital Clinico Universitario (Valencia, Spain). All patient data had been registered prospectively in clinical databases. One group consisted of 314 patients treated with locoregional therapy alone (no adjuvant therapy) from 1954 to 1983. The second group included 568 patients who received adjuvant anthracycline-based chemotherapy between 1974 and 1998 with or without adjuvant tamoxifen. RESULTS: The median follow-up time was 140 months. Disease-free survival rates at 15 and 20 years for the no adjuvant therapy and adjuvant therapy groups were 17% and 16% versus 26% and 24%, respectively. The overall survival rates at 20 years for the no adjuvant therapy and the adjuvant therapy groups were 9% and 21%, respectively. By multivariate analysis, the independent factors associated with survival in the adjuvant therapy group were tumor size and the number of metastatic lymph nodes. CONCLUSIONS: The retrospective analysis suggested that adjuvant anthracycline-based chemotherapy and hormonal therapy have altered the natural history in this high-risk group of patients. However, despite such improvements, survival rates remained low, and innovative therapeutic approaches are, therefore, needed to improve clinical outcomes.
Asunto(s)
Neoplasias de la Mama/mortalidad , Carcinoma/mortalidad , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Axila , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma/patología , Carcinoma/terapia , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Tamoxifeno/administración & dosificaciónRESUMEN
To identify recurrent genomic changes in mantle cell lymphoma (MCL), we used high-resolution comparative genomic hybridization (CGH) to bacterial artificial chromosome (BAC) microarrays in 68 patients and 9 MCL-derived cell lines. Array CGH defined an MCL genomic signature distinct from other B-cell lymphomas, including deletions of 1p21 and 11q22.3-ATM gene with coincident 10p12-BMI1 gene amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with leukemic MCL showed a different genomic profile than nodal cases, including 8p21.3 deletion at tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene cluster (55% versus 19%; P = .01) and gain of 8q24.1 at MYC locus (46% versus 14%; P = .015). Additionally, leukemic MCL exhibited frequent IGVH mutation (64% versus 21%; P = .009) with preferential VH4-39 use (36% versus 4%; P = .005) and followed a more indolent clinical course. Blastoid variants, increased number of genomic gains, and deletions of P16/INK4a and TP53 genes correlated with poorer outcomes, while 1p21 loss was associated with prolonged survival (P = .02). In multivariate analysis, deletion of 9q21-q22 was the strongest predictor for inferior survival (hazard ratio [HR], 6; confidence interval [CI], 2.3 to 15.7). Our study highlights the genomic profile as a predictor for clinical outcome and suggests that "genome scanning" of chromosomes 1p21, 9q21-q22, 9p21.3-P16/INK4a, and 17p13.1-TP53 may be clinically useful in MCL.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Leucemia/genética , Linfoma de Células del Manto/genética , Anciano , Anciano de 80 o más Años , Cromosomas Artificiales Bacterianos , Femenino , Genómica/métodos , Genotipo , Humanos , Leucemia/mortalidad , Leucemia/patología , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Eliminación de Secuencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (> 60 years vs < or = 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs > or = 120 g/L), number of nodal areas (> 4 vs < or = 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> or = 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.
Asunto(s)
Linfoma Folicular/mortalidad , Adulto , Distribución por Edad , Anciano , Femenino , Humanos , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Mantle cell lymphoma (MCL) is a prototypical neoplastic disease in which a common cytogenetic alteration, t11;14, leading to cyclin D1 overexpression, is associated with other changes that need to be considered in an explanation of the clinical, morphological, and molecular variability of this disease. Using a cDNA microarray (Oncochip-CNIO) containing clones for 6386 cancer-related genes, we have analyzed the expression profiles of a series of 38 cases. After normalization with the expression profiling of sorted mantle zone lymphocytes, we have related the findings to conventional clinical and molecular variables, including immunoglobulin variable heavy chain somatic mutation, blastoid cytology, increased proliferation, and long-term survival. MCL signature (446 genes) includes genes involved in apoptosis, cell cycle, signal transduction, and cell structure. Especially striking was the presence of multiple concurrent alterations in the tumor necrosis factor and nuclear factor kappaB pathway, and the overexpression of IL10R and SPARC genes. We also identified a molecular signature for the presence of immunoglobulin variable heavy chain somatic mutation, which includes a number of genes potentially relevant in cancer (CDC14A, ras, and others). Signatures for proliferation and blastoid cytology were also found. An integrated analysis of these data yields a gene-expression based survival predictor (26 genes grouped into two clusters), which distinguishes half of the patients with a survival probability of 52% at 5 years. The predictive model has been confirmed by cross-validation. In conclusion, MCL seems to combine a disease-specific signature and different sets of genes of which the expression is associated with key clinical, molecular, and immunophenotypical events.
