RESUMEN
Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid. Moreover, Btk inhibitors prevented platelet thrombus formation on human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α2ß1 and VWF-dependent platelet adhesion to collagen, which is important for physiologic hemostasis, was not affected. This plaque-selective platelet inhibition was also observed in CLL patients taking 450 mg of ibrutinib and in volunteers after much lower and intermittent dosing of the drug. We conclude that Btk inhibitors, by targeting GPIb and GPVI signal transduction, suppress platelet thrombus accretion from flowing blood on atherosclerotic plaque but spare hemostatic platelet function. Btk inhibitors hold promise as the first culprit lesion-focused oral antiplatelet drugs and are effective at low doses.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Benzamidas/uso terapéutico , Imidazoles/uso terapéutico , Placa Aterosclerótica/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Trombosis/etiología , Trombosis/prevención & control , Adenina/análogos & derivados , Administración Oral , Adulto , Agammaglobulinemia Tirosina Quinasa/metabolismo , Anciano , Benzamidas/administración & dosificación , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Piperidinas , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Trombosis/metabolismo , Trombosis/patologíaRESUMEN
BACKGROUND: Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia. METHODS: In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25â000 cells per µL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503. FINDINGS: Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not. INTERPRETATION: The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation. FUNDING: F Hoffmann-La Roche and AbbVie.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Esquema de Medicación , Femenino , Alemania , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sulfonamidas/efectos adversos , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Sulfonamidas/efectos adversosRESUMEN
PURPOSE OF REVIEW: Antibody-based therapy has revolutionized treatment strategies in follicular lymphoma. This review focuses on current standards and recent innovations in the management of the disease. RECENT FINDINGS: Understanding the mechanism of action of antibodies led to the development of next generation CD20 antibodies, antibodies targeting other molecules and bispecific antibodies. With obinutuzumab, a promising next generation of CD20 antibodies has entered phase III of clinical trials. The bispecific T-cell engager blinatumomab combines targeted therapy with immunologic activation of T cells exerting cytotoxic activity on the target cells. Apart from antibodies, small molecules targeting key pathways in lymphoma have shown promising activity in vitro and are currently in clinical development. SUMMARY: A wealth of new substances has entered various stages of clinical trials and has yet to show superiority over rituximab-based immunochemotherapy. Intelligent therapeutic regimens containing these drugs have to be developed. Large randomized trials comparing promising treatment options are urgently needed.
Asunto(s)
Manejo de la Enfermedad , Linfoma Folicular/terapia , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Humanos , Lenalidomida , Linfoma Folicular/patología , Terapia Molecular Dirigida , Rituximab , Nivel de Atención , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
In chronic lymphocytic leukemia (CLL), 13q14 and 11q22-23 deletions are found in 2/3 of the cases. 11q22-23 deletions are associated with poor survival, whereas 13q14 deletions as single abnormality are often found in indolent disease forms. The molecular basis for this difference in prognosis is not known. We examined the 13q14 and 11q22-23 minimally deleted regions (MDRs) for differentially expressed genes by analyzing 154 microarray CLL gene expression data sets. We were able to generate a detailed gene expression map of the MDRs demonstrating a gene dosage effect. Surprisingly, ARHGAP20 encoding the RHO GTPase activating protein 20, which is located in the 11q22-23 MDR, showed-counterintuitively-a significantly higher expression in cases with 11q22-23 deletions compared with cases with no detectable genetic lesion or trisomy 12. Interestingly, cases with 13q14 deletions also had higher ARHGAP20 expression. These expression level changes were confirmed by quantitative PCR in 110 additional CLL samples. The ARHGAP20 gene encodes an evolutionarily conserved protein. In the zebra fish (Danio rerio) genome the syntenic regions of human chromosomal bands 13q14 and 11q22-23 are juxtaposed. The similar expression profiles of ARHGAP20 in 13q14 and 11q22-23 deleted CLL cases suggest a molecular connection and an intriguing mechanism of regulation.
Asunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 13/genética , Proteínas Activadoras de GTPasa/genética , Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Factores de Transcripción/genética , Dosificación de Gen , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Eliminación de SecuenciaRESUMEN
Despite a wealth of information about the structure of surface membrane immunoglobulin (smIg) on chronic lymphocytic leukemia (CLL) cells, little is known about epitopes reacting with their binding sites. Probing phage-displayed peptide libraries, we identified and characterized mimetopes for Igs of 4 patients with IGHV mutated CLL (M-CLL) and 4 with IGHV unmutated CLL (U-CLL). Six of these mAbs were representatives of stereotyped B-cell receptors characteristic of CLL. We found that mimetic epitopes for U- and M-CLL Igs differed significantly. M-CLL-derived peptides exhibited better amino acid motifs, were more similar to each other, aligned more easily, and formed tighter clusters than U-CLL-derived peptides. Mono-, oligo-, and polyreactivity of peptides correlated with structural changes within antigen-binding sites of selecting M-CLL mAbs. Although M-CLL-isolated peptides and certain U-CLL mAbs bound more effectively to the selecting mAb, others were not as specific, reacting with M-CLL and U-CLL mAbs; these data suggest that in vivo structurally diverse epitopes could bind smIgs of distinct CLL clones, thereby altering survival and growth. Finally, an M-CLL-derived peptide inhibited, in a dose-dependent manner, binding of its homologous mAb to human B lymphocytes; therefore peptides that inhibit or alter the consequences of antigen-smIg interactions may represent therapeutic modalities in CLL.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Autoanticuerpos/inmunología , Epítopos/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Biomimética , Ensayo de Inmunoadsorción Enzimática , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Ligeras de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Mutación/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Biblioteca de PéptidosRESUMEN
Clinical trials in T-cell prolymphocytic leukemia (T-PLL) are scarce. Based on a precursor study testing fludarabine, mitoxantrone, and cyclophosphamide followed by alemtuzumab (FMC-A), we aimed to improve this regimen by upfront combining subcutaneous (s.c.) alemtuzumab with FMC for four cycles followed by an alemtuzumab-maintenance (FMCA + A). This prospective multicenter phase-II trial assessed response, survival, and toxicity of that regimen administered to pretreated (n = 4) and treatment-naïve (n = 12) T-PLL patients. The best overall response rate after FMCA was 68.8% (n = 11) including five CRs (31.3%) and six PRs (37.5%). Six patients entered the alemtuzumab-maintenance. Median overall and progression-free survival was 16.7 and 11.2 months, respectively. Hematologic toxicities were the most frequent grade 3/4 side effects. A reduced incidence of CMV-reactivations was attributed to the prophylactic administration of valganciclovir. Overall, FMCA + A did not improve the efficacy of the FMC-A-regimen or of single i.v. alemtuzumab. It suggests that a chemotherapy backbone prevents efficient alemtuzumab dosing and confirms that intravenous alemtuzumab is to be preferred over its s.c. route in T-PLL. ClinicalTrials.gov identifier: NCT01186640.
Asunto(s)
Alemtuzumab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Adulto , Anciano , Alemtuzumab/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Incidencia , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/mortalidad , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.
Asunto(s)
Apoptosis/inmunología , Epítopos/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Línea Celular Tumoral , Humanos , Técnicas para Inmunoenzimas , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos/inmunología , Microscopía Confocal , Datos de Secuencia Molecular , Oxidación-ReducciónRESUMEN
Chronic lymphocytic leukemia (CLL) follows an extremely variable clinical course with survival ranging from months to decades. Available treatments can often induce remissions, but eventually all patients relapse. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with CLL. Genomic aberrations, the mutational profile of IgVH genes and its surrogate marker ZAP-70 expression, and serum markers like B2-microglobulin (beta2-MG) and thymidine kinase (TK) provide prognostic information for individual patients independently of clinical disease characteristics. These molecular markers are about to enter the stage of risk stratification for individual patients in clinical trials.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/patología , Ensayos Clínicos como Asunto , Humanos , Estadificación de Neoplasias , Pronóstico , Factores de RiesgoRESUMEN
The phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is implicated in the pathogenesis of lymphoma. Deeper understanding of the diversity and biological impact of this pathway has led to the development of specific inhibitors to this pathway. Preclinical data in cell lines, patient samples and disease models have broadened our understanding of PI3K inhibition. Several PI3K inhibitors are currently in advanced stages of clinical development. Idelalisib is the first agent of this new substance class to be approved in chronic lymphocytic leukemia and follicular lymphoma. Other agents specifically target different PI3K isoforms and show promising clinical efficacy.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/farmacología , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38(+)ZAP-70(+) as compared to indolent CD38(-)ZAP-70(-) chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linked immunosorbent assay (ELISA) in the Essen CLL cohort of 131 patients and examined Pgrn for association with established prognostic markers and clinical outcome. We found that high Pgrn plasma levels were strongly associated with adverse risk factors including unmutated IGHV status, expression of CD38 and ZAP-70, poor risk cytogenetics (11q-, 17p-) as detected by flourescence in situ hybridization (FISH) and high Binet stage. Pgrn as well as the aforementioned risk factors were prognostic for time to first treatment and overall survival in this series. Importantly, these results could be confirmed in the independent multicentric CLL1 cohort of untreated Binet stage A patients (nâ=â163). Here, multivariate analysis of time to first treatment revealed that high risk Pgrn (HRâ=â2.06, 95%-CIâ=â1.13-3.76, pâ=â0.018), unmutated IGHV status (HRâ=â5.63, 95%-CIâ=â3.05-10.38, p<0.001), high risk as defined by the study protocol (HRâ=â2.06, 95%-CIâ=â1.09-3.89, pâ=â0.026) but not poor risk cytogenetics were independent prognostic markers. In summary our results suggest that Pgrn is a novel, robust and independent prognostic marker in CLL that can be easily measured by ELISA.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Pronóstico , ProgranulinasRESUMEN
