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Large granular lymphocytic (LGL) leukemia is a rare lymphoproliferative chronic disorder characterized by expansion of either T- or NK- cytotoxic cells. Contrary to EBV-induced aggressive NK-LGL leukemia, chronic T- and NK-LGL leukemia are indolent diseases affecting elderly patients with a median age of 66.5 years old. LGL leukemia is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. An auto/allo antigen is tentatively implicated in disease initiation. LGLs expansion is then triggered by proinflammatory cytokines such as interleukin (IL) IL-15, MIP-1, and RANTES. This proinflammatory environment contributes to deregulation of proliferative and apoptotic pathways. Following the initial description of the JAK-STAT pathway signaling activation in the majority of patients, recurrent STAT3 gain of function mutations have been reported. The JAK-STAT pathway plays a key role in LGL pathogenesis by promoting survival, proliferation and cytotoxicity. Several recent advances have been made towards understanding the molecular landscapes of T and NK LGL leukemia, identifying multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and crosstalk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that the majority of patients will eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting and hypomethylating agents, opening new developments in a still-incurable disease.
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Large granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia.
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Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.
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Infecções Fúngicas Invasivas , Voriconazol , Adulto , Criança , Humanos , Antifúngicos/farmacocinética , Inflamação , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/farmacocinéticaRESUMO
Follicular lymphoma (FL) originates in the lymph nodes (LNs) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSCs) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been identified. In the current work, we demonstrate that FL B cells produce extracellular vesicles (EVs) that can be internalized by BM-MSCs, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activate transforming growth factor ß-dependent and independent pathways in BM-MSCs and modify their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 and angiopoietin-1. Moreover, we provide the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSCs. This work identifies FL-derived EVs as putative mediators of BM stroma polarization and supports further investigation of their clinical interest for targeting the crosstalk between BM-MSCs and malignant B cells.
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Linfócitos B/patologia , Células da Medula Óssea/patologia , Polaridade Celular , Vesículas Extracelulares/patologia , Linfoma Folicular/patologia , Sequência de Bases , Células da Medula Óssea/metabolismo , Comunicação Celular , Diferenciação Celular , Endocitose , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/ultraestrutura , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Linfoma Folicular/genética , Heterotrímero de Linfotoxina alfa1 e beta2/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fenótipo , Transdução de Sinais , Células Estromais/metabolismo , Células Estromais/patologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genéticaRESUMO
Acute myeloid leukemia (AML) can lead to life-threatening complications that may require intensive care unit (ICU) management. It has been advocated that early preemptive (ePE) ICU admission, before the onset of organ failure, could benefit some high-risk patients such as those with hyperleukocytosis. The aim of this study was to retrospectively analyze the outcome of newly diagnosed AML patients who required ICU admission in five academic centers with a special focus on patients with an ePE admission strategy, i.e., those transferred to the ICU without any organ failure (modified SOFA score ≤ 2 [omitting thrombocytopenia] and no life-sustaining intervention in the first 24 h following ICU admission) before the start of induction therapy. Between January 2017 and December 2019, 428 patients were included among which 101 were admitted to the ICU. Among patients requiring life-sustaining interventions (n = 83), 18 (22%) died while in the ICU but ICU survivors had the same survival as those not admitted to the ICU. Patients with an ePE admission (n = 18) had more comorbidities and high-risk disease features such as hyperleukocytosis but required no life-sustaining interventions while in the ICU. In a subgroup analysis of patients with hyperleukocytosis ≥ 50 G/l at diagnosis (n = 85), patients not admitted to the ICU and those admitted with an ePE strategy had similar outcomes. This study provides encouraging results about ICU outcome in AML patients during induction therapy but the potential benefit of an ePE strategy must be confirmed prospectively.
