RESUMEN
Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL).Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eµ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water.Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle.Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831-41. ©2016 AACR.
Asunto(s)
Benzamidas/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Pirazinas/administración & dosificación , Adenina/análogos & derivados , Traslado Adoptivo/métodos , Agammaglobulinemia Tirosina Quinasa , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Transgénicos , Piperidinas , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/genética , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.
Asunto(s)
Actinas/metabolismo , Linfocitos B/inmunología , Citoesqueleto/metabolismo , Proteínas de Unión al ADN/genética , Factores de Intercambio de Guanina Nucleótido/genética , Síndromes de Inmunodeficiencia/genética , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Adolescente , Inhibidores de la Angiogénesis/farmacología , Linfocitos B/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/genética , Niño , Citotoxicidad Inmunológica/genética , Análisis Mutacional de ADN , Dineínas/metabolismo , Femenino , Células HEK293 , Humanos , Cambio de Clase de Inmunoglobulina/genética , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Células Jurkat , Células Asesinas Naturales/efectos de los fármacos , Lenalidomida , Masculino , Mutación/genética , Linaje , ARN Interferente Pequeño/genética , Linfocitos T/efectos de los fármacos , Talidomida/análogos & derivados , Talidomida/farmacologíaRESUMEN
Therapeutic strategies targeting the programmed cell death-ligand 1/programmed cell death-1 pathway have shown significant responses and good tolerability in solid malignancies. Although preclinical studies suggest that inhibiting programmed cell death-ligand 1/programmed cell death-1 interactions might also be highly effective in hematological malignancies, remarkably few clinical trials have been published. Determining patients who will benefit most from programmed cell death-ligand 1/programmed cell death-1-directed immunotherapy and whether programmed cell death-ligand 1/programmed cell death-1 are adequate prognostic markers becomes an increasingly important clinical question, especially as aberrant programmed cell death-ligand 1/programmed cell death-1 expression are key mediators of impaired anti-tumor immune responses in a range of B-cell lymphomas. Herein, we systematically review the published literature on the expression and prognostic value of programmed cell death-ligand 1/programmed cell death-1 in these patients and identify considerable differences in expression patterns, distribution and numbers of programmed cell death-ligand 1+/programmed cell death-1+cells, both between and within lymphoma subtypes, which is reflected in conflicting findings regarding the prognostic value of programmed cell death-ligand 1+/programmed cell death-1+ cells. This can be partly explained by differences in methodologies (techniques, protocols, cutoff values) and definitions of positivity. Moreover, lymphomagenesis, disease progression, and prognosis appear to be determined not only by the presence, numbers and distribution of specific subtypes of T cells, but also by other cells and additional immune checkpoints. Collectively, our findings indicate that programmed cell death-ligand 1/programmed cell death-1 interactions play an essential role in B-cell lymphoma biology and are of clinical importance, but that the overall outcome is determined by additional components. To categorize the exact prognostic value of programmed cell death-ligand 1/programmed cell death-1 expressing cells and cell types, efforts should be made to harmonize their assessment and interpretation, optimally within ongoing clinical immune checkpoint inhibitor trials, and to identify and validate novel high-throughput platforms.
Asunto(s)
Antígeno B7-H1/metabolismo , Linfoma de Células B/diagnóstico , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/análisis , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Pronóstico , Receptor de Muerte Celular Programada 1/análisisRESUMEN
Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy. In the wake of novel treatment approaches that offer high efficacy and highly durable responses with little toxicity, our approach to HSCT in CLL needs to be re-evaluated. While we wait for data on the long-term efficacy of novel therapies to inform the choice of HSCT or alternative treatment, strategies must be assessed individually for every patient, and treatment must be conducted in the setting of randomized clinical trials whenever possible.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/cirugía , Trasplante Homólogo , Humanos , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodos , Trasplante Homólogo/estadística & datos numéricosRESUMEN
A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy. However, several new agents and alternative treatment strategies are available that demonstrate impressive and durable responses, even in CLL patients who previously might have been candidates for transplant. The decision about which patients merit HSCT therefore remains important, and HSCT must now be considered in light of other less toxic therapies. Until data on the long-term efficacy of novel treatment approaches mature, the choice of HSCT vs alternative strategies must be assessed on a patient-by-patient basis, and treatment in the setting of randomized clinical trials should be pursued whenever possible.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Terapia Molecular Dirigida , Morbilidad , Mutación , Guías de Práctica Clínica como Asunto , Pronóstico , Recurrencia , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00-1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05-0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.
