RESUMO
While the bone marrow (BM) microenvironment is significantly remodelled in acute myeloid leukaemia (AML), molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma. We assessed the effect of anthracycline- and cytarabine-based induction chemotherapy on both haematopoietic and non-haematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis. We compared matched human core BM biopsies at diagnosis and 2 weeks after cytarabine- and anthracycline-based induction therapy in responders (<5% blasts present after treatment) and non-responders (≥5% blasts present after treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2 (SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1) and osteonectin (SPARC) was observed in non-responders. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimised therapeutic strategies for AML.
Assuntos
Medula Óssea , Leucemia Mieloide Aguda , Humanos , Medula Óssea/patologia , Transcriptoma , Leucemia Mieloide Aguda/tratamento farmacológico , Citarabina/uso terapêutico , Células da Medula Óssea/patologia , Antraciclinas/uso terapêutico , Biópsia , Microambiente TumoralRESUMO
BACKGROUND: We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma. METHODS: Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). RESULTS: Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died. CONCLUSION: Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Cloridrato de Bendamustina/uso terapêutico , Humanos , Íleus/induzido quimicamente , Lipossomos , Linfoma de Células B/tratamento farmacológico , Linfopenia , Neutropenia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)-based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.
Assuntos
Linfoma de Células B , Linfoma não Hodgkin , Biomarcadores , Sistema Nervoso Central , DNA , HumanosAssuntos
Neoplasias dos Ductos Biliares/virologia , Colangiocarcinoma/virologia , Hepacivirus , Hepatite C/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Antivirais/uso terapêutico , Evolução Fatal , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/complicações , Tempo para o TratamentoRESUMO
Clinical trials comparing bendamustine/rituximab (BR) with cyclophosphamide-based regimens (RCHOP/RCVP) have pooled various histologies of indolent B-cell lymphomas. We examined real-life outcomes of older patients with follicular (FL), mantle cell (MCL), or marginal zone/lymphoplasmacytic lymphoma (MZL/LPL), treated with these first-line regimens. We identified Medicare beneficiaries with FL, MCL, or MZL/LPL, who received either first-line BR or RCHOP/RCVP in 2009-2016, and matched groups using a propensity score. Outcomes of claims-based event-free survival (EFS), overall survival (OS), toxicity, secondary cancers, and costs were compared in the aggregate cohort (N = 2736), and in separately matched histology-specific subcohorts. In the aggregate cohort, EFS was better with BR than with RCHOP/RCVP (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87). Acute toxicity was lower with BR, including rates of hospitalizations (33% vs 45%), infections (21% vs 30%), cardiovascular events, and transfusions, yet OS did not differ (HR, 1.03; 95% CI, 0.91-1.17) and Medicare spending was higher. There was no difference in the cumulative incidence of secondary cancers (subhazard ratio, 1.11; 95% CI, 0.83-1.48). The EFS advantage of BR was pronounced in MCL (N = 690; HR, 0.64; 95% CI, 0.54-0.76), but less so in FL (N = 1330; HR, 0.83; 95% CI, 0.69-0.98) and absent in MZL/LPL (N = 574; HR, 0.92; 95% CI, 0.73-1.17). Despite improved EFS and lower toxicity, the shift from RCHOP/RCVP to BR in clinical practice did not improve OS for older patients with indolent B-cell lymphomas. Frequent infections and hospitalizations underscore the need for safer treatment approaches in this population. Secondary cancers do not appear to be increased after BR compared with RCHOP/RCVP.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Conjuntos de Dados como Assunto , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Pontuação de Propensão , Sistema de Registros , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Resultado do Tratamento , Estados Unidos/epidemiologia , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
BACKGROUND: Induction chemotherapy for acute myeloid leukemia (AML) is based on the "7+3" cytarabine/anthracycline regimen. A nonhypocellular day 14 (D14) bone marrow sample with a blast count > 5% to 10% is suggestive of residual leukemia, for which a second course of induction chemotherapy has been recommended. Although the prognostic value of D14 bone marrow findings has been established, its use as a decision point is controversial because the benefit of repeat induction has been questioned. PATIENTS AND METHODS: In the present single-center retrospective study of 113 patients with newly diagnosed AML, we evaluated the role of cellularity on the clinical outcomes of patients with residual morphologic leukemia (blasts ≥ 5%). Among 64 patients with D14 bone marrow samples, 31 had residual morphologic leukemia. RESULTS: The complete remission (CR) rates were greater for the hypocellular (11 of 16) than for the nonhypocellular (4 of 15) patients (P = .03). The median overall survival (OS) for the hypocellular D14 patients was longer than that for the nonhypocellular patients (17 vs. 8 months; P = .02). No significant difference between the receipt of reinduction therapy and CR or OS was found on logistic or survival model analysis. The specificity for residual leukemia on D14 bone marrow samples was better for cellularity ≥ 20% and blasts ≥ 20% than for blasts ≥ 5%. CONCLUSION: The results of our study have shown that patients with < 20% cellularity and < 20% blasts on the D14 bone marrow assessment should continue observation until recovery rather than receive additional immediate therapy.
