RESUMEN
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki-67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra-nodal involvement, blastoid or pleomorphic histology and high Ki-67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.
Asunto(s)
Antineoplásicos , Linfoma de Células B , Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/terapia , Linfoma de Células del Manto/tratamiento farmacológico , Antígeno Ki-67 , Antineoplásicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Progresión de la EnfermedadRESUMEN
BACKGROUND: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies. METHODS: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing. FINDINGS: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred. INTERPRETATION: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies. FUNDING: F Hoffmann-La Roche and Genentech.
Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Linfoma Folicular , Recurrencia Local de Neoplasia , Anticuerpos Biespecíficos/efectos adversos , Antineoplásicos/efectos adversos , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Positron emission tomography/computed tomography (PET/CT) is used for the staging of lymphomas. Clinical information, such as Ann Arbor stage and number of involved sites, is derived from baseline staging and correlates with tumour volume. With modern imaging software, exact measures of total metabolic tumour volumes (tMTV) can be determined, in a semi- or fully-automated manner. Several technical factors, such as tumour segmentation and PET/CT technology influence tMTV and there is no consensus on a standardized uptake value (SUV) thresholding method, or how to include the volumes in the bone marrow and spleen. In diffuse large B-cell lymphoma, follicular lymphoma, peripheral T-cell lymphoma, and Hodgkin lymphoma, tMTV has been shown to predict progression-free survival and/or overall survival, after adjustments for clinical risk scores. However, most studies have used receiver operating curves to determine the optimal cut-off for tMTV and many studies did not include a training-validation approach, which led to the risk of overestimation of the independent prognostic value of tMTV. The identified cut-off values are heterogeneous, even when the same SUV thresholding method is used. Future studies should focus on testing tMTV in homogeneously-treated cohorts and seek to validate identified cut-off values externally so that a prognostic value can be documented, over and above currently used clinical surrogates for tumour volume.
Asunto(s)
Linfoma de Células B Grandes Difuso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Humanos , Linfoma de Células B Grandes Difuso/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Pronóstico , Estudios Retrospectivos , Carga TumoralRESUMEN
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Disease progression or relapse following frontline chemoimmunotherapy, largely in the form of standard R-CHOP, occurs in 30-40% patients. Relapsed/refractory (R/R) DLBCL represents a major unmet medical need. In particular, patients with primary refractory disease or those whose lymphoma relapses after autologous stem cell transplantation have historically had poor outcomes.Material and methods: Chimeric antigen receptor T-cell (CART) therapy is a promising novel treatment with curative potential in this setting. CART is based on ex vivo genetic modification of autologous T-cells to express chimeric receptors targeting antigens highly expressed in tumors such as CD19 in DLBCL. After lymphocyte-depleting therapy, patients are infused with CARTs that expand in vivo and target CD19-positive lymphoma cells.Results: In initial phase I-II trials, investigators have demonstrated complete responses in 40-50% of patients with R/R DLBCL, resulting in durable remission approaching 3 years of follow-up in most of these patients without further treatment. The logistics of delivery are complex as cell products require timely long-distance transfer between hospitals and production facilities. The unique toxicity profile of CARTs, including the risk of fatal immunological and neurologic events, also requires specific hospital wide management approaches and education. The substantial direct and indirect costs of CART will limit access even in countries with well resourced health care systems.Conclusions: While only two products are commercially available at present, further approvals in coming years appear likely. Future directions include CARTs with reactivity to tumor antigens other than CD19 and products targeting multiple tumor antigens to overcome resistance. The availability of CART has altered the current treatment algorithm for R/R DLBCL, and indications will likely expand to earlier lines of therapy and other hematologic malignancies.
