RESUMO
Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral Tcell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous Bcell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large Bcell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.
Assuntos
Linfoma de Células B/terapia , Linfoma não Hodgkin/terapia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Linfoma , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Linfoma Cutâneo de Células T/mortalidade , Micose Fungoide/mortalidade , Síndrome de Sézary/mortalidade , Neoplasias Cutâneas/mortalidade , Taxa de SobrevidaRESUMO
Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.
Assuntos
Antineoplásicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Linfoma de Células B/terapia , Neoplasias Cutâneas/terapia , Administração Cutânea , Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bexaroteno/uso terapêutico , Borrelia burgdorferi , Ciclofosfamida/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Gerenciamento Clínico , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Humanos , Injeções Intralesionais , Doença de Lyme/tratamento farmacológico , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Mecloretamina/uso terapêutico , Polietilenoglicóis/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on safety and efficacy of autologous CD19-targeted CAR T-cells for these patients; here we report safety and long-term follow-up of CAR T-cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B-cell non-Hodgkin lymphoma (B-NHL). METHODS: We conducted a phase 1 clinical trial investigating CD19-targeted CAR T-cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of 20 patients received conditioning chemotherapy prior to CAR T-cell infusion. Five patients with CLL received ibrutinib at the time of autologous T-cell collection and/or CAR T-cell administration. RESULTS: This analysis included 16 patients with R/R CLL and 4 patients with R/R indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients but grades 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T-cells and proportions of CD4+/CD8+ CAR T-cells with CD62L+CD127+ immunophenotype were significantly greater in patients on ibrutinib at leukapheresis. Three of 12 evaluable CLL patients receiving conditioning chemotherapy achieved CR (two had minimal residual disease-negative CR). All patients achieving CR remained progression-free at median follow-up of 53 months. CONCLUSION: Conditioning chemotherapy and 19-28z CAR T-cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with R/R CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. Ibrutinib therapy may modulate autologous T-cell phenotype. TRIAL REGISTRATION: ClinicalTrials.gov NCT00466531. FUNDING: Juno Therapeutics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Síndrome da Liberação de Citocina/epidemiologia , Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/terapia , Recidiva Local de Neoplasia/terapia , Condicionamento Pré-Transplante/métodos , Adenina/análogos & derivados , Adulto , Idoso , Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Síndrome da Liberação de Citocina/imunologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Linfoma de Células B/imunologia , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/imunologia , Piperidinas , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Receptores de Antígenos Quiméricos/imunologia , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodosRESUMO
Therapeutic progress in primary cutaneous lymphomas continues to be largely dominated by the T-cell lymphomas, towards which the great majority of recent therapeutic innovations have been directed. The latter include local treatments consisting either of relatively classical but "revamped" approaches involving different pharmaceutical forms (example: chlormethine gel) or else lower but seemingly equally effective dosages (electron therapy), or of more innovative approaches (example: UVA-1, dynamic phototherapy, imiquimod, resimiquimod). However, significant progress has been made chiefly in terms of systemic treatments with the emergence of "targeted" drugs that directly and specifically target tumour cells (monoclonal antibodies directed against CD30, CCR4 or CD158k) and the further development of "small" molecules such as histone deacetylase inhibitors and new cytostatics. Immunotherapies, which have proven so effective in other areas of oncodermatology, are also of great interest, while allogeneic haematopoietic stem-cell transplantation has clearly shown its superiority over autologous transplantation and now constitutes a significant component of the therapeutic arsenal in advanced disease. While the innovations in terms of B-cell lymphomas are certainly less significant, mention must also be made of the value of rituximab combined with polychemotherapy (CHOP) and of lenalidomide (as second-line therapy) in primary cutaneous diffuse large B-cell lymphoma, leg type, along with the development of localized (very) low-dose radiotherapy in unilesional or paucilesional indolent forms.
Assuntos
Linfoma Cutâneo de Células T/terapia , Neoplasias Cutâneas/terapia , Alemtuzumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin , Transplante de Células-Tronco Hematopoéticas , Histona Desacetilase 1/antagonistas & inibidores , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Linfoma de Células B/terapia , Terapia de Alvo Molecular , Fototerapia , Rituximab/uso terapêuticoRESUMO
TITLE: Linfoma B intravascular hipotalamico en una paciente inmunocompetente.