Assuntos
Contagem de Células Sanguíneas/métodos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
Microchimerism has generally been shown to protect against cancer (Gilmore et al. in Exp Hematol 36(9):1073-1077, 2008). The mechanism of how this occurs is an area of intense study, as it may lead to new cancer treatments. The leading theory is that microchimeric cells perform immune surveillance by directly fighting cancerous cells and that they also act as stem cells, repairing damaged tissue (Khosrotehrani et al. in JAMA 292:75-80, 2004). However, there is conflicting evidence to support this theory. Several small studies have found few microchimeric cells in tumor tissue (Gadi in Breast Cancer Res Treat 121(1):241-244, 2010; Cirello et al. in Int J Cancer 126:2874-2878, 2010), while another study contradicted these findings by showing microchimeric cells clustered around tumor tissue (O'Donoghue et al. in Reprod Biomed Online 16:382-390, 2008). To date, we have designed the largest and broadest study to investigate this question of whether microchimeric cells really do cluster at tumor tissue. We analyzed 245 samples from a broad range of cancer types. Using PCR for the male chromosome marker TSPY1, we identified only 12 out of 245 samples with microchimerism for a rate of 4.9% (95% confidence interval 2.2-7.6%). Five of these samples were confirmed using Y fluorescence in situ hybridization. This rate of 4.9% microchimerism is the lowest reported in any study. The low percentage of microchimerism observed in our broad study suggests that microchimeric cells do not invade tumors to fight off neoplasm.
Assuntos
Neoplasias/genética , Neoplasias/patologia , Contagem de Células , Proteínas de Ciclo Celular/genética , Quimerismo , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias/imunologiaRESUMO
Cryoglobulinemia and mucosa-associated lymphoid tissue (MALT) lymphoma are diseases characterized by B-cell dysregulation and overproduction of antibodies. Vasculitis and cutaneous manifestations are common, but renal involvement is rare. A 65-year-old woman with type 1 cryoglobulinemia and MALT lymphomas of the right lacrimal and parotid glands successfully treated by excision and chemoradiotherapy, presented with dyspnea on exertion, edema, and hematuria. Renal biopsy findings revealed type 1 cryoglobulinemic glomerulonephritis. She underwent treatment with high-dose oral prednisone and intravenous rituximab with subsequent return of creatinine to baseline levels. To our knowledge, this is the first report of a patient in whom type 1 cryoglobulinemia, multiple MALT lymphomas, and MPGN with IgM cryoglobulin deposits coexist. Evidence for rituximab is sparse with widely varying protocols and mixed results. There is a need for high quality evidence in the treatment of these conditions.
RESUMO
Diffuse large B-Cell lymphoma (DLBCL) is one of the most common and aggressive subtypes of non-Hodgkin's lymphoma (NHL). Gene expression profiling (GEP) studies have identified at least two distinct molecular subtypes of DLBCL termed as germinal center B-cell (GCB) and activated B-cell (ABC). These molecular subtypes represent lymphomas that are driven by very different intracellular oncogenic signaling pathways which have prognostic value and could potentially be exploited for therapeutic benefit in future. There are other oncogenes, namely BCL-2, BCL-6 and MYC, which have been associated with the pathogenesis of DLBCL. Concurrent presence of two oncogenes is present in about 5% of DLBCL and it is termed "double hit lymphoma" (DHL). DHL are associated with an aggressive clinical course and do not respond well to the standard DLBCL immune-chemotherapy regimen, RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Other aggressive therapeutic approaches including autologous bone marrow transplant have not shown any survival benefit in this subgroup of DLBCL patients. New strategies in development to address this resistance in DHL include the regimen DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab). Recent studies have shown increased sensitivity of DHL to DA-EPOCH-R chemotherapy and will likely be the new standard of care in this subset of DLBCL patients in the future.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ligação a DNA/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Prednisona/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-6 , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Until recently, warfarin has been the primary treatment of venous thromboembolism (VTE). Limited data are available regarding physician attitudes toward anticoagulant choice in the setting of novel oral anticoagulant (NOAC) availability. This study sought to evaluate attending physician attitudes toward NOACs. A survey was sent to attending physicians from internal medicine (primary care and hospitalist medicine), family medicine, cardiology, and hematology-oncology asking about their preference and reasoning for choice of oral anticoagulant for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Warfarin was the most common choice of initial treatment of both DVT (85.6%) and PE (89%). Among the specialties surveyed, cardiologists were more likely to use rivaroxaban as initial treatment of VTE as compared to other specialties including internal medicine or hematology (p=0.011 for DVT and 0.004 for PE). Cost-effectiveness and lack of a reversal agent were cited as the major disadvantages for NOAC use.