Asunto(s)
Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia Celular/fisiología , Femenino , Perfilación de la Expresión Génica , Genes de Inmunoglobulinas , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND AND OBJECTIVES: Imatinib mesylate has recently been shown to be highly effective in chronic-phase chronic myeloid leukemia (CML). The results of imatinib treatment in chronic-phase CML patients resistant or intolerant to interferon (IFN) and the factors predicting therapeutic response and progression-free survival were analyzed. DESIGN AND METHODS: One hundred and fifty patients with chronic-phase CML resistant (n=111) or intolerant (n=39) to IFN were treated with imatinib. Prognostic factors for response and disease progression were assessed by multivariate analysis. RESULTS: The median time from diagnosis was 43 months (0.5-188), median IFN therapy 21.5 months (0.5-140) and median follow-up from starting imatinib 13.6 months (range: 3-23). Complete hematologic response was achieved in 96 of 97 patients. Complete, partial and minor cytogenetic responses were present in 44%, 22%, and 8% of patients at 12 months. Grade III-IV neutropenia, thrombocytopenia, and anemia developed in 33%, 16%, and 6% of patients, respectively. Sixty-five patients discontinued treatment for a median of 4 weeks (1-36) due to toxicity. The rate of progression-free survival (lack of accelerated/blastic phase with persistent response) was 89.2% (95% CI: 84-94.4) at 12 months and 80.2% (95% CI: 72.2-88.2) at 18 months. Platelets > 450x10(9)/L and treatment discontinuation > 4 weeks were associated with a lower rate of major (complete plus partial) cytogenetic response. Patients in Sokal's high-risk group and those who did not achieve a major cytogenetic response had significantly shorter progression-free survival. INTERPRETATION AND CONCLUSIONS: Imatinib is highly effective in chronic-phase CML patients resistant or intolerant to IFN, especially in those with normal platelet counts and in those not requiring prolonged treatment discontinuation due to neutropenia.
Asunto(s)
Interferones/metabolismo , Interferones/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/metabolismo , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Administración Oral , Adolescente , Adulto , Anciano , Benzamidas , Supervivencia sin Enfermedad , Esquema de Medicación , Hipersensibilidad a las Drogas/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib , Interferones/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/toxicidad , Pronóstico , Pirimidinas/administración & dosificación , Pirimidinas/toxicidad , España , Resultado del TratamientoRESUMEN
Early reconstitution of lymphoid populations was monitored by immunophenotyping in 57 allogeneic peripheral blood stem cell (allo-PBSC) transplant patients either with or without cytomegalovirus (CMV) viremia or disease. Cell counts for total lymphocytes and CD4(+) T cells above the percentile 60th at day 14 postransplant were associated significantly with CMV viremia-free survival within 120 days after transplant. Recovery of total lymphocyte, CD3(+), and CD8(+) T-cell counts proceeded at a more rapid rate in CMV viremic patients than in nonviremic patients, irrespective of whether preemptive treatment with ganciclovir had been prescribed. Significant expansion of CD8(+) and CD8(+) CD57(+) T-cell subsets was associated with recovery from viremia and no progression to CMV disease. Immunophenotyping may provide useful information for the clinical management of CMV infection in allo-PBSC transplant recipients.