Assuntos
Hipotálamo/irrigação sanguínea , Linfoma de Células B/patologia , Neoplasias Vasculares/patologia , Idoso , Terapia Combinada , Confusão/etiologia , Irradiação Craniana , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Hipotireoidismo/etiologia , Imunocompetência , Linfoma de Células B/complicações , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/terapia , Invasividade Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transtornos do Sono do Ritmo Circadiano/etiologia , Neoplasias Vasculares/complicações , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/terapia , Vasopressinas/deficiência , Redução de PesoRESUMO
BACKGROUND: Tumor immunotherapy with chimeric antigen receptor-T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening. CASE PRESENTATION: A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1 × 106/kg of engineered anti-CD19 CAR-T cells was administered. After infusion of CAR-T cells (day 0), the patient underwent a typical CRS reaction, with increases in fever, muscle soreness, and inflammatory cytokines. He was treated with antiallergic and antipyretic drugs, glucocorticoids, and tocilizumab (4 mg/kg, days 3 and 5). However, CRS was not under control, and his condition rapidly deteriorated. He was transferred to the intensive care unit, where dexamethasone 10 mg q6h was administered, and plasma exchange was performed, with 3,000 mL of plasma replaced by fresh frozen plasma per day for 3 consecutive days. His symptoms gradually improved, and the CRS-related symptoms were relieved. Additionally, a bone marrow smear showed no lymphoblast cells, and minimal residual disease was negative on day 28. The patient was eventually discharged in a normal condition. CONCLUSIONS: CRS is caused by an exaggerated systemic immune response, potentially resulting in organ damage that can be fatal. Although therapeutic plasma exchange is not included in CRS management guidelines, this case shows that plasma exchange is feasible in at least some patients with severe CRS.
Assuntos
Síndrome da Liberação de Citocina/terapia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adulto , Antígenos CD19/sangue , Antígenos CD19/uso terapêutico , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Citocinas/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imunoterapia Adotiva/métodos , Linfoma de Células B/sangue , Linfoma de Células B/patologia , Masculino , Troca Plasmática/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
ANTECEDENTES Y OBJETIVO: Los linfomas primarios cutáneos son enfermedades poco frecuentes. Este artículo describe el Registro de linfomas cutáneos primarios de la AEDV y sus primeros resultados. PACIENTES Y MÉTODOS: Registro de enfermedad de pacientes con linfomas cutáneos primarios. Los centros participantes recogieron datos prospectivamente de todos los pacientes, incluyendo datos del diagnóstico, de los tratamientos, de las pruebas realizadas y del estado actual del paciente. Se realizó un análisis descriptivo. RESULTADOS: En diciembre del 2017 el registro tenía datos de 639 pacientes pertenecientes a 16 hospitales universitarios. Un 60% eran hombres y los diagnósticos, por orden de frecuencia, fueron: micosis fungoide/síndrome de Sézary (MF/SS) (348 casos; 55%), linfoma cutáneo primario de células B (LCCB) (184; 29%), trastorno linfoproliferativo de células T CD30+ (LTCD30+) (70; 11%) y otro tipo de linfoma T (OLT) (37; 5%). El número de casos incidentes recogidos durante el primer año fue de 105 (16,5%). En los pacientes con MF/SS, el diagnóstico más frecuente fue MF clásica (77,3%). La mitad de estos casos se diagnosticaron en estadio IA. La mayoría de los pacientes estaban en remisión parcial (32,5%) o enfermedad estable (33,1%). Los tratamientos más usados fueron los corticoides tópicos (90,8%) seguidos de fototerapia. En los pacientes con LCCB el diagnóstico más frecuente fue el linfoma de la zona marginal (50%). Casi todos los pacientes tuvieron afectación exclusivamente cutánea y casi la mitad fue T1a. La mayoría (76,1%) estaba en remisión completa. Los tratamientos más utilizados fueron la cirugía (55,4%) y la radioterapia (41,9%). En los pacientes con LTCD30+, el diagnóstico más frecuente fue la papulosis linfomatoide (68,6%). La mayoría fueron clasificados T3b (31,4%). La mitad de los casos estaban en remisión completa. Los tratamientos más frecuentes fueron los esteroides tópicos (68,6%), seguidos de la quimioterapia sistémica (32,9%). CONCLUSIÓN: Las características del paciente con linfoma cutáneo primario en España no difieren de otras series descritas en la literatura. El registro facilitará al grupo de linfomas de la AEDV realizar investigación clínica
BACKGROUND AND OBJECTIVE: Primary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. PATIENTS AND METHODS: Disease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. RESULTS: In December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical coricosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). CONCLUSION: The characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma de Células B/epidemiologia , Linfoma Cutâneo de Células T/epidemiologia , Sistema de Registros , Neoplasias Cutâneas/epidemiologia , Bases de Dados Factuais , Linfoma de Células B/terapia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Papulose Linfomatoide/diagnóstico , Papulose Linfomatoide/epidemiologia , Estudos Prospectivos , Espanha/epidemiologiaRESUMO
BACKGROUND AND OBJECTIVE: Primary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. PATIENTS AND METHODS: Disease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. RESULTS: In December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical corticosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). CONCLUSION: The characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group.
