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1.
Oncoimmunology ; 13(1): 2388304, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39135889

RESUMO

The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients' clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.


CD137-expressing immune cells and HRS cells are more abundant and in closer proximity in refractory patients than in responders.Monocytic myeloid-derived suppressor cells (m-MDSCs) are associated with unfavorable outcomes and relapse in cHL, unlike granulocytic MDSCs (g-MDSCs), which are located far from HRS cells in non-responders.The cHL tumor microenvironment promotes immune escape in refractory patients by holistically driving polarization and/or recruitment of several cell types with increased expression of CD137 and PD-L1 checkpoints.


Assuntos
Doença de Hodgkin , Células Supressoras Mieloides , Células de Reed-Sternberg , Microambiente Tumoral , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral , Humanos , Doença de Hodgkin/patologia , Doença de Hodgkin/imunologia , Doença de Hodgkin/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Microambiente Tumoral/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Células de Reed-Sternberg/patologia , Células de Reed-Sternberg/metabolismo , Idoso , Análise Espacial , Adulto Jovem , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Adolescente , Prognóstico , Biomarcadores Tumorais/metabolismo
2.
Mod Pathol ; 37(9): 100551, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38936478

RESUMO

As around 25% to 30% of classical Hodgkin lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the tumor microenvironment. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the NanoString GeoMx digital spatial profiling technology, based on the selection of distinct functional areas of patients' tissues followed by gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.


Assuntos
Linfócitos T CD4-Positivos , Doença de Hodgkin , Microambiente Tumoral , Humanos , Doença de Hodgkin/patologia , Doença de Hodgkin/imunologia , Linfócitos T CD4-Positivos/imunologia , Microambiente Tumoral/imunologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Idoso , Adulto Jovem , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia
3.
EJHaem ; 5(1): 70-75, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38406538

RESUMO

The value of circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients has not yet been well established. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high spatial and temporal heterogeneity. Although ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based on measures of total ctDNA, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

4.
Sci Rep ; 14(1): 710, 2024 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-38184757

RESUMO

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.


Assuntos
Doença de Hodgkin , Humanos , Doença de Hodgkin/genética , Matriz Extracelular , Células Mieloides , Células de Reed-Sternberg , Linfócitos T CD4-Positivos , Antígenos de Histocompatibilidade Classe II , Microambiente Tumoral/genética
5.
Exp Cell Res ; 430(2): 113718, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37468057

RESUMO

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.


Assuntos
Antineoplásicos , Doença de Hodgkin , Humanos , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patologia , NF-kappa B/metabolismo , Regulação para Baixo/genética , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Antineoplásicos/uso terapêutico
6.
Br J Haematol ; 202(4): 776-784, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37386877

RESUMO

The aims of our study were to analyse compliance with the 2014 GELTAMO SMZL Guidelines, in patients with splenic marginal zone lymphoma (SMZL), and to evaluate the outcome according to the HPLLs/ABC-adapted therapeutic strategy. Observational prospective multicenter study of 181 SMZL patients diagnosed between 2014 and 2020. Lymphoma-specific survival (LSS), composite event-free survival (CEFS) and response rates were assessed. 57% of the 168 patients included in the analysis followed the Guidelines. The overall response rate was higher in the rituximab chemotherapy and in the rituximab arms compared with the splenectomy arm (p < 0.001). The 5-year overall survival was 77% and the 5-year LSS of 93%. There were no differences in the 5-year LSS according to the treatment received (p = 0.68). The 5-year CEFS in the overall series was 45%, and there were significant differences between scores A and B (p = 0.036). There were no significant differences when comparing LSS and progression-free survival in patients treated with rituximab or rituximab chemotherapy at diagnosis or after observation. Our data support HPLLs/ABC score as a practical tool for the management of SMZL, observation as the best approach for patients in group A and rituximab as the best treatment for group B.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Zona Marginal Tipo Células B , Neoplasias Esplênicas , Humanos , Rituximab/uso terapêutico , Resultado do Tratamento , Estudos Prospectivos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/patologia , Esplenectomia/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
7.
Blood Adv ; 7(15): 4135-4147, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-36459489