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Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Hospitalização , Unidades de Terapia Intensiva , ComorbidadeRESUMO
The value of pretransplant splenectomy in patients with myelofibrosis (MF) is subject to debate, since the procedure may preclude subsequent allogeneic hematopoietic cell transplantation (allo-HCT). To determine the impact of pretransplant splenectomy on the incidence of allo-HCT, we conducted a comprehensive retrospective study of all patients with MF for whom an unrelated donor search had been initiated via the French bone marrow transplantation registry (RFGM) between 1 January 2008 and 1 January 2017. Additional data were collected from the patients' medical files and a database held by the French-Language Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC). We used a multistate model with four states ("RFGM registration"; "splenectomy"; "death before allo-HCT", and "allo-HCT") to evaluate the association between splenectomy and the incidence of allo-HCT. The study included 530 patients from 57 centers. With a median follow-up time of 6 years, we observed 81 splenectomies, 99 deaths before allo-HCT (90 without splenectomy and nine after), and 333 allo-HCTs (268 without splenectomy and 65 after). In a bivariable analysis, the hazard ratio [95% confidence interval (CI)] for the association of splenectomy with allo-HCT was 7.2 [5.1-10.3] in the first 4 months and 1.18 [0.69-2.03] thereafter. The hazard ratio [95% CI] for death associated with splenectomy was 1.58 [0.79-3.14]. These reassuring results suggest that splenectomy does not preclude allo-HCT in patients with MF.
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Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Sistema de Registros , Esplenectomia , Aloenxertos , Intervalo Livre de Doença , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/mortalidade , Mielofibrose Primária/terapia , Taxa de SobrevidaRESUMO
Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Aloenxertos , Clofarabina/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (Pâ¯=â¯.78). Overall, the DIPSS was not significantly predictive of outcome (Pâ¯=â¯.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (Pâ¯=â¯.05), whereas groups with intermediate 2 and high risk showed no significant difference (Pâ¯=â¯.44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (Pâ¯=â¯.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (Pâ¯=â¯.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
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Transplante de Células-Tronco Hematopoéticas/métodos , Policitemia Vera/terapia , Mielofibrose Primária/terapia , Trombocitemia Essencial/terapia , Transplante Homólogo/métodos , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Policitemia Vera/mortalidade , Mielofibrose Primária/mortalidade , Prognóstico , Análise de Sobrevida , Trombocitemia Essencial/mortalidade , Resultado do TratamentoRESUMO
Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by the accumulation of germinal center-derived malignant B cells engaged in a bidirectional crosstalk with their supportive microenvironment in invaded lymph nodes (LNs) and bone marrow (BM). T follicular helper (TFH) cells and infiltrating stromal cells have been shown to favor FL B-cell growth, but the mechanisms of their protumoral effect and how the LN/BM microenvironment is converted into a lymphoma-permissive cell niche remain poorly understood. We demonstrated here that FL-infiltrating LN and BM stromal cells overexpressed CXCL12 in situ. Interleukin-4 high (IL-4hi) FL-TFH cells, unlike FL B cells themselves, triggered CXCL12 upregulation in human stromal cell precursors. In agreement, expression of CXCL12 was associated with IL-4 expression and signaling within the FL BM and LN niches. This IL-4/CXCL12 axis was amplified in activated lymphoid stromal cells as shown in our in vitro model of human lymphoid stroma differentiation and in an inducible mouse model of ectopic lymphoid organ formation. Finally, CXCL12 triggered primary FL B-cell activation, migration, and adhesion, a process antagonized by BTK and PI3K inhibitors. These data identified the IL-4/CXCL12 loop as a previously unrecognized pathway involved in lymphoid stroma polarization and as a potential therapeutic target in FL patients.
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Medula Óssea/imunologia , Quimiocina CXCL12/imunologia , Interleucina-4/imunologia , Linfonodos/imunologia , Linfoma Folicular/imunologia , Transdução de Sinais/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Medula Óssea/patologia , Movimento Celular/genética , Movimento Celular/imunologia , Quimiocina CXCL12/genética , Feminino , Humanos , Interleucina-4/genética , Linfonodos/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaAssuntos
Vacina de mRNA-1273 contra 2019-nCoV/administração & dosagem , Anticorpos Antivirais/biossíntese , Vacina BNT162/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , SARS-CoV-2/imunologia , Idoso , Aloenxertos , Anticorpos Antivirais/sangue , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunização Secundária , Hospedeiro Imunocomprometido/imunologia , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos RetrospectivosRESUMO
Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1+ T cells and decreased ratios of T-regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade.