Assuntos
Linfoma de Células B/epidemiologia , Linfoma Cutâneo de Células T/epidemiologia , Sistema de Registros , Neoplasias Cutâneas/epidemiologia , Bases de Dados Factuais , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Linfoma Anaplásico de Células Grandes/epidemiologia , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Papulose Linfomatoide/diagnóstico , Papulose Linfomatoide/epidemiologia , Estudos Prospectivos , Espanha/epidemiologiaRESUMO
Primary cutaneous Bcell lymphomas are rarely encountered and represent 25% of all cutaneous lymphomas. Follicular Bcell lymphoma and marginal zone lymphoma belong to indolent subtypes which as a rule have no systemic dissemination and, thus, a mostly unchanged life expectancy. Therefore, skin-directed treatment options such as excision or radiotherapy are usually sufficient to control the disease. In contrast, cutaneous diffuse large Bcell lymphoma and EBV-associated Bcell lymphomas of the skin belong to more aggressive entities which demand a systemic first-line upfront therapy with RCHOP. Nevertheless, mortality is still high and comparable to that of systemic/nodal large Bcell lymphomas so that the identification of pathogenetic driver mutations or novel therapeutic targets may pave the way to better target-oriented therapies.
Assuntos
Linfoma de Células B/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Imunoterapia , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Pele/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de SobrevidaRESUMO
Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.
Assuntos
Linfoma de Células B/etiologia , Linfoma de Células B/terapia , Animais , Dano ao DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/microbiologia , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/genética , Linfoma de Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/etiologia , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/microbiologia , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma Folicular/etiologia , Linfoma Folicular/genética , Linfoma Folicular/microbiologia , Linfoma Folicular/terapia , Terapia de Alvo Molecular/métodos , Mutação , Transdução de SinaisRESUMO
Near infrared photoimmunotherapy (NIR-PIT) is a new, highly-selective cancer theranostics that employs an antibody-photo absorber conjugate (APC). NIR-PIT has successfully treated preclinical tumor models with APCs and is now in the first-in-human phase 1 clinical trial for head and neck cancer patients against EGFR. CD20 is highly expressed in many B-cell lymphomas and is emerging as a molecular target for this disease. Here, we describe the use of the anti-CD20 monoclonal antibody (mAb), rituximab-IR700 APC for NIR-PIT of B-cell lymphoma in two CD20-expressing lymphoma mouse models. CD20 expressing B-cell lymphoma cell lines (Daudi and Ramos) were used in this study. Rituximab-IR700, rituximab conjugated with IRDye700DX, showed specific binding, and cell-specific killing only after exposure of NIR light to both cells in vitro. To evaluate effects of NIR-PIT in vivo, tumor-bearing mice were separated into 4 groups: (1) control; (2) APC i.v. only; (3) NIR light exposure only; (4) APC and NIR light (NIR-PIT). These were performed every week for up to 3 weeks. Rituximab-IR700 showed high tumor accumulation and high target-to-background ratio in vivo. Tumor growth was significantly inhibited by NIR-PIT in comparison with the other groups (p < 0.001 for both tumors), and survival was significantly prolonged in both tumors (p < 0.001 for Daudi tumors and p < 0.0001 for Ramos tumors vs other groups). More than half of tumors were cured with this single regimen of NIR-PIT. In conclusion, anti-CD20 rituximab-IR700 works as a highly effective APC for NIR-PIT against B-cell lymphoma.
