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1.
Leukemia ; 34(5): 1342-1353, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31768015

RESUMO

Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient's DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p < 0.001). An increase in the percentage of recipient DNA in CD3-negative cells was associated with an increased risk of relapse (p < 0.001) but not with overall survival. Comparable performances between monitoring of CD3-negative cell chimerism and WT1 expression to predict relapse was observed up to more than 90 days before hematological relapse, with sensitivity of 82% and 78%, respectively, and specificity of 100% for both approaches. Quantitative specific chimerism of the CD3-negative mononuclear fraction, enriched in blastic cells, is a new and powerful tool for monitoring measurable residual disease and could be used for AML patients without available molecular markers.


Assuntos
Biomarcadores Tumorais/metabolismo , Complexo CD3/metabolismo , Quimerismo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/metabolismo , Neoplasia Residual/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Proteínas WT1/metabolismo , Adulto Jovem
2.
Eur J Haematol ; 101(4): 570-574, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30007088

RESUMO

Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long-term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/etiologia , Doadores de Tecidos , Adulto , Biomarcadores , Biópsia , Medula Óssea/patologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
3.
Ann Hematol ; 97(9): 1601-1609, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29717367

RESUMO

The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1-2.7, p = 0.04). Time between first organ injury and ICU admission was also associated with an increased in-hospital survival (OR 1.4, 95% CI 1.1-1.8, p = 0.02). A score combining these two covariates-the number of organ injuries/day (sum of days spent with each individual organ injury)-further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1-1.7, p = 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in-hospital mortality.


Assuntos
Cuidados Críticos/estatística & dados numéricos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospitalização/estatística & dados numéricos , Tempo para o Tratamento , Adulto , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade
4.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
5.
Biol Blood Marrow Transplant ; 24(5): 1013-1021, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29337223

RESUMO

The results of conventional allogeneic stem cell transplantation (SCT) in refractory hematologic malignancies are poor. Sequential strategies have shown promising results in refractory acute myelogenous leukemia (AML), but have not been validated in a haploidentical (Haplo) transplant setting. We have developed a new sequential approach combining chemotherapy with broad antitumor activity (thiotepa 10 mg/kg, etoposide 400 mg/m2, and cyclophosphamide 1600 mg/m2 from day -15 to day -10), followed after 3 days of rest by a reduced-intensity conditioning regimen (fludarabine 150 mg/m2, i.v. busulfan 6.4 mg/kg, and thymoglobulin 5 mg/kg from day -6 to day -2). High-dose post-transplantation cyclophosphamide was added in cases with Haplo donors. Seventy-two patients (median age, 54 years) with a refractory hematologic malignancy (44 with acute myelogenous leukemia, 7 with acute lymphoblastic leukemia, 15 with myelodysplastic syndrome/myeloproliferative neoplasms, and 6 with lymphomas) were included in this retrospective multicenter study. Donors were Haplo (n = 27), matched related (MRD; n = 16), and unrelated (UD; n = 29). With a median follow-up of 21 months, the 2-year overall survival (OS) and event-free survival (EFS) were 54.7% and 49.3%, respectively, in recipients of Haplo transplants, 49.2% and 43.8%, respectively, in recipients of MRD transplants, and 37.9% and 28%, respectively, in recipients of UD transplants. Compared with UD, the outcomes were improved in Haplo in terms of the incidences of acute grade II-IV graft-versus-host disease (GVHD) (11.1% versus 41.4%; P < .001) and GVHD-free, relapse-free survival (44.4 versus 10.3%; P = .022). These results support the safety and efficacy of a thiotepa-based sequential approach in allogeneic SCT with a Haplo donor with post-transplantation immune modulation. Thus, in patients with refractory hematologic malignancies, there seems to be no benefit in searching for a UD when a Haplo donor is readily available.


Assuntos
Neoplasias Hematológicas/terapia , Terapia de Salvação/métodos , Tiotepa/uso terapêutico , Condicionamento Pré-Transplante/métodos , Antineoplásicos Alquilantes/uso terapêutico , Feminino , Neoplasias Hematológicas/mortalidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação/mortalidade , Análise de Sobrevida , Doadores de Tecidos , Transplante Haploidêntico , Doadores não Relacionados
7.
Clin Transplant ; 31(4)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28181304

RESUMO

The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness.


