RESUMEN
The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.
Asunto(s)
Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Adulto , Factores de Edad , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype.
Asunto(s)
Algoritmos , Centro Germinal , Linfoma de Células B Grandes Difuso , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Inmunoterapia , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
The means of optimally managing very elderly patients with diffuse large B-cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80-100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression-free survival (PFS) and overall survival (OS). One hundred sixty-three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow-up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1-2) R-IPI, and treatment with R-CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R-CHOP-like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0-1 vs. 2-3 risk factors (age > 85 years, R-IPI 3-5 or CIRS > 5). In conclusion, treatment with R-CHOP-like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.
Asunto(s)
Linfoma de Células B Grandes Difuso/diagnóstico , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Manejo de la Enfermedad , Doxorrubicina/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab , España , Análisis de Supervivencia , Vincristina/uso terapéuticoRESUMEN
The study included 1848 diffuse large B-cell lymphoma (DLBCL)patients treated with chemotherapy/rituximab. The aims were to validate the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and explore the effect of adding high Beta-2 microglobulin (ß2M), primary extranodal presentation and intense treatment to the NCCN-IPI variables in order to develop an improved index. Comparing survival curves, NCCN-IPI discriminated better than IPI, separating four risk groups with 5-year overall survival rates of 93%, 83%, 67% and 49%, but failing to identify a true high-risk population. For the second aim the series was split into training and validation cohorts: in the former the multivariate model identified age, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, Stage III-IV, and ß2M as independently significant, whereas the NCCN-IPI-selected extranodal sites, primary extranodal presentation and intense treatments were not. These results were confirmed in the validation cohort. The Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI developed here, with 7 points, significantly separated four risk groups (0, 1-3, 4 or ≥5 points) with 11%, 58%, 17% and 14% of patients, and 5-year overall survival rates of 93%, 79%, 66% and 39%, respectively. In the comparison GELTAMO IPI discriminated better than the NCCN-IPI. In conclusion, GELTAMO-IPI is more accurate than the NCCN-IPI and has statistical and practical advantages in that the better discrimination identifies an authentic high-risk group and is not influenced by primary extranodal presentation or treatments of different intensity.
Asunto(s)
Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/mortalidad , Microglobulina beta-2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Inducción de Remisión , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
(1) Background: New therapeutic strategies have improved the prognosis of multiple myeloma (MM), changing the accepted view of this disease from being incurable to treatable. (2) Methods: We studied 1001 patients with MM between 1980 and 2020, grouping patients into ten-year periods by diagnosis 1980-1990, 1991-2000, 2001-2010 and 2011-2020. (3) Results: After 65.1 months of follow-up, the median OS of the cohort was 60.3 months, and OS increased significantly over time: 22.4 months in 1980-1990, 37.4 months in 1991-2000, 61.8 months in 2001-2010 and 103.6 months in 2011-2020 (p < 0.001). Using novel agents in the front-line setting for myeloma patients yielded a significantly better OS than in those treated with conventional therapies, especially when combinations of at least two novel agents were used. The median OS of patients treated with the combination of at least two novel agents in induction was significantly prolonged compared to those treated with a single novel agent or conventional therapy in induction: 143.3 vs. 61.0 vs. 42.2 months (p < 0.001). The improvement was apparent in all patients regardless of age at diagnosis. In addition, 132 (13.2%) patients were long-term survivors (median OS ≥ 10 years). Some independent clinical predictors of long-term survival were identified: ECOG < 1, age at diagnosis ≤ 65 years, non-IgA subtype, ISS-1 and standard-risk cytogenetic. Achieving CR and undergoing ASCT were positively associated with >10 years of survival. (4) Conclusions: The combination of novel agents appears to be the main factor for the improvement in survival in MM, which is becoming a chronic and even curable disease in a subtype of patients without high-risk features.