Assuntos
Imunoterapia , Raios Infravermelhos , Linfoma de Células B/terapia , Fototerapia , Animais , Antígenos CD20/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Linfoma de Células B/patologia , Camundongos Nus , Microscopia de Fluorescência , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours. METHODS: Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively. RESULTS: The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%). CONCLUSIONS: These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.
Assuntos
Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Neoplasias Abdominais/tratamento farmacológico , Neoplasias Abdominais/terapia , Polipose Adenomatosa do Colo/tratamento farmacológico , Polipose Adenomatosa do Colo/terapia , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/terapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Extremidades , Fibromatose Agressiva/tratamento farmacológico , Fibromatose Agressiva/terapia , Tumores de Células Gigantes/tratamento farmacológico , Tumores de Células Gigantes/terapia , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/terapia , Melfalan/uso terapêutico , Perfusão , Doenças Raras/tratamento farmacológico , Doenças Raras/terapia , Sinovite Pigmentada Vilonodular/tratamento farmacológico , Sinovite Pigmentada Vilonodular/terapia , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is the standard therapy for patients with chemosensitive-relapsed or chemosensitive-refractory aggressive lymphoma. The use of rituximab, an anti-CD20 monoclonal antibody, has dramatically changed the outcome of patients with aggressive lymphoma, increasing both response and survival rates. However, despite this progress a significant proportion of patients are still refractory or relapse after frontline rituximab-containing therapy. Moreover, it is increasingly more difficult to rescue these patients with current salvage chemotherapy and ASCT approaches. Novel approaches are needed for these high-risk patients, especially in the rituximab era. Radioimmunotherapy (RIT) is a form of targeted therapy using the parent monoclonal antibody to deliver radiation emitted by a conjugated radioisotope, to the vicinity of antigen-positive tissues. Two radioimmunoconjugates--yttrium-90 ibritumomab tiuxetan (Zevalin) and iodine-131 tositumomab (Bexxar) have been in clinical use. There are multiple studies demonstrating the safety and efficacy of both agents in both indolent and aggressive lymphoma. Radiolabeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. RIT targets radiation to disease sites while limiting exposure of uninvolved critical organs, thus it can safely replace total-body irradiation during conditioning for ASCT. The major toxicity and limiting factor in RIT is myelotoxicity that is easily reversed by stem-cell rescue. RIT can be combined at standard doses with high-dose chemotherapy or can be given in escalated doses either alone or with high-dose chemotherapy before ASCT. Several phase II studies have shown the safety and potential efficacy of both agents using these approaches. A small randomized study comparing standard-dose Zevalin with combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) high-dose chemotherapy and BEAM alone suggested a survival advantage of Zevalin-BEAM. However, a large randomized study comparing Bexxar-BEAM and rituximab-BEAM did not show any advantage. More studies are needed to establish the role and the dose of RIT given for ASCT.
Assuntos
Linfoma de Células B/terapia , Radioimunoterapia/métodos , Transplante de Células-Tronco/métodos , Humanos , Linfoma de Células B/radioterapia , Linfoma de Células B/cirurgia , Dosagem Radioterapêutica , Transplante AutólogoRESUMO
The present study was performed to examine the induction of apoptotic cell death and autophagy by blue LED irradiation, and the contribution of autophagy to apoptosis in B cell lymphoma A20 and RAMOS cells exposed to blue LED. Irradiation with blue LED reduced cell viability and induced apoptotic cell death, as indicated by exposure of phosphatidylserine on the plasma outside membrane and fragmentation of DNA. Furthermore, the mitochondrial membrane potential increased, and apoptotic proteins (PARP, caspase 3, Bax, and bcl-2) were observed. In addition, the level of intracellular superoxide anion (O2(-)) gradually increased. Interestingly the formation of autophagosomes and level of LC3-II were increased in blue LED-irradiated A20 and RAMOS cells, but inhibited after pretreatment with 3-methyladenine (3-MA), widely used as an autophagy inhibitor. Inhibition of the autophagic process by pretreatment with 3-MA blocked blue LED irradiation-induced caspase-3 activation. Moreover, a significant reduction of both the early and late phases of apoptosis after transfection with ATG5 and beclin 1 siRNAs was shown by the annexin V/PI staining, indicating a crucial role of autophagy in blue LED-induced apoptosis in cells. Additionally, the survival rate of mice irradiated with blue LED after injection with A20 cells increased compared to the control group. Our data demonstrate that blue LED irradiation induces apoptosis via the mitochondrial-mediated pathway, in conjunction with autophagy. Further studies are needed to elucidate the precise mechanism of blue LED-induced immune cell death.
