RESUMO
Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.
Assuntos
Antígenos CD/fisiologia , Inibidores de Checkpoint Imunológico , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/fisiologia , Antígenos CD/biossíntese , Antígenos CD/genética , Linfócitos B/metabolismo , Variações do Número de Cópias de DNA , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Linfócitos do Interstício Tumoral/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Síndrome , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
Assuntos
Adenina/análogos & derivados , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Linfoma/tratamento farmacológico , Linfoma/mortalidade , Piperidinas/administração & dosagem , Adenina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Reino Unido/epidemiologiaRESUMO
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.
Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva , Fatores de RiscoRESUMO
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.
Assuntos
Macroglobulinemia de Waldenstrom/diagnóstico , Tirosina Quinase da Agamaglobulinemia , Idoso de 80 Anos ou mais , Humanos , Imunoglobulina M/metabolismo , Mutação/genética , Fator 88 de Diferenciação Mieloide/genética , Proteínas Tirosina Quinases/genética , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologiaRESUMO
PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Folicular , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diarreia/induzido quimicamente , Humanos , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Rituximab/uso terapêuticoRESUMO
Follicular lymphoma is the most common indolent non-Hodgkin lymphoma. Although median overall survival rates exceed 12 years with rituximab, follicular lymphoma remains largely incurable. The growing understanding of the molecular drivers of lymphomagenesis and the tumor microenvironment have led to novel therapies. Prognostic markers have identified a subset of patients with chemoresistant and/or refractory disease-associated poor outcomes. We identify the patients with follicular lymphoma in need of novel therapies, describe the drivers of lymphomagenesis and importance of the tumor microenvironment, and summarize the novel agents under investigation in relapsed/refractory and upfront follicular lymphoma.
Assuntos
Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Linfoma Folicular/etiologia , Linfoma Folicular/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Terapia de Alvo Molecular , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Recidiva , Retratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ipilimumab/efeitos adversos , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Humanos , Ipilimumab/administração & dosagem , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/imunologia , Melanoma/imunologia , Melanoma/secundário , Nivolumabe/administração & dosagem , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Esteroides/uso terapêutico , Resultado do TratamentoRESUMO
AIM: To determine whether the Aged Care Funding Instrument (ACFI) provides more funding than the Residential Classification Scale (RCS) for residents in the Hellenic Residential Care Facility. METHODS: All residents within the care facility were assessed over a six 6-month period using ACFI, RCS and Clifton Assessment Procedures for the Elderly (CAPE) scores. Differences in funding levels were calculated using ACFI and RCS instruments against a standardised CAPE score. RESULTS: CAPE dependency RCS funding per resident per day varied from $32.20 for grade A to $116.20 for grade E4 residents. CAPE ACFI funding varied from $20.20 for grade A to $127.50 for grade E4. There was no significant difference in mean overall funding between the two scales (ACFI $92.50 vs RCS $90.35, P = 0.76). CONCLUSIONS: The ACFI does provide a small but not significant increase in funding to residents in residential care. It redirects funding to higher dependency residents.