Assuntos
Anticoagulantes/uso terapêutico , Dabigatrana/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Administração Oral , Anticoagulantes/economia , Cardiologia/estatística & dados numéricos , Análise Custo-Benefício , Estudos Transversais , Dabigatrana/economia , Pesquisas sobre Atenção à Saúde , Hematologia/estatística & dados numéricos , Humanos , Medicina Interna/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Rhode Island/epidemiologia , Rivaroxabana/economia , Especialização , Tromboembolia Venosa/economia , Tromboembolia Venosa/prevenção & controle , Varfarina/economiaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance. METHODS/DESIGN: The trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy. DISCUSSION: Cellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome. TRIAL REGISTRATION: NCT01685606.
Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia/métodos , Leucemia Mieloide Aguda/terapia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro , Humanos , Indução de Remissão , Reprodutibilidade dos Testes , Projetos de Pesquisa , Transplante de Células-Tronco/métodosRESUMO
BACKGROUND: Little is known on racial differences in patients with diffuse large B-cell lymphoma (DLBCL). The aim of this retrospective study is to compare characteristics, prognostic factors and outcomes of Asian and Western patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). METHODS: Patient-level data was collected from 8 centers. All patients were diagnosed with DLBCL and treated with R-CHOP. Patients were divided into Asian and Western, according to the country of report. Comparisons and univariate/multivariate survival analyses were performed. RESULTS: 712 patients, 455 Asian and 257 Western patients were included. Westerners were more likely to present with elevated LDH (64% vs. 48%, p<0.01) and advanced stage (58% vs. 49%, p<0.01). After a median follow-up of 36 months, there was no difference in progression-free (PFS; p=0.33) or overall survival (OS; p=0.69). There were no PFS or OS differences between races when evaluating separately each age-adjusted International Prognostic Index category. In the multivariate analyses, performance status and stage were associated with PFS and OS in both races. CONCLUSIONS: There are no differences in prognostic factors, PFS and OS between Asian and Western patients with DLBCL treated with R-CHOP.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Resultado do Tratamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Ásia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Rituximab , Vincristina/administração & dosagem , Adulto JovemRESUMO
Spontaneous remission of chronic lymphocytic leukemia (CLL) is an unusual and poorly characterized event. We performed a search for spontaneous remission in patients with CLL. Cases must have had a pathological diagnosis of CLL with disease duration > 6 months. Spontaneous remission was defined as absence of lymphadenopathy or splenomegaly with lymphocyte counts < 5 × 10(9)/L for > 9 months without therapy. We identified 20 cases and included one additional case from our institution. Fourteen cases (67%) showed remission into monoclonal B lymphocytosis (MBL) and seven (33%) into a normal phenotype. There was no difference in age distribution, lymphocyte count or stage between groups. There was a significant difference in the median duration of CLL prior to remission, 13 years in the MBL versus 3 years in the normal phenotype group (p = 0.03). This difference in the duration of CLL prior to remission could be due to a possible distinct pathophysiology for these events.
Assuntos
Linfócitos B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfocitose/patologia , Regressão Neoplásica Espontânea , Fenótipo , Idoso , Linfócitos B/patologia , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfocitose/metabolismo , MasculinoRESUMO
Primary effusion lymphoma (PEL) is a rare lymphoma associated with Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), and characterized by a malignant body cavity effusion without solid organ or nodal involvement. Prognostic factors in patients with PEL have not been systematically studied. We conducted a literature search for patients with HHV8-positive PEL to identify potential prognostic factors for survival. Our search identified 147 patients, among which 104 patients were HHV8-positive. The median overall survival was 9 months. The median age was 57 years with a male predominance (6:1). Pathologically, 33% of the patients expressed CD20 and 69% expressed CD30. Patients with PEL with > 1 body cavity involved had a median overall survival (OS) of 4 months compared with 18 months in patients with only one cavity involved (p = 0.003). Additionally, in patients with one involved body cavity, pericardial involvement was associated with a longer median OS than pleural followed by peritoneal involvement (40, 27 and 5 months, respectively; p = 0.04). In conclusion, our study suggests that the number and location of body cavities involved are prognostic in patients with PEL.