Assuntos
Autofagia/efeitos da radiação , Linfócitos B/efeitos da radiação , Linfoma de Células B/terapia , Mitocôndrias/efeitos da radiação , Fototerapia/métodos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos da radiação , Linfócitos B/metabolismo , Linfócitos B/patologia , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos da radiação , Feminino , Humanos , Luz , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Potencial da Membrana Mitocondrial/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/metabolismo , Transplante de Neoplasias , Fagossomos/metabolismo , Fagossomos/efeitos da radiação , Fototerapia/instrumentação , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Superóxidos/agonistas , Superóxidos/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Multi-agent chemotherapy is the standard treatment for most B cell malignancies. Since chemotherapy can be associated with significant toxicity and since relapses resistant to chemotherapy often develop, new therapies are needed. Blinatumomab (AMG 103 or MT103) is a late-stage candidate in clinical development, which belongs to a novel class of antibody constructs termed bi-specific T cell engager antibodies. This antibody construct has dual specificity for CD19 and CD3 and can re-direct polyclonal cytotoxic T lymphocytes toward the tumor. This review focuses on the pre-clinical and clinical development of blinatumomab as a powerful new tool in the treatment of B cell malignancies.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Linfoma de Células B/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Complexo CD3/imunologia , Ensaios Clínicos como Assunto , Citotoxicidade Imunológica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfoma de Células B/imunologia , Terapia de Alvo MolecularRESUMO
The first Japanese edition of guidelines for management of cutaneous lymphoma was published jointly in 2009 by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) - Lymphoma Study Group; the guidelines were revised in 2011, and published in English in 2013. The JDA/JSCS guidelines are unique because they describe information and management practices for lymphomas specific to Asia, such as adult T-cell leukemia/lymphoma and extranodal natural killer/T-cell lymphoma, nasal type. In the present article, we have highlighted the essential points of management for cutaneous lymphomas in Asia. In order to complement the guidelines, we have added further information and our clinical experience of some currently available agents for cutaneous lymphomas in Japan.
Assuntos
Linfoma de Células T/terapia , Neoplasias Cutâneas/terapia , Humanos , Linfoma de Células B/terapia , Guias de Prática Clínica como AssuntoRESUMO
This study reports the case of a 47-year old female with low back pain radiating to groin and anterior regions of the left thigh and leg. At symptoms onset, electromyography showed left L3-L4 radiculopathy, and nuclear magnetic resonance revealed disc protrusion at the same level with impingement of the spinal nerve root. The clinical symptoms were ascribed to lumbar disco-radicular conflict. The patient underwent steroidal anti-inflammatory treatment with epidural steroid injections, chiropractic spinal manipulations and rehabilitation program, with no relief. Thirteen months after the onset of pain, a computed tomography of sacroiliac joints showed osteolytic lesion in the iliac bone of left joint, and a bone scintigraphy highlighted foci of intense uptake at left iliac bone and left proximal extremity of the femur. The bone biopsy and pathological examinations showed findings consistent with large B-cell non-Hodgkin lymphoma. This case report highlights the fact that in making differential diagnosis of low back pain radiating to the leg we have to consider the rare possibility that pain can be due to non-Hodgkin lymphoma that involves simultaneously the iliac bone and proximal extremity of the femur.