Asunto(s)
Infecciones por Citomegalovirus/terapia , Citomegalovirus/aislamiento & purificación , Trasplante de Células Madre de Sangre Periférica , Subgrupos de Linfocitos T/inmunología , Adulto , Antivirales/administración & dosificación , Complejo CD3/análisis , Recuento de Linfocito CD4 , Relación CD4-CD8 , Antígenos CD57/análisis , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/virología , Femenino , Ganciclovir/administración & dosificación , Humanos , Inmunofenotipificación , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Viremia/inmunologíaRESUMEN
Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusively in the transformation phase included amplification and/or translocation of bands 7p22-q22 and 19p13. These findings suggest that the loss of + 3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of SMZL. We hypothesize that the trisomy of 3q may correlate with the indolent nature of SMZL, and that the loss of this acquired abnormality leads to or accompanies the development of blastic tumors.
Asunto(s)
Crisis Blástica/genética , Aberraciones Cromosómicas , Cromosomas Humanos/ultraestructura , Linfoma de Células B/genética , Neoplasias del Bazo/genética , Crisis Blástica/patología , Deleción Cromosómica , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 3 , Progresión de la Enfermedad , Humanos , Cariotipificación , Linfoma de Células B/patología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Neoplasias del Bazo/patología , Trisomía , Células Tumorales Cultivadas/ultraestructuraRESUMEN
The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5' MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed, one centered around BCL2 and the other around MALT1. Ofthe 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription-polymerase chain reaction (QRT-PCR), and Western blotting. To determine if comparable events occurred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL.
Asunto(s)
Amplificación de Genes , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B/genética , Proteínas de Neoplasias/genética , Translocación Genética , Anciano , Caspasas , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes bcl-2 , Humanos , Linfoma de Células B/etiología , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/etiología , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/análisisRESUMEN
Imatinib mesylate (STI571) is a highly effective and well-tolerated treatment for patients with chronic-phase chronic myeloid leukaemia (CML), but information on its efficacy and tolerance in intensively pretreated patients is scarce. Thirty-three chronic-phase CML patients who were resistant or intolerant to interferon (IFN) and had been previously submitted to autologous stem cell transplantation were treated with imatinib for a median of 14 months (range: 6-19 months). Seven patients were in haematological response (HR) at the start of treatment; the remaining 26 attained a HR at a median of 3 weeks (range: 1-4 weeks). Major cytogenetic response rates at 3, 6 and 12 months were 42%, 45% and 55%, respectively, including 21%, 24% and 33% complete responses. Grade 3-4 neutropenia, thrombocytopenia and anaemia developed in 33%, 27% and 12% of patients respectively. Non-haematological toxicity included superficial oedema (21% of patients), gastrointestinal symptoms (18%), muscle cramps (15%), skin rash and liver enzyme increase (3% each). These results were not significantly different from those in 65 chronic-phase CML patients, resistant or intolerant to interferon without a previous ASCT, who were included in the same protocol. Imatinib mesylate is effective and safe in chronic-phase CML patients with a previous history of intensive treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Supervivencia sin Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Interferones/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide de Fase Crónica/terapia , Masculino , Persona de Mediana Edad , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
This study explores whether the presence of somatic mutations or a biased use of IgV(H) genes were associated with the clinical features in a series of 96 patients with mantle cell lymphoma (MCL). The cases were studied by seminested polymerase chain reaction using primers from the FR1 and J(H) regions. There was an unexpectedly high frequency of somatic mutations, with 29 of 103 sequences showing more than 2% of mutations. Biased usage of specific V(H) segments was also found; the most widely used genes in this series were V(H)3-21 (10 cases), V(H)3-23 (9 cases), V(H)4-34 (11 cases), and V(H)4-59 (9 cases). V(H) mutation frequency, taking into account different thresholds, did not distinguish different overall survival probabilities. Nevertheless, a more frequent use of V(H)3-21 or V(H)4-59 (8 of 18) was observed in the group of long-term survivors (18 cases > 5 years; P <.01). None of these long-term survivors presented the V(H)3-23 gene rearrangement. As in other lymphoproliferative disorders, the expression of CD38 or p53 or both was associated with a poorer survival probability. This nonrandom usage of IgV(H) segments suggests that specific antigens may play a pathogenically relevant role in the genesis or progression of subsets of MCL cases and may help in distinguishing a significant group of MCL long-term survivors.