RESUMEN
OBJECTIVES: The myeloproliferative neoplasms displaying a PDGFRB rearrangement are rare diseases derived from a haematopoietic stem cell. The goals of the study were to assess the incidence of these disorders and to define the clinical and biological characteristics as well as the response to the imatinib therapy. METHODS: A total of 556 patients with myeloproliferative neoplasms were studied by means of molecular cytogenetics. RESULTS: The incidence of myeloproliferative neoplasms (MPN) with PDGFRB rearrangement was low (10 cases, 1.8% of all MPN). Most of the patients showed moderate anaemia (median Hb was 10.0 gr/dL; range from 7.5 to 13 g/dL), leukocytosis (median white blood cells was 21.7 × 10(9) /L with a range from 4 to 43 × 10(9) /L) and eosinophilia (median circulating eosinophils was 2.4 × 10(9) /L with a range of 1.1-5.7 × 10(9) /L) with a median of bone marrow infiltration cells displaying PDGFRB rearrangement of 55% (range, 37-85%). In three cases, a t(5;12) was observed while two patients showed rearrangements of 17q21 region. In two cases, a del(5)(q31) was observed. Most of the patients responded to standard dosage of imatinib, and the response was maintained in the time in those patients with a follow-up higher than 9 years. CONCLUSIONS: The incidence of patients with PDGFRB rearrangement is low. These patients showed leukocytosis with eosinophilia and anaemia. The efficacy of imatinib therapy in patients showing PDGFRB rearrangement is high. For this reason, in all patients with MPN without any other molecular aberration, PDGFRB rearrangement should be ascertained.
Asunto(s)
Neoplasias de la Médula Ósea/epidemiología , Neoplasias de la Médula Ósea/genética , Trastornos Mieloproliferativos/epidemiología , Trastornos Mieloproliferativos/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Benzamidas , Neoplasias de la Médula Ósea/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Incidencia , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/tratamiento farmacológico , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Resultado del TratamientoRESUMEN
We have evaluated 9 new molecular markers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression levels plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute myeloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAME expressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to 3 score was given by assigning a value of 0 to favorable parameters (low ERG, low EVI1, and high PRAME) and 1 to adverse parameters. This model distinguished 4 subsets of patients with different OS (2-year OS of 79%, 65%, 46%, and 27%; P = .001) and RFS (2-year RFS of 92%, 65%, 49%, and 43%; P = .005). Furthermore, this score identified patients with different OS (P = .001) and RFS (P = .013), even within the FLT3/NPM1 intermediate-risk/high-risk subgroups. Here we propose a new molecular score for cytogenetically normal acute myeloblastic leukemias, which could improve patient risk-stratification.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/genética , Modelos Genéticos , Adulto , Anciano , Antígenos de Neoplasias/genética , Análisis Citogenético , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Marcadores Genéticos , Humanos , Leucemia Mieloide Aguda/mortalidad , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Mutación , Nucleofosmina , Pronóstico , Proto-Oncogenes/genética , Factores de Riesgo , España/epidemiología , Tasa de Supervivencia , Transactivadores/genética , Factores de Transcripción/genética , Regulador Transcripcional ERGRESUMEN
We have analyzed brain and acute leukemia, cytoplasmic (BAALC) gene expression and other genetic markers (ERG, EVI1, MN1, PRAME, WT1, FLT3, and NPM1 mutations) in 127 intermediate-risk acute myeloid leukemia (AML) patients: 98 cytogenetically normal and 29 with intermediate-risk cytogenetic alterations. High versus low BAALC expressers showed a higher refractoriness to induction treatment (31% vs 10%; p = .005), lower complete remission rate after salvage therapy (82% vs 97%; p = .010), and lower 3-year overall (23% vs 58%, p < .001) and relapse-free survival (26% vs 52%, p = .006). Similar results were found when cytogenetic subgroups were analyzed separately. Multivariate models confirmed the unfavorable prognosis of this marker. In conclusion, BAALC is a relevant prognostic marker in intermediate-risk AML.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/biosíntesis , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/biosíntesis , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Nucleofosmina , Valor Predictivo de las Pruebas , Factores de Riesgo , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. METHODS: Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19- early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities. RESULTS: NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19- early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. CONCLUSIONS: Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.