Assuntos
Deslocamento do Disco Intervertebral/complicações , Dor Lombar/etiologia , Vértebras Lombares/patologia , Linfoma de Células B/complicações , Osteólise/etiologia , Ciática/etiologia , Aminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Ácidos Cicloexanocarboxílicos/uso terapêutico , Ciclofosfamida , Diagnóstico Tardio , Diagnóstico Diferencial , Doxorrubicina , Feminino , Gabapentina , Humanos , Dor Lombar/terapia , Linfoma de Células B/diagnóstico , Linfoma de Células B/terapia , Manipulação Quiroprática , Pessoa de Meia-Idade , Osteólise/diagnóstico por imagem , Prednisona , Radiografia , Indução de Remissão , Ciática/diagnóstico , Ciática/terapia , Vincristina , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
BACKGROUND: Radioimmunotherapy (RIT) has been used to treat relapsed/refractory CD20+ Non-Hodgkin lymphoma (NHL). Myeloablative anti-CD20 RIT followed by autologous stem cell infusion (ASCT) enables high radiation doses to lymphoma sites. We performed a phase I/II trial to assess feasibility and survival. METHODS: Twenty-three patients with relapsed/refractory NHL without complete remission (CR) to salvage chemotherapy were enrolled to evaluate RIT with Iodine-131 labelled rituximab (131I-rituximab) in a myeloablative setting. Biodistribution and dosimetric studies were performed to determine 131I activity required to induce a total body dose of 21-27Gy to critical organs. In 6/23 patients RIT was combined with high-dose chemotherapy. 8/23 patients received a sequential high-dose chemotherapy with a second ASCT. The median follow-up is 9.5 years. RESULTS: 6.956-19.425GBq of 131I was delivered to achieve the limiting organ dose to lungs or kidneys. No grade III/IV non-hematologic toxicity was seen with RIT alone. Significant grade III/IV toxicity (mucositis, fever, infection, one therapy related death) was observed in patients treated with RIT combined with high-dose chemotherapy. The overall response rate was 87% (64% CR). The median progression-free (PFS) and overall survival (OS) is 47.5 and 101.5 months. An international prognostic index score >1 was predictive for OS. CONCLUSION: Myeloablative RIT with 131I-rituximab followed by ASCT is feasible, well-tolerated and effective in high risk CD20+ NHL. Combination of RIT and high-dose chemotherapy increased toxicity significantly. Long-term results for PFS and OS are encouraging.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/terapia , Radioimunoterapia/métodos , Adulto , Idoso , Anticorpos Monoclonais Murinos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Radioisótopos do Iodo/administração & dosagem , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Risco , Rituximab , Análise de Sobrevida , Transplante Autólogo/métodosRESUMO
BACKGROUND: Primary intestinal lymphoma in the setting of inflammatory bowel disease (IBD) is uncommon and may be associated with immune suppressive therapy. We report clinical features and outcomes in patients with both conditions prior to use of biologic therapy. METHODS: All patients with primary intestinal lymphoma and IBD at our institution from 1960-2000 were retrospectively identified. Data reported are frequency (proportion) or median (interquartile range). Kaplan-Meier analysis was performed. RESULTS: Fifteen patients were identified: 14 (93%) were male, 10 (66%) had Crohn's disease. Median age at diagnosis of IBD and lymphoma was 30 (22-51) and 47 (28-68) years, respectively, with bloody diarrhea the most common presenting symptom for each diagnosis. Lymphoma location was colorectal in nine (60%), small bowel in four (27%), and one (6.25%) each: stomach, duodenum, and ileal pouch. Treatments were surgery plus chemotherapy (n = 6), surgery alone (n = 3), chemotherapy alone (n = 2), chemotherapy and radiation (n = 1), surgery and radiation (n = 1); two patients died before treatment. Most patients (n = 11, 73%) were Ann Arbor stages I or II. Large cell B-type histology was most common (n = 9, 60%). Three patients died within 30 days of lymphoma diagnosis. Survival free of death from lymphoma at 1- and 5-years was 78% and 63%, respectively, and was associated with advanced lymphoma stage (P = 0.004). CONCLUSIONS: Diagnosis and treatment of primary intestinal lymphoma in patients with IBD can be challenging and requires a high index of suspicion. Optimal survival requires multimodality therapy.