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Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Adulto , Idoso , Aloenxertos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Estatísticas não Paramétricas , Adulto JovemRESUMO
The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n=287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P=0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versus-host disease without increasing the risk of relapse.
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Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Mielofibrose Primária/complicações , Mielofibrose Primária/terapia , Irmãos , Idoso , Soro Antilinfocitário/farmacologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/farmacologia , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Prognóstico , Condicionamento Pré-Transplante , Transplante Haploidêntico , Resultado do TratamentoRESUMO
It has been shown recently that donor and/or recipient cytomegalovirus (CMV) seropositivity is associated with a significant overall survival (OS) decline in acute leukemia patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We now analyzed the prognostic impact of the donor/recipient CMV serostatus in 6968 patients with chronic hematological malignancies who underwent allo-HSCT. Donor and/or recipient CMV seropositivity was associated with a significantly reduced 2-year progression-free survival (PFS, 50% vs. 52%, p = 0.03) and OS (62% vs. 65%, p = 0.01). Multivariate Cox regression analyses showed an independent negative prognostic impact of donor and/or recipient CMV seropositivity on PFS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.03), OS (HR, 1.1; 95% CI, 1.0-1.2; p = 0.003), and non-relapse mortality (HR, 1.2; 95% CI, 1.0-1.3; p = 0.02). OS decline was strongest for CMV-seropositive recipients with a CMV-seronegative donor (HR, 1.2; 95% CI, 1.1-1.3), followed by CMV-seropositive patients with a CMV-seropositive donor (HR, 1.1; 95% CI, 1.0-1.2). Conversely, OS did not differ significantly between CMV-seronegative recipients allografted from a CMV-seropositive donor (HR, 1.0; 95% CI, 0.9-1.2) and patients with donor/recipient CMV seronegativity (p = 0.001 for the four groups together). Non-relapse mortality was also significantly (p = 0.01) higher for CMV-seropositive patients with a CMV-seronegative graft (HR, 1.2; 95% CI, 1.1-1.4) than for CMV-seropositive patients with a CMV-seropositive graft (HR, 1.1; 95% CI, 0.9-1.2) or CMV-seronegative recipients with a CMV-seropositive graft (HR, 1.0; 95% CI, 0.8-1.2). Donor and/or recipient CMV seropositivity still results in an OS decline in patients with chronic hematological malignancies who have undergone allo-HSCT. However, this OS decline seems to be lower than that described for acute leukemia patients previously.
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Infecções por Citomegalovirus , Citomegalovirus , Seleção do Doador , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Adulto , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/terapia , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
In standard-risk acute promyelocytic leukemia, recent results have shown that all-trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all-trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all-trans retinoic acid and the "classical" cytarabine for consolidation treatment (after all-trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x109/L, after an induction treatment consisting of all-trans retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all-trans retinoic acid. Patients with a white blood cell count >10x109/L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all-trans retinoic acid consolidation groups, respectively (P=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (P=0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (P=0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (P=0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adulto , Antraciclinas/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Bélgica , Intervalo Livre de Doença , Feminino , França , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Suíça , Resultado do Tratamento , Tretinoína/administração & dosagemRESUMO
Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM(+) FL B cells activated a stronger BCR signaling network than IgG(+) FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM(+) FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN-dependent adhesion of highly mannosylated IgM(+) FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN-expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets.
Assuntos
Moléculas de Adesão Celular/imunologia , Regulação da Expressão Gênica/imunologia , Imunoglobulina M/imunologia , Lectinas Tipo C/imunologia , Linfoma Folicular/imunologia , Macrófagos/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Superfície Celular/imunologia , Transdução de Sinais/imunologia , Comunicação Celular/imunologia , Técnicas de Cocultura , Feminino , Glicosilação , Humanos , Linfoma Folicular/patologia , Macrófagos/patologia , Masculino , Células Tumorais CultivadasRESUMO
UNLABELLED: Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia. TRIAL REGISTRATION: The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Assuntos
Expressão Gênica , Proteínas de Homeodomínio/genética , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Timo/metabolismo , Timo/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Large granular lymphocytic (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or NK lymphocytes. Neutropenia-related infections represent the main clinical manifestation. Even if the disease follows an indolent course, most patients will ultimately need treatment in their lifetime. Interestingly, LGL leukemia is characterized by a high frequency of autoimmune disorders with rheumatoid arthritis being the most frequent. AREAS COVERED: This review covers the pathophysiology, clinic-biological features and the advances made in the treatment of LGL leukemia. A special focus will be made on the similarities in the pathophysiology of LGL leukemia and the frequently associated rheumatic disorders. EXPERT OPINION: Recent advances in the phenotypic and molecular characterization of LGL clones have uncovered the key role of JAK-STAT signaling in the pathophysiology linking leukemic cells expansion and autoimmunity. The description of the molecular landscape of T- and NK-LGL leukemia and the improved understanding of the associated rheumatic disorders open the way to the development of new targeted therapies effective on both conditions.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Leucemia Linfocítica Granular Grande , Neutropenia , Humanos , Leucemia Linfocítica Granular Grande/tratamento farmacológico , Células Matadoras NaturaisRESUMO
INTRODUCTION: Pulmonary pneumocystis causes interstitial lung disease, particularly in patients with solid cancers. The aim of this study is to clarify its incidence, which remains poorly understood, and to identify patients at risk and prognostic factors. METHODS: Data on patients with solid tumors and pulmonary pneumocystis were retrospectively collected from January 1, 2014 to December 31, 2019 in two hospitals in Rennes. Incidence was estimated via the Poisson model. Survival data were estimated using Kaplan-Meier method and Log-rank test. A multivariate Cox model was performed to identify risk factors for death. RESULTS: The incidences of pulmonary pneumocystis in metastatic cancer patients receiving parenteral systemic therapy are 198 and 349 cases per 100,000 patients per year in these two centers, respectively. Most patients were being treated with corticosteroids and chemotherapy at the time of pulmonary pneumocystis. The mortality rate for patients with pulmonary pneumocystis is 38%. Median overall survival was 2,7 months. Risk factors for death are corticotherapy greater than 20mg, prednisone equivalent, daily and chemotherapy. DISCUSSION: Pulmonary pneumocystis pneumonia is rare but not exceptional and has a poor prognosis in solid oncology. It frequently occurs in patients treated with long-term corticosteroids. Oncologists need to be better informed to discuss prophylaxis whenever corticosteroids are prescribed for several weeks.
RESUMO
Haematopoietic stem cells (HSCs) reside in specialized microenvironments, also referred to as niches, and it has been widely believed that HSC numbers are determined by the niche size alone 1-5 . However, the vast excess of the number of niche cells over that of HSCs raises questions about this model. We initially established a mathematical model of niche availability and occupancy, which predicted that HSC numbers are restricted at both systemic and local levels. To address this question experimentally, we developed a femoral bone transplantation system, enabling us to increase the number of available HSC niches. We found that the addition of niches does not alter total HSC numbers in the body, regardless of whether the endogenous (host) niche is intact or defective, suggesting that HSC numbers are limited at the systemic level. Additionally, HSC numbers in transplanted wild-type femurs did not increase beyond physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are also constrained at the local level. Our study demonstrates that HSC numbers are not solely determined by niche availability, thereby rewriting the long-standing model for the regulation of HSC numbers.
RESUMO
Functional stromal cells are known to support bone marrow regeneration after chemotherapy or radiation-induced injury to prevent prolonged myelosuppression. However, it is not known how stromal cells within the bone marrow are regenerated after injury. We have utilized a whole bone transplantation model that mimics the initial bone marrow necrosis and fatty infiltration that is seen after bone marrow injury and subsequent recovery. We demonstrate that periosteal skeletal stem cells (P-SSCs) can migrate into the bone marrow and contribute to stromal regeneration and hematopoietic recovery. Once in the bone marrow, P-SSCs are phenotypically and functionally reprogrammed into bone marrow mesenchymal stem cells (BM-MSCs), expressing high levels of hematopoietic stem cell (HSC) niche factors, such as Cxcl12 and Kitl. Additionally, our results further indicate that P-SSCs are more resistant to acute stress than BM-MSCs. Here, we report a new function of P-SSCs, highlighting their major plasticity and the role of the periosteum as a potential source of BM-MSCs following acute bone marrow injury.