Asunto(s)
Aberraciones Cromosómicas , Células Madre Hematopoyéticas/patología , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Antígenos CD19 , Antígenos CD34 , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/genéticaRESUMEN
The evaluation of bone disease in multiple myeloma (MM) by conventional radiology has low reproducibility. In the last decade, several serum and urine biochemical parameters, for evaluation of bone turnover, have become available. The present study was designed to explore the value of six bone remodelation markers. It was studied in a series of 176 newly diagnosed patients with monoclonal gammopathies (107 MM and 69 monoclonal gammopathies of unknown significance (MGUS)). As control groups we used 25 patients with benign osteoporosis (BO) and 32 healthy individuals (HI). The bone markers analyzed included: bone resorption markers (BRM) (total pyridinoline, total deoxypyridinoline, free deoxypyridinoline and C-terminal telopeptide of collagen I) and bone formation markers (BFM) (bone alkaline phosphatase (bAP) and osteocalcin (OC)). Serum or urinary levels of BRM were significantly higher in MM patients than in MGUS patients, BO patients or HI (P < 0.001, respectively). BRM were higher in MM patients with lytic lesions. However, only C-terminal telopeptide discriminated MM patients without bone lesions from MGUS patients. BFM did not show significant differences in the aforementioned comparisons, although a trend toward higher values of OC and lower values of bAP in patients with early bone affectation was observed. Ratios BRM/BFM that contained bAP exhibited differences that were most significant between the MM group and other entities, as well as between the different MM subgroups. In fact, the ratios BRM/bAP provided discrimination between the MM subgroup without lyses and MGUS group (P < 0.01). BRM and BFM, especially the ratios, are useful in the evaluation of bone lesions in patients with monoclonal gammopathies.
Asunto(s)
Biomarcadores de Tumor , Remodelación Ósea , Mieloma Múltiple/diagnóstico , Paraproteinemias/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/orina , Biomarcadores/sangre , Biomarcadores/orina , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/orina , Resorción Ósea/diagnóstico , Resorción Ósea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/orina , Osteocalcina/sangre , Osteocalcina/orina , Osteoporosis/sangre , Osteoporosis/diagnóstico , Osteoporosis/orina , Paraproteinemias/sangre , Paraproteinemias/orina , Valor Predictivo de las Pruebas , Pronóstico , Valores de Referencia , Estudios RetrospectivosRESUMEN
The employment of current treatments based on chemotherapy and immunotherapy leads to inmunosuppression. The presence of mutations or polymorphisms in genes related to immune system might involve an additional disadvantage. The aim of the present study was to analyze mannose-binding lectin (MBL-2 gene) mutations and their association with severe infections and event-free survival in patients diagnosed with follicular lymphoma, treated uniformly, in the clinical trial LNHF-03. The results of this trial showed impressive clinical efficacy but was complicated with 80 documented infectious episodes. Patients were classified into two genotypic groups, AA and AO/OO, based on their haplotypic inheritance. Neither the number of infectious episodes nor differences in event-free survival was found as a function of MBL-2 groups. Other factors, including the lymphoma malignancy and the immune alterations associated with the disease, should be considered responsible for this observation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones/epidemiología , Linfoma Folicular/genética , Lectina de Unión a Manosa/genética , Adulto , Anciano , Alelos , Antiinfecciosos/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Fase II como Asunto/estadística & datos numéricos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Terminación Anticipada de los Ensayos Clínicos , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos/genética , Humanos , Infecciones/etiología , Infecciones/genética , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/epidemiología , Linfopenia/inducido químicamente , Linfopenia/complicaciones , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Neutropenia/inducido químicamente , Neutropenia/complicaciones , Estudios Prospectivos , Riesgo , Rituximab , España/epidemiología , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
The PI3/AKT pathway is up-regulated in acute myeloid leukemia (AML), but its prognostic relevance in cytogenetically normal AML (CN-AML) is unclear. We evaluated RNA levels of AKT and two downstream substrates (FOXO3a-p27) in 110 de novo CN-AML, included in the Spanish PETHEMA therapeutic protocols. Patients with high FOXO3a gene expression displayed shorter OS (p=0.015) and RFS (p=0.048) than low FOXO3a expressers. Features selected in the multivariate analysis as having an independent prognostic value for a shorter survival were WBC>50x10(9)/L, age >65 years and high FOXO3a expression. We concluded that FOXO3a assessment could contribute to improve the molecular-based risk stratification in CN-AML.