Asunto(s)
Antineoplásicos/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rituximab/efectos adversos , Resultado del TratamientoRESUMEN
T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eµ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in the spleen. CD3(+)CD8(+) T cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1(+) T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8(+) T cells, showing the potential of reprogramming and selective subset expansion to restore antitumor immunity.
Asunto(s)
Envejecimiento/inmunología , Antígeno B7-H1/fisiología , Linfocitos T CD8-positivos/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Envejecimiento/genética , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Cadenas mu de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas/genética , Transducción de Señal/inmunologíaRESUMEN
Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint augments antitumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias are sparse. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunologic synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the Eµ-TCL1 mouse model for CLL. In this study, we treated mice after adoptive transfer of Eµ-TCL1 CLL with PD-L1-blocking antibodies, which prevented CLL development and was accompanied by a reactivation of immune effector functions. This included restoration of mature macrophages and major histocompatibility complex class II-expressing dendritic cells and prevention of aberrant and exhaustion-like T-cell phenotypes. In addition, PD-L1 blockade restored CD8 T-cell cytotoxicity and immune synapse formation and normalized T-cell cytokines and proliferation ex vivo and in vivo. Our data demonstrate that early PD-L1 blockade effectively corrects leukemia-induced immune dysfunction and thus prevents CLL development in mice. Targeting PD-L1/PD-1 interactions should therefore be further explored in clinical studies with CLL patients, ideally in combination with novel compounds to help eliminate CLL.
Asunto(s)
Anticuerpos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Transformación Celular Neoplásica/efectos de los fármacos , Enfermedades del Sistema Inmune/prevención & control , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/prevención & control , Animales , Antígeno B7-H1/inmunología , Antígeno B7-H1/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Transformación Celular Neoplásica/inmunología , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Células Dendríticas/fisiología , Modelos Animales de Enfermedad , Femenino , Inflamación/prevención & control , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCßII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCß inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCßII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis.
Asunto(s)
Linfocitos B/metabolismo , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteína Quinasa C beta/genética , Proteína Quinasa C-alfa/genética , Animales , Linfocitos B/patología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Infiltración Leucémica/patología , Tejido Linfoide/patología , Ratones , Ratones Noqueados , Pronóstico , Proteína Quinasa C beta/antagonistas & inhibidores , Proteína Quinasa C beta/metabolismo , Proteína Quinasa C-alfa/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción Genética , Carga Tumoral/efectos de los fármacos , Proteína Tirosina Quinasa ZAP-70/genética , Proteína Tirosina Quinasa ZAP-70/metabolismoRESUMEN
Allogeneic stem cell transplantation (HSCT) offers the only potentially curative approach in chronic lymphocytic leukemia (CLL). However, this applies only to a minority of patients, and is associated with significant treatment-related mortality and morbidity. HSCT must therefore always be considered in view of other, potentially less toxic therapies. Several new agents demonstrate impressive and durable responses in high-risk patients who might be candidates for HSCT. Therefore the choice of HSCT versus a novel agent is one that must be gauged on a patient-by-patient basis; this will change as data mature on the use of these novel agents in CLL.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Terapia Molecular Dirigida/métodos , Humanos , Factores de Riesgo , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with ß2-integrin expression being modulated by NOTCH1 mutation status.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Integrinas/biosíntesis , Leucemia Linfocítica Crónica de Células B/metabolismo , Mutación , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Regulación hacia Arriba , Anciano , Movimiento Celular/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 12/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Integrinas/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes/patología , Receptor Notch1/genética , Trisomía/genética , Trisomía/patología , Proteínas de Unión al GTP rap/genética , Proteínas de Unión al GTP rap/metabolismoRESUMEN