Assuntos
Corticosteroides/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Doença Enxerto-Hospedeiro/radioterapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfonodos/efeitos da radiação , Dermatopatias/radioterapia , Neoplasias de Tecidos Moles/radioterapia , Adulto , Doença Crônica , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Dermatopatias/etiologia , Neoplasias de Tecidos Moles/etiologia , Transplante Homólogo , Adulto Jovem
8.
Blood ; 129(10): 1380-1388, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28073785

RESUMO

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.


Assuntos
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 Jovem
9.
Transplantation ; 101(2): 437-444, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26950729

RESUMO

BACKGROUND: Admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) remains controversial, especially when graft-versus-host disease (GVHD) is present. METHODS: We performed a retrospective study to assess prognostic factors of survival in all allogeneic SCT recipients admitted to the ICU between 2002 and 2013 in our center which has flexible admission criteria, especially regarding GVHD. RESULTS: Of 349 patients who underwent allogeneic SCT during the study period, 92 patients (26%) were admitted to the ICU. Intensive care unit and hospital discharge rates were 66% and 46%, respectively, whereas 1 year survival was 24%. Acute GVHD, either grade III to IV (30 patients, 33%) or refractory (12 patients, 13%) had a nonsignificant impact on hospital mortality (odds ratio [OR], 2.1; P = 0.1; OR, 5, P = 0.05, respectively). Fifty percent of patients required invasive mechanical ventilation, 30% required vasopressors, 17% required renal replacement therapy, and 28% had liver impairment (bilirubin >34 µmol/L), each of these parameters defining organ failure. Mortality was closely associated with the number of organ failures as hospital discharge rates were 69%, 50%, 42%, and 0% among patients with 0 (26 patients), 1 (26 patients), 2 (26 patients), and 3 to 4 (14 patients) organ failures, respectively (OR, 2.7; 95% confidence interval, 1.6-4.6; P < 0.001 according to the number of organ failures). CONCLUSIONS: Early mortality of allogeneic SCT recipients admitted to the ICU is especially influenced by the number of organ failures and therefore patients with 0 to 2 organ failures should be considered if required. Refractory GVHD affects survival but not within the confined ICU admission.


Assuntos
Cuidados Críticos , Doença Enxerto-Hospedeiro/terapia , Insuficiência de Múltiplos Órgãos/terapia , Transplante de Células-Tronco/efeitos adversos , Adulto , Distribuição de Qui-Quadrado , Feminino , França , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Análise Multivariada , Razão de Chances , Admissão do Paciente , Alta do Paciente , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento
10.
Bull Cancer ; 103(11S): S229-S242, 2016 Nov.
Artigo em Francês | MEDLINE | ID: mdl-27842860

RESUMO

Haploidentical hematopoietic stem cell transplantation (HSCT) is being increasingly used due to improvement of the transplantation procedures allowing a reduction of graft-versus-host-disease (GVHD) and of transplant-related mortality (TRM). Such improvements have been particularly observed after administration of T-replete HSCT graft associated to an in vivo T cell depletion by the administration of high-doses of cyclophosphamide (HD-Cy) after transplantation. Here, we have analyzed the results of haplo-identical T replete HSC transplants, in particular, when performed with post-transplant HD-Cy in order to provide recommendations for the clinical practice. Criteria of choice for a haploidentical donor by priority order are absence of donor-specific antibodies (DSA) and to prioritize: CMV seronegative recipient/donor couples, ABO matching in case of deserythrocytation, male donor for a male recipient, the youngest donor. There is no clear argument in favor of the use of bone marrow versus peripheral blood stem cells (PBSC) after non myeloablative conditioning regimen, while after ablative conditioning PBSC seem to be associated with higher risks of GVHD without obvious impact on survival. Results of haploidentical HSCT, confirmed by several groups, are interesting in lymphomas (in particular Hodgkin disease) and for acute leukemia. Outcomes of patients rely on age, disease status at transplant and conditioning intensity. At equivalent disease risk, results of haploidentical HSCT seem comparable to those of HLA matched HSCT, raising the question of the classification of such transplants as alternatives. In all cases, we recommend to include patients in prospective clinical trials.