Asunto(s)
Genes de Inmunoglobulinas , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/inmunología , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Reordenamiento Génico , Humanos , Inmunohistoquímica , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Factores de TiempoRESUMEN
Genomic aberrations in a series of paired biopsy samples from patients who presented initially with follicle center lymphoma (FCL) and subsequently transformed to diffuse large B-cell lymphoma (DLBCL) were measured by array comparative genomic hybridization (CGH). The consequences of these aberrations on gene expression were determined by comparison with expression analysis on these specimens using cDNA microarrays. A heterogeneous pattern of acquired genomic abnormalities was observed upon transformation, some of which were recurrent in small subsets of patients. Some of the genomic aberration acquired upon transformation, such as gain/amplification of 1q21-q24, 2p16 (REL/BCL11A gene loci), 3q27-q29 (including the BCL6 locus), 7q11.2-q22.1, 12pter-q12, 18q21 (including the BCL2 locus) and Xq, and deletion of 6q22-q24, 13q14-q21 and 17p13 (P53 locus) have been previously implicated in the FCL/DLBCL pathogenesis. In addition, novel genomic imbalances not previously reported in association with FCL transformation, such as overrepresentation of 4p12-pter, 5p12-p15, 6p12.3-p21, 9p23, 9q13-q31, 16q, 17q21, and loss of 1p36.3, 4q21-q23, 5q21-q23, 9q31-qter, 11q24-q25, and 15q23, were identified. We observed a differential expression profile of many genes within regions of gain and deletion upon transformation, including novel target genes associated with FCL transformation. However, other genes did not show deregulated expression despite their location within these areas. In summary, the combination of array CGH and expression analysis provides a more comprehensive picture of the transformation of FCL to DLBCL. This process is associated with the acquisition of a variable spectrum of genomic imbalances affecting recurrent chromosomal areas that harbor overexpressed or underexpressed genes targeted upon transformation.
Asunto(s)
Aberraciones Cromosómicas , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/genética , Desequilibrio Alélico , Transformación Celular Neoplásica/genética , Deleción Cromosómica , Cromosomas Humanos/genética , Cromosomas Humanos/ultraestructura , ADN Complementario/genética , Progresión de la Enfermedad , Amplificación de Genes , Perfilación de la Expresión Génica , Humanos , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/patología , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
The impact of the genomic imbalances on the clinical outcome of 34 patients with lymph-node positive high-risk breast cancer (HRBC) was investigated using comparative genomic hybridization. All of the patients were uniformly treated with high-dose chemotherapy and autologous stem cell transplantation. The average number of chromosomal imbalances per tumor was 11 (range, 2-24), including DNA overrepresentation on chromosomes 1q (59%), 17q (38%), 8q and 16p (35% each), 20q (32%), and 19p (26%), and genomic losses involving 9p and 18q (41%), 8p, 11q, and 18p (38%), 17p (32%), 4p and Xq (29%), and 16q (26%). The most significant association among genomic changes and clinical-pathological features was the correlation of the loss of 8p with progesterone receptor positivity (P < 0.005). With a median follow-up time of 74 months, 15 patients (44%) have relapsed. In the univariate analysis, patients with gain/amplification of 17q including the HER-2/neu gene locus had a longer disease-free survival (P = 0.02), whereas those with genomic loss of 18p had a higher probability of relapse (P = 0.003). In multivariate analysis, the loss of 18p was the only parameter correlated with shorter disease-free survival (relative risk, 4.8; 95% confidence interval, 1.57-14.8; P = 0.006). In summary, our data indicate that the tumoral genomic profile may represent a valuable marker for predicting the clinical outcome in HRBC. Furthermore, the genomic loss of 18p may identify a poor prognostic subgroup of patients with HRBC.