BACKGROUND: In marginal zone lymphoma (MZL), clinical and follow-up data on large cohorts of patients are difficult to obtain. The objective of this single-center, retrospective analysis of a large cohort of 144 patients with MZL was to elucidate the role of prognostic markers, treatments, and outcomes in this disease. METHODS: In total, 144 patients were identified who were diagnosed with MZL at the authors' institution between 2003 and 2010. Data on clinical parameters, treatments, response, and survival were analyzed. In addition, the validity of the International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) prognostic scores were tested in patients with MZL. RESULTS: Among 144 patients with MZL, 96 patients (67%) had extralymph node (extranodal) MZL, 32 patients (22%) had lymph node (nodal) MZL, and 16 patients (11%) had splenic MZL. The 5-year progression-free survival rate was 82% in the nodal MZL group, 88% in the extranodal MZL group, and 74% in the splenic MZL group and did not different between the 3 groups (P = .60). The 5-year overall survival rate was excellent in all 3 MZL groups (nodal MZL, 89%; extranodal MZL, 92%; splenic MZL, 82%; P = .46). In our cohort, the FLIPI score was a significant prognostic marker: The 5-year progression-free survival rate for patients who had FLIPI scores of 0 to 2 (low or intermediate risk) was excellent at 92%, whereas it was only 62% for patients who had FLIPI scores of 3 to 5 (poor risk; P = .003). Similarly, the 5-year overall survival rate for patients who had FLIPI scores of 0 to 2 was 95%, whereas it was only 62% for patients who had FLIPI scores of 3 to 5 (P = .0009). CONCLUSIONS: The FLIPI score had strong prognostic value in patients with MZL. Patients who have low-risk or intermediate-risk FLIPI scores have an excellent prognosis, whereas patients with poor-risk FLIPI scores are candidates for novel treatment approaches.
Asunto(s)
Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma Folicular/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL.
Asunto(s)
Citocinas/metabolismo , Leucemia Linfocítica Crónica de Células B/inmunología , Linfocitos T/metabolismo , Linfocitos T/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Complejo CD3/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Estudios de Casos y Controles , Células Cultivadas , Proteínas Ligadas a GPI/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL). In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD), autoSCT has lost its place as a standard treatment option for CLL.
RESUMEN
The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/terapia , Trasplante de Células Madre , Adolescente , Adulto , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/métodos , Análisis de Supervivencia , Factores de Tiempo , Trasplante Autólogo , Adulto JovenRESUMEN
Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden.
Asunto(s)
Médula Ósea/patología , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mieloma Múltiple/patología , Adulto , Anciano , Biopsia , Estudios de Casos y Controles , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Vértebras Lumbares/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Invasividad Neoplásica , Huesos Pélvicos/patología , Células Plasmáticas/patologíaRESUMEN
BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool for quantification of cellularity in the investigated area. Recently published examples cover breast cancer, CNS tumors, head and neck cancer, gastrointestinal cancer, prostate cancer as well as hematologic malignancies. PURPOSE: To investigated the influence of age, sex, and localization of the investigated region on findings of DCE-MRI and DWI. MATERIAL AND METHODS: DCE-MRI-parameters amplitude A and exchange rate constant kep as well as the DWI-parameter ADC of the bone marrow of the lumbar vertebral column of 30 healthy individuals covering the typical range of age of tumor patients were evaluated. ADC was calculated using b=0 and a maximal b value of either 400 or 750 s/mm(2). RESULTS: Amplitude A of DCE-MRI decreased with age (P = 0.01) and amplitude A, exchange rate constant kep as well as ADC based on b = 400 s/mm(2) and b = 750 s/mm(2,) respectively, decreased significantly from the first to the fifth lumbar vertebra with P = 0.02, P = 0.05, P = 0.003, and P = 0.002, respectively. CONCLUSION: Quantitative parameters of functional imaging techniques in bone marrow are influenced by the age of the examined individual and the anatomical location of the investigated region.