Abstract We recently identified the marginal zone B and B1 cell-specific protein (MZB1) as part of a gene expression signature associated with outcomes in chronic lymphocytic leukemia (CLL). MZB1 is important for B cell function as a key regulator of antibody secretion, calcium homeostasis and adhesion. Therefore, we analyzed the role of MZB1 expression levels in 139 patients with CLL using quantitative real-time polymerase chain reaction (qRT-PCR) and microarray data sets in CLL, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and acute myeloid leukemia (AML). High MZB1 expression was associated with inferior survival in CLL (hazard ratio [HR]: 1.63 [confidence interval (CI): 1.14-2.33], p = 0.007), FL (221286_s_at HR: 1.16 [CI: 0.98-1.37], p = 0.086; 223565_at: HR: 1.3 [CI: 1.1-1.61], p = 0.015) and DLBCL (221286_s_at: HR: 1.17 [CI: 1.06-1.3], p = 0.003; 223565_at: HR: 1.21 [CI: 1.08-1.35], p = 0.001). In DLBCL MZB1 expression was an additive prognostic marker in a multivariate model including activated B-cell like (ABC) versus germinal center (GCB) subtype. Additionally, MZB1 expression correlated with a unique gene expression pattern. This study is the first to show that the expression level of a single gene has prognostic significance in different lymphoma subtypes. Due to its biological function, MZB1 may play a central role in B cell neoplasms and is a potential target for future therapeutic interventions.
Asunto(s)
Citocinas/genética , Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/genética , Transcriptoma , Proteínas Adaptadoras Transductoras de Señales , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/mortalidad , Mieloma Múltiple/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , PronósticoRESUMEN
Advanced-stage follicular lymphoma has previously been described as an incurable disease. However, the introduction of monoclonal antibodies such as rituximab has considerably changed the management of the disease in the last decade with a significant subset of patients remaining in remission for a decade or longer. Rituximab, a CD20-targeting antibody, is approved for treatment both upfront and in the relapse setting. The most dramatic impact of this antibody is observed in combinations with conventional chemotherapy regimens. Encouraging results have also been reported from radiolabeled anti-CD20 antibodies. High response rates and durable remissions have been seen with both (90)Y-ibritumomab tiuxetan and (131)I-tositumomab. However, refractoriness to immunochemotherapy still remains a problem, especially in relapsed disease. Several novel targeted agents show encouraging activity in follicular lymphoma. This review will focus on current treatment strategies in this disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Linfoma Folicular/patología , Inducción de Remisión , RituximabAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Diagnóstico Diferencial , Resultado Fatal , Hemianopsia/inducido químicamente , Hemianopsia/diagnóstico , Humanos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Masculino , Rituximab , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
PURPOSE: Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. PATIENTS AND METHODS: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. RESULTS: ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. CONCLUSION: There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.
Asunto(s)
Biomarcadores de Tumor/genética , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Eliminación de Gen , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteína Tirosina Quinasa ZAP-70/genética , Biomarcadores de Tumor/análisis , Citometría de Flujo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Análisis de Secuencia de ADN , Análisis de Supervivencia , Proteína Tirosina Quinasa ZAP-70/análisisRESUMEN
The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.
Asunto(s)
Regulación Leucémica de la Expresión Génica/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteínas de Neoplasias/genética , Receptores de Antígenos de Linfocitos B/genética , Apoptosis/genética , Ciclo Celular/genética , Estudios de Cohortes , Humanos , Cadenas Pesadas de Inmunoglobulina/metabolismo , Región Variable de Inmunoglobulina/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos/genética , Proteínas de Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal/genéticaRESUMEN
In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (V(H)) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V(H) mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q-, +8q, 11q-, +12q, 13q-, t(14q), 17p-) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V(H) mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (P(cor)) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% V(H) homology (95% confidence interval [CI], 96%-98% homology, P(cor) <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, P(cor) =.02). In univariate analyses, unmutated V(H) genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in the V(H) unmutated and V(H) mutated subgroups. High-risk genomic aberrations such as 17p- and 11q- occurred almost exclusively in the V(H) unmutated subgroup, whereas favorable aberrations such as 13q- and 13q- as single abnormalities were overrepresented in the V(H) mutated subgroup. In multivariate analysis, unmutated V(H), 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of V(H) mutation status and genomic aberrations to predict outcome in CLL.