Assuntos
Seleção do Doador/normas , Haploidia , Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade/genética , Sistema ABO de Grupos Sanguíneos , Fatores Etários , Transplante de Medula Óssea/normas , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Teste de Histocompatibilidade , Doença de Hodgkin/terapia , Humanos , Leucemia/terapia , Linfoma não Hodgkin/terapia , Fatores Sexuais , Sociedades Médicas , Linfócitos T/imunologia , Condicionamento Pré-Transplante/métodos
11.
Cancer Med ; 5(11): 3068-3076, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27748046

RESUMO

We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow-up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05-4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02-4.61, P = 0.04) and a trend for lower leukemia-free survival (LFS, HR: 1.75; 95%CI: 0.94-3.26, P = 0.08). These results were confirmed using a propensity score-matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2-year OS FB2A2: 38% [14.5-61.6] vs. CloB2A2: 79.2% [62.9-95.4], P = 0.01; 2-year LFS FB2A2: 38% [16-59.9] vs. CloB2A2: 70.8% [52.6-89], P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2-year RI FB2A2: 41.2% [19-62.4] vs. CloB2A2: 16.7% [5-34.2], P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante , Nucleotídeos de Adenina/administração & dosagem , Adulto , Idoso , Arabinonucleosídeos/administração & dosagem , Clofarabina , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
12.
J Virol ; 90(19): 8686-97, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27440893

RESUMO

UNLABELLED: Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella upon primary infection and zoster upon reactivation from latency in sensory ganglion neurons. The replication of herpesviruses requires manipulation of cell signaling pathways. Notably, CREB, a factor involved in the regulation of several cellular processes, is activated upon infection of T cells with VZV. Here, we report that VZV infection also induced CREB phosphorylation in fibroblasts and that XX-650-23, a newly identified inhibitor of the phosphorylated-CREB (pCREB) interaction with p300/CBP, restricted cell-cell spread of VZV in vitro CREB phosphorylation did not require the viral open reading frame 47 (ORF47) and ORF66 kinases encoded by VZV. Evaluating the biological relevance of these observations during VZV infection of human skin xenografts in the SCID mouse model of VZV pathogenesis showed both that pCREB was upregulated in infected skin and that treatment with XX-650-23 reduced infectious-virus production and limited lesion formation compared to treatment with a vehicle control. Thus, processes of CREB activation and p300/CBP binding are important for VZV skin infection and may be targeted for antiviral drug development. IMPORTANCE: Varicella-zoster virus (VZV) is a common pathogen that causes chicken pox and shingles. As with all herpesviruses, the infection is acquired for life, and the virus can periodically reactivate from latency. Although VZV infection is usually benign with few or no deleterious consequences, infection can be life threatening in immunocompromised patients. Otherwise healthy elderly individuals who develop zoster as a consequence of viral reactivation are at risk for postherpetic neuralgia (PHN), a painful and long-lasting complication. Current vaccines use a live attenuated virus that is usually safe but cannot be given to many immunodeficient patients and retains the capacity to establish latency and reactivate, causing zoster. Antiviral drugs are effective against severe VZV infections but have little impact on PHN. A better understanding of virus-host cell interactions is relevant for developing improved therapies to safely interfere with cellular processes that are crucial for VZV pathogenesis.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína p300 Associada a E1A/metabolismo , Herpesvirus Humano 3/fisiologia , Interações Hospedeiro-Patógeno , Fragmentos de Peptídeos/metabolismo , Sialoglicoproteínas/metabolismo , Replicação Viral , Animais , Modelos Animais de Doenças , Herpes Zoster/patologia , Herpes Zoster/virologia , Humanos , Camundongos SCID , Fosforilação , Processamento de Proteína Pós-Traducional , Pele/patologia
13.
Biol Blood Marrow Transplant ; 22(2): 240-247, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26256942

RESUMO

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT.


Assuntos
Transplante de Medula Óssea/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Doadores de Tecidos , Adulto Jovem
14.
Biol Blood Marrow Transplant ; 21(8): 1452-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25911579

RESUMO

Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Resultado do Tratamento
15.
Eur J Haematol ; 94(5): 449-55, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25238651

RESUMO

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto-SCT; n = 82; median age: 48 years; median follow-up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow-up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good-risk cytogenetics and lower number of previously transplanted patients, 3-year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo-SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11-0.82, P = 0.02), but higher non-relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46-11.9, P = 0.008). Results from this large study suggest that UCB allo-SCT provides better disease control than auto-SCT, which is especially important in the setting of high-risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo-SCT.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Sistema de Registros , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Autólogo , Transplante Homólogo
16.
Eur J Haematol ; 94(3): 265-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25130897