Assuntos
Herpesvirus Humano 8/isolamento & purificação , Linfoma de Efusão Primária/patologia , Cavidade Peritoneal/patologia , Cavidade Pleural/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20/metabolismo , Feminino , Herpesvirus Humano 8/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-1/metabolismo , Linfoma de Efusão Primária/tratamento farmacológico , Linfoma de Efusão Primária/virologia , Masculino , Pessoa de Meia-Idade , Pericárdio/efeitos dos fármacos , Pericárdio/patologia , Pericárdio/virologia , Cavidade Peritoneal/virologia , Cavidade Pleural/efeitos dos fármacos , Cavidade Pleural/virologia , Derrame Pleural Maligno/tratamento farmacológico , Derrame Pleural Maligno/patologia , Derrame Pleural Maligno/virologia , Prognóstico , Literatura de Revisão como Assunto , Fatores SexuaisRESUMO
Much of the therapeutic benefit of allogeneic transplant is by a graft versus tumor effect. Further data shows that transplant engraftment is not dependant on myeloablation, instead relying on quantitative competition between donor and host cells. In the clinical setting, engraftment by competition alone is not feasible due to the need for large numbers of infused cells. Instead, low-level host irradiation has proven to be an effective engraftment strategy that is stem cell toxic but not myeloablative. The above observations served as the foundation for clinical trials utilizing allogeneic matched and haploidentical peripheral blood stem cell infusions with minimal conditioning in patients with refractory malignancies. Although engraftment was transient or not apparent, there were compelling responses in a heavily pretreated patient population that appear to result from the breaking of tumor immune tolerance by the host through the actions of IFNγ, invariant NK T cells, CD8 T cells, NK cells, or antigen presenting cells.
RESUMO
Our objective was to evaluate the non-germinal center (GC) profile as a marker for response and survival in DLBCL and to compare the characteristics of patients with GC and non-GC DLBCL treated with rituximab-containing regimens. In this patient-level meta-analysis, retrospective data from 712 newly diagnosed DLBCL patients treated with chemoimmunotherapy from 7 centers were analyzed. GC and non-GC profiles were defined according to the Hans algorithm. Although the non-GC profile showed a trend towards worse overall survival (HR 1.24, 95% CI 0.92-1.66; p=0.15) and progression-free survival (HR 1.29, 95% CI 0.96-1.73; p=0.09), it did not retain its value in the multivariate survival analysis. Additionally, the non-GC profile was independently associated with worse complete response rates (OR 0.55, 95% CI 0.37-0.83; p<0.01) in the multivariate logistic regression analysis. Interestingly, Asian patients had higher proportion of GC DLBCL (p=0.01).
Assuntos
Algoritmos , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Rituximab , Adulto JovemRESUMO
EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is an entity recently included in the WHO classification of lymphoid tumors. We have reviewed our experience and clinical outcomes of this distinct subtype of DLBCL. Between 2002 and 2009, cases of DLBCL were identified from medical records of the Hospital Nacional Edgardo Rebagliati Martins in Lima, Peru, and underwent pathological evaluation including immunohistochemistry for CD20, CD10, bcl-6, MUM1/IRF4, and EBV-encoded RNA in situ hybridization. Clinical data were gathered, tabulated, and reported descriptively. Survival analyses were performed using Kaplan-Meier estimates. Out of 199 cases of DLBCL, 28 cases of EBV-positive DLBCL of the elderly were identified. The median age was 75 years with male predominance (1.5:1). B-symptoms were present in 43%, advanced stage in 50% and International Prognostic Index (IPI) score > 2 in 57% of patients; 68% of patients had a nongerminal center (NGC) phenotype. The complete response rates to R-CHOP and CHOP were 63% and 33%, respectively. The median overall survival (OS) for the group was 5 months. In the univariate analysis, age ≥70 years, lymphocyte count <1.0 × 10(9) /L, and advanced clinical stage were associated with worse OS in patients treated with chemotherapy with and without rituximab. EBV-positive DLBCL of the elderly is a clinically aggressive entity with a short OS and typically presents with advanced stage, high IPI score, and a NGC phenotype. Further studies are needed to investigate if rituximab-containing regimens are associated with better response and OS rates in EBV-positive DLBCL of the elderly.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Herpesvirus Humano 4/isolamento & purificação , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/virologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Humanos , Contagem de Linfócitos , Linfoma Difuso de Grandes Células B/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Peru , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Rituximab , Distribuição por Sexo , Análise de Sobrevida , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
PURPOSE: Gemcitabine induces a 20% response as single-agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS: Patients received CHOP plus gemcitabine at 500 mg/m(2) (Cohort 1) or 750 mg/m(2) (Cohort 2) on days 1 and 4 of each 21-day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose-limiting toxicity. RESULTS: Between April 2002 and May 2004, 10 patients were enrolled and completed the study treatment (6 in Cohort 1, 4 in Cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia, and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose-limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction in gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS: This Phase I trial concludes that gemcitabine 500 mg/m(2) on days 1 and 4 of each 21-day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL.