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1.
Lancet Haematol ; 7(2): e157-e167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32004485

RESUMO

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco/efeitos adversos , Gerenciamento Clínico , Monitoramento de Medicamentos , Resistência a Medicamentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos
2.
J Korean Med Sci ; 35(7): e46, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32080987

RESUMO

BACKGROUND: This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA). METHODS: From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors. RESULTS: With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; P = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) (P = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; P = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; P = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, P = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; P = 0.001) and GFFS (85.7% vs. 35.7%; P = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome. CONCLUSION: This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.


Assuntos
Anemia Aplástica , Inibidores Enzimáticos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Vidarabina/análogos & derivados , Adolescente , Anemia Aplástica/terapia , Criança , Intervalo Livre de Doença , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Masculino , Estudos Retrospectivos , Transplante Homólogo , Vidarabina/uso terapêutico
3.
Ann Hematol ; 99(2): 385-388, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773213

Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Terapia de Alvo Molecular , Segunda Neoplasia Primária/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Aloenxertos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/etiologia , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/terapia , Masculino , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protoporfiria Eritropoética/terapia , Recidiva , Indução de Remissão , Ativação Viral , Adulto Jovem
4.
Ophthalmic Res ; 63(1): 50-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31117087

RESUMO

PURPOSE: Ocular graft-versus-host disease (oGvHD) following allogeneic hematopoietic stem cell transplantation develops as severe dry eye disease (DED) and is initially treated with lubricants, although no clinical trials are available using artificial tears in oGvHD. This trial was set up to test perfluorohexyloctane (NovaTears®) as nonpreserved layer-forming agent for the treatment of DED in oGvHD. METHODS: 25 patients with severe DED due to oGvHD received 1 drop perfluorohexyloctane 4 times daily during a prospective, multicenter, observational 12-week study on top of established topical therapy. Clinical parameters included Schirmer test, tear film breakup time, corneal staining, meibum secretion and ocular surface disease index. Adverse events, visual acuity and intraocular pressure were key safety parameters. RESULTS: From 25 patients recruited, 23 presented for the second visit. Perfluorohexyloctane treatment did not lead to any changes in clinical or safety parameters but led to fast relief in symptoms in 57% of the patients. One adverse reaction occurred. CONCLUSIONS: This study showed no change in clinical signs in severe DED due to oGvHD, which was not unexpected due to the underlying pathomechanisms. However, the study showed improvement of symptoms in individual patients allowing application of perfluorohexyloctane as an additional symptomatic therapy in oGvHD.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Fluorcarbonetos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
Ann Hematol ; 99(2): 343-349, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31879790

RESUMO

Ruxolitinib is a promising option for treating steroid-refractory acute graft-versus-host disease (SR-aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe ruxolitinib treatment for SR-aGVHD in HSCT patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) to evaluate its effectiveness. We evaluated the outcomes of 12 patients who received ruxolitinib for SR-aGVHD between January 2017 and March 2019. Of the 12 patients who received ruxolitinib, 7 patients achieved a complete response (CR), 3 had a partial response (PR), and 2 experienced treatment failure (TF). OS and CR rates were 83.3% and 58.3%, respectively. Moreover, CR was achieved by the six patients who had aGVHD with skin involvement. The mean time of steroid application in the patients who received ruxolitinib was 28.1 days. Median survival after HSCT was 64.6 weeks. The adverse effects of ruxolitinib included grades 3 to 4 neutropenia (n = 7) and grades 3 to 4 thrombocytopenia (n = 6). Cytomegalovirus reactivation was observed in three patients. A high rate of CR and short steroid application time of ruxolitinib as a salvage treatment were observed in HSCT patients with EBV-HLH. Consequently, from this study, it was determined that ruxolitinib is an optimal choice to treat SR-aGVHD in patients with EBV-HLH.


Assuntos
Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica , Pirazóis/administração & dosagem , Dermatopatias , Doença Aguda , Adolescente , Adulto , Aloenxertos , Criança , Intervalo Livre de Doença , Resistência a Medicamentos/efeitos dos fármacos , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/terapia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Estudos Retrospectivos , Dermatopatias/tratamento farmacológico , Dermatopatias/mortalidade , Esteroides/administração & dosagem , Taxa de Sobrevida
6.
J Oncol Pharm Pract ; 26(1): 5-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30854922

RESUMO

BACKGROUND: Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE: The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS: This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS: Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR (p < 0.001). CONCLUSION: This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.


Assuntos
Antifúngicos/farmacocinética , Transplante de Células-Tronco Hematopoéticas/tendências , Imunossupressores/farmacocinética , Transplante de Células-Tronco/tendências , Tacrolimo/farmacocinética , Triazóis/farmacocinética , Adulto , Antifúngicos/administração & dosagem , Esquema de Medicação , Interações de Medicamentos/fisiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Triazóis/administração & dosagem
7.
Invest Ophthalmol Vis Sci ; 60(14): 4511-4519, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675422

RESUMO

Purpose: The present study was designed to investigate the role of ocular surface glycocalyx and mucins in graft versus host disease (GVHD)-associated dry eye. The ameliorative effect of topical rebamipide, a mucin secretagogue, on GVHD-associated dry eye was also tested. Methods: A mouse model of allogeneic transplantation was used to induce ocular GVHD with C57BL/6 as donors and B6D2F1 as recipient mice. Phenol red thread method and fluorescein staining was used to quantify tear secretion and corneal keratopathy. At 8 weeks after the allogeneic transplantation, corneas were harvested to perform glycocalyx staining and confocal microscopy. Goblet cell staining was performed using periodic acid Schiff's staining. Corneal and tear film levels of Mucin 1, 4, 16, 19, and 5AC were quantified using ELISA and real-time PCR. Rebamipide was applied topically twice daily to mice eyes. Results: Allogeneic transplantation resulted in ocular GVHD-associated dry eye characterized by a significant decrease in tear film volume and the onset of corneal keratopathy. Ocular GVHD caused a significant decrease in the area and thickness of corneal glycocalyx. A significant decrease in the goblet cells was also noted. A significant decrease in mucin 4 and 5AC levels was also observed. Topical treatment with rebamipide partially attenuated ocular GVHD-mediated decrease in tear film volume and significantly reduced the severity of corneal keratopathy. Conclusions: Ocular GVHD has detrimental impact on ocular surface glycocalyx and mucins. Rebamipide, a mucin secretagogue, partially prevents ocular GVHD-associated decrease in tear film and reduces the severity of corneal keratopathy.


Assuntos
Alanina/análogos & derivados , Antioxidantes/uso terapêutico , Síndromes do Olho Seco/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Mucinas/metabolismo , Quinolonas/uso terapêutico , Administração Oftálmica , Alanina/uso terapêutico , Animais , Transplante de Medula Óssea , Antígeno Ca-125/metabolismo , Modelos Animais de Doenças , Síndromes do Olho Seco/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Proteínas do Olho/metabolismo , Feminino , Células Caliciformes/metabolismo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Mucina-5AC/metabolismo , Mucina-1/metabolismo , Mucina-4/metabolismo , Reação do Ácido Periódico de Schiff , Reação em Cadeia da Polimerase em Tempo Real , Lágrimas/metabolismo , Transplante Homólogo
8.
Transplant Proc ; 51(9): 3150-3154, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611124

RESUMO

BACKGROUND: X-linked immunodysregulation syndrome with polyendocrinopathy and enteropathy (IPEX) is caused by FOXP3 gene mutations that block the generation of regulatory T lymphocytes. We report an 18-month-old boy with classic IPEX who underwent 2 hematopoietic stem cell transplantations (HSCTs). METHODS: The first HSCT from an unrelated 8/10 HLA-matched umbilical cord blood donor (UCB) was performed after a conditioning regimen consisting of treosulfan, fludarabine, thiotepa, and thymoglobulin. Due to complete rejection of the UCB transplant, a second transplantation from a 6/10 HLA-matched mother was performed after alpha-beta T-cell depletion. The second conditioning regimen consisted of busulfan, fludarabine, a single dose of cyclophosphamide 1 g/m2, and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 106 CD34+ cells per kilogram body weight (BW) and 4.19 x 105 alpha-beta T lymphocytes per kilogram BW. Due to acute graft rejection, the boy was treated with thymoglobulin, and full donor chimerism in both T lymphocytes and mononuclear cells was achieved. The immunosuppressive therapy was stopped 1 year after transplantation. To date, the patient remains free from graft-vs-host disease (GVHD) and immunosuppression. CONCLUSIONS: HSCT after busulfan-based reduced-toxicity conditioning in patients with IPEX syndrome is feasible and well tolerated and can result in full donor engraftment. Monitoring of chimerism and aggressive therapy in cases of graft rejection are warranted due to the high reactivity of residual autologous T lymphocytes. T-cell depletion reduces the risk of GVHD and the need for steroid therapy, which is especially challenging in patients with diabetes.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/cirurgia , Depleção Linfocítica/métodos , Condicionamento Pré-Transplante/métodos , Soro Antilinfocitário/uso terapêutico , Bussulfano/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Fatores Imunológicos/uso terapêutico , Lactente , Masculino , Suíça
9.
BMJ Case Rep ; 12(9)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511262

RESUMO

A 12-year-old boy presented with central chest pain, shortness of breath and type 1 respiratory failure. He had a background of graft versus host disease (GvHD), which was currently managed with imatinib therapy. A focused bedside ultrasound scan was performed revealing a large pericardial effusion. The child was referred to a tertiary paediatric cardiology centre where he underwent emergency pericardiocentesis, draining a total of 800 mL of pericardial fluid. Fluid analysis excluded infection, and with no other concerns for a GvHD flare the diagnosis of an imatinib-induced pericardial effusion was made. On terminating the therapy, the pericardial collection did not reaccumulate. Tyrosine kinase inhibitor-induced pericardial and/or pleural effusion should be considered as a differential diagnosis in paediatric patients on this therapy presenting in a similar manner.


Assuntos
Mesilato de Imatinib/efeitos adversos , Derrame Pericárdico/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Masculino , Derrame Pericárdico/diagnóstico
10.
Rinsho Ketsueki ; 60(8): 953-959, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484895

RESUMO

Graft-versus-host-disease (GvHD) is a major complication and leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids remain the standard initial therapy for GvHD; however, patients frequently become steroid-refractory (SR) or remain steroid dependent. Cytokine inhibition appears to be a potential option; however, blockade of any single cytokine may not be sufficient probably because of the redundant effects of multiple cytokines. The Jak1/2 inhibitor ruxolitinib can simultaneously inhibit the signaling pathway of multiple cytokines with relevance for GvHD, such as interferon (IFN-γ), IL-2, and IL-6. A recent retrospective survey reported that ruxolitinib produced a high response rate for SR-GvHD, leading to better survival odds. A prompt and sustained ruxolitinib response contributes to the steroid-sparing effect; however, accumulating evidence showed that ruxolitinib exerts substantial myelosuppression and immunosuppressive activity in patients with myelofibrosis (MF). Additionally, serious adverse events following discontinuation of ruxolitinib treatment, characterized by acute relapse of the disease and/or GvHD, have been recognized. Herein we discuss the advantages and disadvantages of ruxolitinib as treatment for GvHD in patients with MF.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Pirazóis/uso terapêutico , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Mielofibrose Primária/complicações , Estudos Retrospectivos
12.
Ann Hematol ; 98(10): 2399-2405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31375860

RESUMO

Rituximab was recently described also as first-line therapy of chronic graft-versus-host disease (cGvHD). We retrospectively analyzed the efficacy and safety of all patients receiving rituximab for treatment of cGvHD between 2005 and 2016 at the Regensburg University transplant center with a median follow-up after rituximab therapy of 2.8 years. Responses of 29 allogeneic stem cell-transplanted patients (median age 49) with previous failure of response to steroids including one patient after donor lymphocyte infusion were assessed. Three months after rituximab application, the overall response rate was 31% (7% complete (n = 2) and 24% partial remission (n = 7)). At 12 months, overall survival was 72% (n = 21) and failure-free survival was 24% (n = 7). We further analyzed associations of rituximab response with clinical characteristics showing a higher response rate in steroid-dependent cGvHD patients (89% of 9 responding compared to steroid refractory patients (11% responding)). However, this difference was not statistically significant. Seven patients (24%) (including four lethal infectious complications) developed serious infections requiring hospitalization within 1-9 months after rituximab therapy exclusively in patients failing to respond to rituximab. In conclusion, rituximab appears to be an effective treatment of cGvHD especially in steroid dependent patients, but identification of biomarker predicting response will be crucial to avoid long-term infectious morbidity and mortality in non-responders.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/mortalidade , Rituximab/administração & dosagem , Adulto , Idoso , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco , Taxa de Sobrevida
13.
Ann Hematol ; 98(9): 2187-2195, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273420

RESUMO

Organizing pneumonia (OP) is a poorly understood complication of hematopoietic stem cell transplant (HSCT). We identified 15 patients diagnosed with OP following HSCT and described their clinical course. CT chest findings were remarkable for multifocal infiltrates that were predominantly consolidating or ground glass opacities. Bronchoalveolar lavage (BAL) was performed on 14 patients with five having lymphocytosis (> 25% lymphocytes), three with eosinophilia (> 5% eosinophils), three with neutrophilia (> 30% neutrophils), and three with normal cell counts. Flow cytometry was analyzed on BAL fluid in 13 patients with 11 having a CD4/CD8 of < 0.9. Initial treatment with 0.3-1.0 mg/kg prednisone resulted in improvement in symptoms, in radiographic findings, and in pulmonary function testing for the majority of patients. Six patients had recurrence of OP after completing treatment. Eleven patients had evidence of extra-pulmonary graft-versus-host disease prior to diagnosis of OP, and seven patients were diagnosed with an upper respiratory tract infection (URI) within 8 weeks of OP diagnosis. Most patients respond well to prednisone with significant improvement in pulmonary function, but risk of recurrence is high after cessation of steroid treatment. Risk factors for the development of OP may include prior URI.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Pulmão , Pneumonia , Tomografia Computadorizada por Raios X , Adulto , Idoso , Líquido da Lavagem Broncoalveolar , Eosinofilia/diagnóstico por imagem , Eosinofilia/tratamento farmacológico , Eosinofilia/fisiopatologia , Eosinófilos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico por imagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neutrófilos , Pneumonia/diagnóstico por imagem , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Pneumonia/fisiopatologia , Testes de Função Respiratória
14.
Drugs ; 79(14): 1499-1509, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359326

RESUMO

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for many hematological malignant and non-malignant diseases. A major complication of the procedure is the donor T-cell-mediated graft-versus-host disease (GvHD). GvHD accounts for about 10% of early mortality after transplantation. GVHD is also the major cause of morbidity and disability in the late follow-up phase of transplanted patients, mainly because of the low response to first-line steroids, and the lack of efficient second-line standard treatments. The increasing knowledge regarding GVHD pathogenesis provides new pharmacological targets, potentially exploitable in clinical practice, in order to prevent and treat this complication. This review provides a description of GVHD pathogenesis, with a focus on the central role of the Janus kinase-related mechanisms. The first inflammatory innate-immunity response is triggered by a JAK/STAT dependent pathway, and JAK inhibition impairs antigen-presenting cell differentiation and activation and downregulates the expression of signals for T-cell triggering. The chronic evolution of alloreactivity, characterized by the long-term maintenance of inflammation and fibrosis, is also dependent on JAK/STAT activation. Based on preclinical data, we reviewed the rationale behind the clinical use of JAK-inhibitors in GVHD, presenting available results of clinical trials and reports, and looked at future implementation of this new promising treatment approach.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Animais , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/metabolismo
15.
Immunohorizons ; 3(3): 110-120, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31240276

RESUMO

Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. Here, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L monoclonal antibody (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD (x-aGVHD) model in both preventative and therapeutic modes. Mechanistically, blocking OX40L-OX40 interaction with an anti-hOX40L antibody reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21- and TNF-producing T cell responses, while promoting regulatory T cell (Treg) responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L-OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L-OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Ligante OX40/metabolismo , Receptores OX40/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Doença Aguda , Animais , Anticorpos Monoclonais/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Progressão da Doença , Etanercepte/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Humanos , Interleucinas/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos , Ligante OX40/antagonistas & inibidores , Ligação Proteica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
16.
Blood ; 134(9): 776-781, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31243040

RESUMO

Soluble thrombomodulin plasma concentrations are elevated in steroid-resistant graft-versus-host disease (GVHD), implying endothelial hypofunctioning for thrombomodulin-dependent generation of activated protein C's (APC) anticoagulant, anti-inflammatory, and antiapoptotic functions. Recombinant thrombomodulin or APC administration decreases acute GVHD, manifested by intense inflammation and tissue destruction. Here, we administered recombinant murine wild-type (WT) APC to mice with established chronic GVHD (cGVHD), a less-inflammatory autoimmune-like disease. WT APC normalized bronchiolitis obliterans-induced pulmonary dysfunction. Signaling-selective APC variants (3A-APC [APC with lysine 191-193 replaced with 3 alanines] or 5A-APC [APC with lysine 191-193 replaced with 3 alanines and arginine 229/230 replaced with 2 alanines]) with normal cytoprotective properties, but greatly reduced anticoagulant activity, provided similar results. Mechanistically, WT APC and signaling-selective variants reduced T follicular helper cells, germinal center formation, immunoglobulin, and collagen deposition. WT APC can potentially cleave protease-activated receptor 1 (PAR1) at Arg41 or Arg46, the latter causing anti-inflammatory signaling. cGVHD was reduced in recipients of T cells from WT PAR1 or mutated Gln41-PAR1 donors but not from mutated Gln46-PAR1 donors. These data implicate donor T-cell APC-induced noncanonical cleavage at Arg46-PAR1, which is known to confer cytoprotective and anti-inflammatory activities. Together, these data indicate that APC anticoagulant activity is dispensable, whereas anti-inflammatory signaling and cytoprotective cell signaling by APC are essential. Because a phase 2 ischemic stroke clinical trial did not raise any safety issues for 3A-APC treatment, our studies provide a foundational platform for testing in clinical cGVHD therapy.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Proteína C/uso terapêutico , Receptor PAR-1/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Doença Crônica , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Proteínas Recombinantes/uso terapêutico , Linfócitos T/metabolismo , Linfócitos T/patologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-31152638

RESUMO

Posterior reversible encephalopathy syndrome (PRES) is one of the most serious complication after allogeneic stem cell transplantation in paediatric setting. It is most commonly reported as adverse event of immunosuppressive strategies during transplantation. We present a case of a 7 years old girl with myelodysplastic syndrome (MDS) treated with allogeneic stem cell transplantation (ASCT) at our department. Diagnosis of PRES was confirmed by imaging techniques during the first month after transplant and it was very likely connected with cyclosporine neurotoxicity. The aim of this article is to present our first experience in diagnosing and treating PRES in paediatric stem cell transplantation. Our experience showed that PRES is one of the reasons for higher transplant related mortality in children. Early prediction of factors contributing to PRES and closely monitoring of patient's vital signs, especially blood pressure, neurological status and vision are the main contributors for challenging the patient with another immunosuppressive agent that has less neurological toxicity. Still studies have to be initiated to confirm the influence of PRES on transplant outcome.


Assuntos
Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Síndromes Mielodisplásicas/terapia , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Criança , Ciclosporina/uso terapêutico , Evolução Fatal , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Síndromes Neurotóxicas/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/tratamento farmacológico , Transplante de Células-Tronco/métodos , Transplante Homólogo/métodos
18.
Turk J Haematol ; 36(3): 186-192, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31208159

RESUMO

Objective: Steroid-resistant acute graft-versus-host disease (srAGVHD) is the most important cause of morbidity and mortality after allogeneic stem cell transplantation. There are several treatment methods available, including mesenchymal stem cell (MSC) application. The aim of this study was to evaluate the results of MSC therapy performed in children with srAGVHD. Materials and Methods: MSC therapy was used in our center between November 2014 and December 2017 for 22 patients who developed srAGVHD. The patients were retrospectively evaluated in terms of treatment response and survival. Results: After application of MSCs, complete response was obtained in 45.5% of the subjects, partial response was obtained in 13.6%, and no response was obtained in 40.9%. We found that 45.5% of the patients were alive and 54.5% had died and our treatment results were similar to those in the literature. Response to MSC treatment was found to be the only prognostic marker affecting mortality. Conclusion: MSC application is a treatment method that can be used safely together with other treatment methods in srAGVHD, a condition that has a high mortality rate. There are almost no acute side effects. There are also no serious long-term side effects in the literature. Prospective randomized studies are required to obtain high-quality data.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Esteroides/uso terapêutico , Doença Aguda , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
19.
Int Immunopharmacol ; 72: 479-486, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31051404

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γnull (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.


Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fenetilaminas/uso terapêutico , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos , Fenetilaminas/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
20.
Biomed Res Int ; 2019: 8163780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956985

RESUMO

Objective: Steroid-resistant graft-versus-host disease (GvHD) is a major challenge after allogeneic stem cell transplantation and associated with significant morbidity and mortality. There is no therapeutic standard defined beyond calcineurin inhibitors (CNI) and steroids. Furthermore, some patients may have contraindications against CNI or high-dose steroids. Efficacy of ruxolitinib against GvHD has been described recently. Methods: Ruxolitinib was used for treatment of acute or chronic GvHD in eight patients. The patients either needed intensification of therapy or had contraindications against use of CNI or high-dose steroids. Results: Supplementation of therapy in acute GvHD with severe diarrhea with ruxolitinib was unsuccessful. All these patients died from acute GvHD. Introduction of ruxolitinib into therapy and relapse prophylaxis in other patients was successful in 4/4 cases (CR=3, PR=1). Indications for ruxolitinib were contraindications against CNI due to aHUS in two cases and the need for steroid sparing in two other cases. None of these patients suffered from diarrhea at the initiation of ruxolitinib. Conclusion: Ruxolitinib was effective for therapy of acute and chronic GvHD in higher lines in patients without severe diarrhea. Ruxolitinib could replace successfully CNI and high-dose steroids. Further investigations are necessary to define the position of ruxolitinib in GvHD-therapy.


Assuntos
Resistência a Medicamentos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Pirazóis/administração & dosagem , Doença Aguda , Adulto , Idoso , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Esteroides/administração & dosagem , Esteroides/efeitos adversos
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