RESUMO

Constitutive activation of the JAK/STAT pathway is a common phenomenon in classic Hodgkin lymphoma (cHL). The clinical potential of anti-JAK/STAT therapy is being explored in early-stage clinical trials. Notwithstanding, very little information is available about the complex biological consequences of this blockade. Here, we investigated the effects of JAK/STAT pharmacological inhibition on cHL cell models using ruxolitinib, a JAK 1/2 inhibitor that induces apoptosis by concentration- and time-dependent mechanisms. An unbiased whole-transcriptome approach identified expression of the anti-GCSF receptor (CSF3R) as a potential surrogate biomarker of JAK/STAT overactivation. In addition, longitudinal gene expression analyses provided further mechanistic information about pertinent biological pathways involved, including 37 gene pathways distributed in 3 main clusters: cluster 1 was characterized by upregulation of the G2/M checkpoint and major histocompatibility complex-related clusters; 2 additional clusters (2 and 3) showed a progressive downregulation of the tumor-promoting inflammation signatures: JAK/STAT and interleukin 1 (IL-1)/IL-4/IL-13/IL-17. Together, our results confirm the therapeutic potential of JAK/STAT inhibitors in cHL, identify CSF3R as a new biomarker, and provide supporting genetic data and mechanistic understanding.


Assuntos
Doença de Hodgkin , Células de Reed-Sternberg , Humanos , Transdução de Sinais , Janus Quinases , Fatores de Transcrição STAT/metabolismo , Doença de Hodgkin/genética , Fenótipo
8.
Haematologica ; 107(11): 2675-2684, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35320921

RESUMO

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Transplante Autólogo , Transplante de Células-Tronco Hematopoéticas/métodos , Estudos Retrospectivos , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença
9.
Cancers (Basel) ; 14(5)2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35267668

RESUMO

The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies.

10.
Curr Drug Targets ; 23(4): 373-392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34488581

RESUMO

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is important and interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, improve the solubility of drugs, have active molecules in their outer layer, and, due to their nanometric size, they can take advantage of the EPR effect, prolong circulation time and avoid renal clearance. Furthermore, bioactive molecules (could be joined covalently or by host-host interaction), such as drugs, bioimaging molecules, proteins, targeting ligands, "cross-linkable" molecules, or linkages sensitive to internal or external stimuli, can be incorporated into them. The confined multivalent cooperativity and the ability to modify the dendritic structure provide versatility to create and improve the amphiphiles used in the micellar supramolecular field. As discussed in this review, the most studied structures are hybrid copolymers, which are formed by the combination of linear polymers and dendrons. Amphiphilic dendrimer micelles have achieved efficient and promising results in both in vitro and in vivo tests, and this encourages research for their future application in nanotherapies.


Assuntos
Antineoplásicos , Dendrímeros , Antineoplásicos/farmacologia , Dendrímeros/química , Dendrímeros/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Micelas , Polímeros/química
11.
Leuk Lymphoma ; 63(1): 93-100, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34459702

RESUMO

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.


Assuntos
Linfoma Folicular , Anticorpos Monoclonais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Seguimentos , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/etiologia , Radioimunoterapia/métodos , Rituximab/efeitos adversos , Resultado do Tratamento , Radioisótopos de Ítrio/uso terapêutico
12.
Curr Med Chem ; 28(38): 7937-7960, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33781182

RESUMO

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, have active molecules in their outer layer, and due to their nanometric size, can take advantage of the enhanced permeability and retention (EPR) effect, prolong the time in circulation and avoid renal clearance. In addition, nanobioactive molecules (joined in covalent form or by host-host interaction), such as drugs, bioimaging molecules, targeting ligands, "crosslinkable" molecules or bonds, sensitive to internal or external stimuli, can be incorporated into them and showed better activity as anticancer agents, siRNA delivery agents as well as antiviral and antiparasitic compounds. The present work is a review of the information published, which is the most important about the synthesis and biological importance of the confined multivalent cooperation and the ability to modify the dendritic structure, provide the versatility to create and improve the amphiphiles used in the micellar supramolecular field. The most studied structures are the hybrid copolymers formed by the combination of linear polymers and dendrons. However, small dendritic molecules that do not involve linear polymers have also been developed, such as Janus dendrimers, facial dendrons, and dendritic amphiphiles with only one dendron. Amphiphilic dendrimer micelles have achieved efficient and promising results, both in in vitro and in vivo tests, which encourage their research for future application in nanotherapies.