Asunto(s)
Antígenos CD19/uso terapéutico , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Antígenos CD19/efectos adversos , Antígenos CD19/economía , Productos Biológicos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Análisis Costo-Beneficio , Progresión de la Enfermedad , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/economía , Recurrencia , Insuficiencia del TratamientoRESUMEN
Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60 years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectively-assigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166 (23%) had chemotherapy delays and 26/198 (13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2·892, 95% confidence interval 1·275-6·559, P = 0·011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Evaluación Geriátrica/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Australia , Femenino , Anciano Frágil , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Rituximab/administración & dosificación , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
De novo diffuse large B-cell lymphoma (DLBCL) presenting with synchronous central nervous system (CNS) and systemic disease (synDLBCL) is not well described and is excluded from clinical trials. We performed a retrospective analysis of 80 synDLBCL patients treated across 10 Australian and UK centres. Of these patients, 96% had extranodal systemic disease. CNS-directed treatment with combination intravenous cytarabine and high-dose methotrexate ("CNS-intensive") (n = 38) was associated with favourable survival outcomes compared with "CNS-conservative" strategies such as intravenous high-dose methotrexate monotherapy, intrathecal therapy and/or radiotherapy (2-year progression-free survival [PFS] 50% vs. 31%, P = 0·006; 2-year overall survival [OS] 54% vs. 44%, P = 0·037). Outcomes were primarily dictated by the ability to control the CNS disease, with 2-year cumulative CNS relapse incidence of 42% and non-CNS relapse 21%. Two-year OS for CNS-relapse patients was 13% vs. 36% for non-CNS relapses (P = 0·02). Autologous stem cell transplantation as consolidation (n = 14) was not observed to improve survival in those patients who received CNS-intensive induction when matched for induction outcomes (2-year PFS 69% vs. 56%, P = 0·99; 2-year OS 66% vs. 56%, P = 0·98). Hyperfractionated or infusional systemic treatment did not improve survival compared to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (2-year OS 49% for both groups). Our study suggests that adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/mortalidad , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Reino Unido/epidemiologíaRESUMEN
Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis.
Asunto(s)
Neoplasias del Sistema Nervioso Central/terapia , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/terapia , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia , Factores de RiesgoRESUMEN
Nodular lymphocyte Hodgkin lymphoma (NLPHL) is a rare disease for which the optimal therapy is unknown. We hypothesized that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) could decrease rates of relapse and transformation. We retrospectively reviewed patients with NLPHL diagnosed between 1995 and 2015 confirmed by central pathologic review. Fifty-nine had sufficient treatment and follow-up data for analysis. We described progression-free survival (PFS), overall survival (OS), and histologic transformation according to treatment strategy and explored prognostic factors for PFS and OS. The median age at diagnosis was 41 years; 75% were male, and 61% had a typical growth pattern. Twenty-seven patients were treated with R-CHOP with an overall response rate of 100% (complete responses 89%). The median follow-up was 6.7 years, and the estimated 5- and 10-year PFS rates for patients treated with R-CHOP were 88.5% (95% confidence interval [CI], 68.4% to 96.1%) and 59.3 (95% CI, 25.3% to 89.1%), respectively. Excluding patients with histologic transformation at diagnosis, the 5-year cumulative incidence of histologic transformation was 2% (95% CI, 87% to 100%). No patient treated with R-CHOP experienced transformation. A high-risk score from the German Hodgkin Study Group was adversely prognostic for OS (P = .036), whereas male sex and splenic involvement were adversely prognostic for PFS (P = .006 and .002, respectively) but not OS. Our data support a potential role for R-CHOP in patients with NLPHL. Larger prospective trials are needed to define the optimal chemotherapy regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Retrospectivos , Rituximab , Tasa de Supervivencia , Factores de Tiempo , Vincristina/administración & dosificaciónRESUMEN
Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant-eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant-eligible patients to assess impact of induction chemoimmunotherapy and conditioning regimens on clinical outcomes. We identified 228 patients meeting inclusion criteria. Baseline characteristics were similar among the induction groups except for some variation in age. The type of induction chemoimmunotherapy received did not influence overall response rates (ORRs) (0.43), progression-free survival (PFS) (P > .67), or overall survival (OS) (P > .35) on multivariate analysis (PFS and OS). Delivery of autologous stem cell transplant (ASCT) was associated with favorable PFS and OS (0.01) on univariate analysis only; this benefit was not seen on multivariate analysis-PFS (0.36) and OS (0.21). Compared with busulfan and melphalan (BuMel), the use of the carmustine, etoposide, cytarabine, melphalan (BEAM)-conditioning regimen was associated with inferior PFS (HR = 2.0 [95% CI 1.1-3.6], 0.02) but not OS (HR = 1.1 [95% CI 0.5-2.3], 0.81) on univariate analysis only. Within the limits of a retrospective study and modest power for some comparisons, type of induction therapy did not influence ORR, PFS, or OS for transplant-eligible patients with MCL. International efforts are required to perform randomized clinical trials evaluating chemoimmunotherapy induction regimens.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Inmunoterapia/métodos , Quimioterapia de Inducción/métodos , Linfoma de Células del Manto/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/uso terapéutico , Citarabina/uso terapéutico , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Etopósido/uso terapéutico , Femenino , Humanos , Cooperación Internacional , Linfoma de Células del Manto/mortalidad , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inducción de Remisión , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
Stage I non-Hodgkin lymphoma (NHL) is rare; prognostic impact of different histologic subtypes and treatment modality is still unclear. We used the Surveillance, Epidemiology and End Results (SEER) database to evaluate survival outcomes among adult patients (age ≥ 18 years, N = 58,230) diagnosed with stage I NHL of various histologic subtypes between 1998 and 2014. Five-year disease-specific survival of patients with stage I diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL), and peripheral T cell lymphoma (PTCL) was 82%, 92%, 95%, 89%, 78%, 77%, and 77%, respectively. The median disease-specific survival was not reached in all histologic subtypes analyzed; however, there does not appear to be a plateau in disease-specific survival of patients with stage I NHL irrespective of subtypes. Although lymphoma was the most common cause of death (40.7%), death from other cancer (17.4%) and cardiovascular disease (13.6%) were also frequent. Chemotherapy appeared favorably associated with OS in patients with DLBCL, BL, and MCL while patients with FL, MZL, SLL, and PTCL who require chemotherapy for initial treatment showed shorter OS. Patients with stage I NHL have favorable disease-specific survival; however, no plateau was seen regardless of histologic subtypes thus suggesting that patients may need attention and follow-up even in aggressive lymphomas after 5 years of remission.
Asunto(s)
Bases de Datos Factuales , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
Inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway as an anticancer therapeutic strategy was realized with the approval of the orally bioavailable small molecule PI3Kδ inhibitor idelalisib. In this focused review, we highlight the rationale for targeting the pathway in lymphomas, provide a brief summary of the preclinical data, and describe the clinical experience with this agent in patients with lymphoma. We describe some of the idiosyncratic toxicities of this agent, some of the mechanisms of resistance, and some of the ongoing combination strategies.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Linfoma/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/efectos adversos , Humanos , Linfoma/enzimología , Linfoma/patología , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Purinas/efectos adversos , Quinazolinonas/efectos adversosRESUMEN
The application of molecular genomics and our understanding of its clinical implications in the diagnosis, prognostication and treatment of lymphoproliferative disorders has rapidly evolved over the past few years. Of particular importance are indolent B-cell malignancies where tumour cell survival and proliferation are commonly driven by mutations involving the B-cell receptor and downstream signalling pathways. In addition, the increasing number of novel therapies and targeted agents have provided clinicians with new therapeutic options with the aim of exploiting such mutations. In this case report, we highlight one such success story involving the diagnostic impact of the MYD88L265P mutation in Waldenstrom's macroglobulinemia (WM), its prognostic implications and effect on choice of therapy in the era of novel therapies.