Asunto(s)
Médula Ósea/anatomía & histología , Vértebras Lumbares/anatomía & histología , Imagen por Resonancia Magnética/métodos , Adulto , Anciano , Medios de Contraste/administración & dosificación , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Gadolinio DTPA/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
BACKGROUND: The strategy to apply involved-field radiotherapy (IF-RT) after immunochemotherapy in patients with bulky follicular lymphoma (FL) remains controversial. PATIENTS AND METHODS: To evaluate the benefit of consolidating IF-RT, we retrospectively analysed relapse patterns and survival of patients with bulky FL. All patients were treated within a multicenter prospective randomized trial on 126 patients with one, three or six cycles Rituximab and six cycles CHOP. According to the protocol, patients presenting with bulky disease were to undergo consolidating IF-RT after immunochemotherapy. Forty-two eligible patients with bulky disease were identified, of which 26 were irradiated and 16 were not, contrary to the demand of the protocol. RESULTS: There was no significant difference between the irradiated and the non-irradiated group regarding presenting characteristics (P > 0.05). After a median follow-up of 60 months, 21 patients relapsed. In the irradiated group, relapse occurred in 12 of 26 patients. Fifty percent of relapses were located within the original bulk or within the bulk plus a new location. In the non-irradiated group, 9 of 16 patients relapsed. There was no statistically significant difference between exposure to IF-RT and the likelihood of a relapse per se (P = 0.751) or at a specific location (P = 0.66). Six-yr-PFS- (P = 1.0) and OS-rates (P = 0.68) were 52% and 80% after IF-RT and 48% and 73% without IF-RT. CONCLUSION: There was no difference in relapse rate, PFS and OS between patients treated with and without consolidating IF-RT. This is the first analysis of its kind conducted in the Rituximab era. However, these results are based on a relatively small cohort size and are derived from a retrospective analysis, with the limitations of such an analysis being well known.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/radioterapia , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Estudios Prospectivos , Radioterapia Adyuvante , Recurrencia , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Adulto JovenRESUMEN
Previous studies have reported substantially increased risks of breast cancer among survivors of childhood cancer at 10-20 years posttreatment. Whether these excess risks are sustained beyond 40 years of age when general population incidence of breast cancer begins its steep increase is largely unknown. We quantified the risk of breast cancer in adult female survivors with considerably more survivors followed-up beyond 40 years of age than previously available. Standardized Incidence Ratios (SIR), Excess Absolute Risks (EAR), and cumulative incidence were calculated within a population-based cohort of 8,093 female survivors of childhood cancer. Poisson regression models were used to model SIRs and EARs in a multivariable setting. Eighty-one survivors developed a primary breast cancer, where 37.5 were expected (SIR= 2.2, 95% CI: 1.7-2.7). SIRs decreased significantly with increasing attained age (p(trend) < 0.001) to an SIR of 0.9 (95% CI: 0.5-1.8) at ages beyond 50 years; EARs increased significantly to about 40 years of age (p(trend) < 0.001) but then plateau. Between 30 and 49 years of age survivors experienced approximately 1 extra breast cancer per 1,000 survivors per year. Overall, 3% developed breast cancer by the age of 50. The substantially increased relative risks of breast cancer observed at 10-20 years postdiagnosis are not sustained into ages at which the risk of breast cancer in the general population becomes substantial. Among women who survived to an age of at least 50 years there is currently no evidence of an increased risk of breast cancer.