Assuntos
Antineoplásicos , Micelas , Sistemas de Liberação de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Polímeros
13.
Bioorg Med Chem Lett ; 30(14): 127275, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527536

RESUMO

The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Fenilalanina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células COS , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Relação Estrutura-Atividade
14.
Eur J Haematol ; 104(5): 400-408, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31804029

RESUMO

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida , Doxorrubicina , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prednisona , Prognóstico , Sistema de Registros , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Vincristina , Adulto Jovem
15.
Cancer Med ; 8(16): 6955-6966, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31573746

RESUMO

BACKGROUND: Consensus is lacking regarding the optimal salvage therapy for patients with follicular lymphoma who relapse after or are refractory to immunochemotherapy. METHODS: This phase II trial evaluated the efficacy and safety of response-adapted therapy with rituximab, bendamustine, mitoxantrone, and dexamethasone (RBMD) in follicular lymphoma patients who relapsed after or were refractory to first-line immunochemotherapy. Sixty patients received three treatment cycles, and depending on their response received an additional one (complete/unconfirmed complete response) or three (partial response) cycles. Patients who responded to induction received rituximab maintenance therapy for 2 years. RESULTS: Thirty-three (55%) and 42 (70%) patients achieved complete/unconfirmed complete response after three cycles and on completing induction therapy (4-6 cycles), respectively (final overall response rate, 88.3%). Median progression-free survival was 56.4 months (median follow-up, 28.3 months; 95% CI, 15.6-51.2). Overall survival was not reached. Progression-free survival did not differ between patients who received four vs six cycles (P = .6665), nor between patients who did/did not receive rituximab maintenance after first-line therapy (P = .5790). Median progression-free survival in the 10 refractory patients was 25.5 months (95% CI, 0.6-N/A) and was longer in patients who had shown progression of disease after 24 months of first-line therapy (median, 56.4 months; 95% CI, 19.8-56.4) than in those who showed early progression (median, 42.31 months; 95% CI, 24.41-NA) (P = .4258). Thirty-six (60%) patients had grade 3/4 neutropenia. Grade 3/4 febrile neutropenia and infection were recorded during induction (4/60 [6.7%] and 5/60 [8.3%] patients, respectively) and maintenance (2/43 [4.5%] and 4/43 [9.1%] patients, respectively). CONCLUSIONS: This response-adapted treatment with RBMD followed by rituximab maintenance is an effective and well-tolerated salvage treatment for relapsed/refractory follicular lymphoma following first-line immunochemotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01133158.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Dexametasona/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Mitoxantrona/uso terapêutico , Rituximab/uso terapêutico , Terapia de Salvação , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Dexametasona/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoterapia , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , Rituximab/efeitos adversos
18.
Oncotarget ; 9(64): 32383-32399, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30190794

RESUMO

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of non-Hodgkin lymphoma (NHL) cases in adult series. DLBCL is characterized by marked clinical and biological heterogeneity, encompassing up to 16 distinct clinicopathological entities. While current treatments are effective in 60% to 70% of patients, those who are resistant to treatment continue to die from this disease. An expert panel performed a systematic review of all data on the diagnosis, prognosis, and treatment of DLBCL published in PubMed, EMBASE and MEDLINE up to December 2017. Recommendations were classified in accordance with the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework, and the proposed recommendations incorporated into practical algorithms. Initial discussions between experts began in March 2016, and a final consensus was reached in November 2017. The final document was reviewed by all authors in February 2018 and by the Scientific Committee of the Spanish Lymphoma Group GELTAMO.

19.
Br J Haematol ; 182(4): 534-541, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29978453

RESUMO

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype.


Assuntos
Algoritmos , Centro Germinativo , Linfoma Difuso de Grandes Células B , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Feminino , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/metabolismo , 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 , Prognóstico , Medição de Risco , Fatores de Risco , Taxa de Sobrevida
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