Asunto(s)
Macroglobulinemia de Waldenström/diagnóstico , Agammaglobulinemia Tirosina Quinasa , Anciano de 80 o más Años , Humanos , Inmunoglobulina M/metabolismo , Mutación/genética , Factor 88 de Diferenciación Mieloide/genética , Proteínas Tirosina Quinasas/genética , Macroglobulinemia de Waldenström/metabolismo , Macroglobulinemia de Waldenström/patologíaRESUMEN
The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11-12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents.
Asunto(s)
Linfocitos B/patología , Leucemia de Células B/etiología , Leucemia de Células B/patología , Linfoma de Células B/etiología , Linfoma de Células B/patología , Microambiente Tumoral , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Leucemia de Células B/diagnóstico , Leucemia de Células B/terapia , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Terapia Molecular Dirigida , Clasificación del Tumor , Estadificación de Neoplasias , Transducción de Señal , Escape del Tumor/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Double hit lymphomas (DHL) represent a subset of highly aggressive B-cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting MYC and either BCL2 and/or BCL6. Recent studies have expanded the concept to include MYC/BCL2 protein co-expressing lymphomas. Around 5-10% of diffuse large B-cell lymphomas are 'double hit' using the cytogenetic definition, whilst around 30-40% are MYC/BCL2 protein co-expressing. In this review, we provide a comprehensive overview of this condition written with the practicing clinician in mind, covering the definition and classification, when DHL should be suspected and how to make the diagnosis, the prognostic factors and a detailed discussion of recent evidence regarding optimal therapy. In particular, we discuss choice of induction regimen, the role of central nervous system-directed prophylaxis, stem cell transplantation and relapsing or refractory disease and provide our opinions based on the currently available evidence. Finally, we highlight some of the more exciting therapies currently in development for this highly aggressive disease.
Asunto(s)
Linfoma de Células B/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Reordenamiento Génico de Linfocito B , Genes bcl-2/genética , Genes myc/genética , Humanos , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/terapia , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
PURPOSE OF REVIEW: The development of 'immune checkpoint inhibitors' or drugs targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been a stunning success of cancer immunotherapy. This review provides a timely overview of the biology and function of the PD-1 pathway and discusses the rationale for therapeutic inhibition of this pathway in lymphoma. RECENT FINDINGS: Recent studies have evaluated the prevalence and prognostic implications of PD-1, PD-L1/2 expression in various lymphoma subtypes. We present an overview of the clinical trials evaluating pidilizumab, nivolumab, and pembrolizumab in patients with lymphoid malignancies, and highlight some of the more promising agents in this class, currently in development. Finally, we discuss biomarkers that may predict response to therapy in patients with lymphoma across these clinical trials. SUMMARY: A plethora of clinical trials are in progress testing immune checkpoint inhibitors in many subtypes of lymphoma, which will define their role both as a monotherapy and in combination with other biologic agents.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunoterapia , Linfoma/tratamiento farmacológico , Terapia Molecular Dirigida , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Anticuerpos Monoclonales , Antígeno B7-H1/inmunología , Biomarcadores/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma/genética , Linfoma/inmunología , Nivolumab , Pronóstico , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Linfocitos T/metabolismoRESUMEN
Secondary central nervous system (CNS) progression in patients with non-Hodgkin lymphoma (NHL) is associated with a particularly poor prognosis. In this review, we summarize and critically evaluate the current literature to guide the practicing clinician in estimating CNS relapse risk in order to select individual patients who may benefit from CNS prophylaxis, covering histologic subtype, anatomic location, and molecular and clinical factors. We summarize the data regarding different prophylaxis strategies used and provide our recommendation regarding who should receive it, what they should receive, and when it should be administered.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/prevención & control , Neoplasias del Sistema Nervioso Central/secundario , Humanos , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/prevención & control , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.
Asunto(s)
Anticuerpos Biespecíficos , Linfoma de Células B Grandes Difuso , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Resistencia a Antineoplásicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.