RESUMO

T-prolymphocytic leukemia (T-PLL), a rare aggressive mature T-cell disorder, remains frequently resistant to conventional chemotherapy. Studies have suggested that allogeneic hematopoietic stem cell transplantation (HSCT) might possibly serve to consolidate the response to initial chemotherapy. The current report summarizes the outcome of 27 T-PLL cases identified in the registry in French Society for stem cell transplantation (SFGM-TC). Prior to HSCT, 14 patients were in complete remission (CR), 10 in partial response, three refractory, or in progression. Following HSCT, 21 patients achieved CR as best response. With a median follow-up for surviving patients of 33 (range, 6-103) months, 10 patients are still alive in continuous CR. Overall survival and progression-free survival estimates at 3 yr were 36% (95% CI: 17-54%) and 26% (95% CI: 14-45%), respectively. The relapse incidence after HSCT was 47% occurring at a median of 11.7 (range, 2-24) months. Overall cumulative incidence of transplant-related mortality was 31% at 3 yr. These results suggest that HSCT may allow long-term survival in patients with T-PLL following induction treatment; however, it is associated with a significant rate of toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Raios gama/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T/terapia , Sistema de Registros , Adulto , Idoso , Feminino , Seguimentos , França , Humanos , Leucemia Prolinfocítica de Células T/mortalidade , Leucemia Prolinfocítica de Células T/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Sociedades Médicas , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
17.
Orphanet J Rare Dis ; 9: 162, 2014 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-25496809

RESUMO

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.


Assuntos
Gerenciamento Clínico , Doenças do Sistema Endócrino/terapia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doenças Metabólicas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/etiologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/tendências , Terapia de Reposição Hormonal/métodos , Terapia de Reposição Hormonal/tendências , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/etiologia
18.
Biol Blood Marrow Transplant ; 20(5): 646-54, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24462982

RESUMO

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 consecutive patients who underwent allo-SCT for progressive MDS between October 1999 and December 2009, 93 received ATG (ATG group) at the median dose of 5 mg/kg, whereas 149 patients did not (no-ATG group). Donors were sibling (n = 153) or HLA-matched unrelated (n = 89). Patients received blood (n = 90) or marrow (n = 152) grafts after either myeloablative (n = 109) or reduced-intensity (n = 133) conditioning. Three-year overall and event-free survival, nonrelapse mortality, relapse, and chronic graft-versus-host disease (GVHD) development were not significantly different between the 2 groups. In contrast, acute grade II to IV GVHD occurred more often in the no-ATG group (55% of the patients) than in the ATG group (27%, P < .0001). Similar results were observed with acute grade III to IV GVHD (28% and 14% in the no-ATG group and ATG group, respectively; P = .009). In multivariate analysis, after adjustment with propensity score, the absence of ATG was the strongest parameter associated with an increased risk of acute grade II to IV GVHD (hazard ratio, 2.13; 95% confidence interval, 1.35 to 3.37; P = .001]. ATG had no impact on overall and event-free survival or cumulative incidence of the relapse. In conclusion, the addition of ATG to allo-SCT conditioning did not increase the incidence of relapse of patients with progressive MDS. The incidence of acute GVHD was decreased without compromising outcomes.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adulto , Idoso , Doença Crônica , Feminino , França , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Sociedades Médicas , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo
19.
Haematologica ; 99(3): 527-34, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24213148

RESUMO

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/terapia , Adolescente , Adulto , Transplante de Medula Óssea/efeitos adversos , Criança , Progressão da Doença , Feminino , Seguimentos , França , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma Cutâneo de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Recidiva , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
20.
PLoS Pathog ; 9(4): e1003292, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593002

RESUMO

Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi's Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68), are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naïve males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent the spread of these viruses in natural populations.


Assuntos
Gammaherpesvirinae/patogenicidade , Genitália Feminina/virologia , Genitália Masculina/virologia , Infecções por Herpesviridae/transmissão , Doenças Virais Sexualmente Transmissíveis/virologia , Animais , Linhagem Celular , Cricetinae , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Evasão da Resposta Imune , Transmissão Vertical de Doença Infecciosa , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Replicação Viral , Eliminação de Partículas Virais
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