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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
3.
Lancet Haematol ; 7(2): e100-e111, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958417

RESUMO

BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60-7·60]; p=0·0016. At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9-23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9-25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2-29·2) versus 31·3% (21·9-40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5-35·1) in the anti-thymocyte globulin group and 41·3% (31·3-51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 53·3% (95% CI 42·8-62·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 70.6% (95% CI 60·6-78·6) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35-0·90]; p=0·017. Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient died of Epstein-Barr virus hepatitis. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including a decrease in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin could be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.


Assuntos
Soro Antilinfocitário/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Imunossupressores/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adolescente , Adulto , Idoso , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressores/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Linfócitos T/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
4.
Ann Hematol ; 99(1): 147-155, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786646

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2-2.5 mg/kg) and methylprednisolone (mPSL, 1 mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P < 0.001) and having undergone multiple HSCT (26.1% vs. 11.1%, P = 0.045). However, we found no significant differences in the 1-year overall survival (OS, 31.7% vs. 29.1%; P = 0.25), disease-free survival (DFS, 20.5% vs. 23.7%; P = 0.23), cumulative incidence of relapse (CIR, 40.0% vs. 42.8%; P = 0.92), non-relapse mortality (NRM, 39.5% vs. 33.5%; P = 0.22), or 100-day grade II-IV acute graft-versus-host disease (32.6% vs. 34.7%; P = 0.64) following HID-HSCT vs. non-HID-HSCT, respectively. Subgroup analysis stratified by disease and intensity of conditioning regimen demonstrated the same results between HID-HSCT and non-HID-HSCT. Furthermore, multivariate analysis showed that HID-HSCT was not an independent prognostic factor for OS (hazard ratio (HR) = 0.95 [95% confidence interval (CI), 0.58-1.58]), DFS (HR = 1.05 [95%CI, 0.67-1.68]), CIR (HR = 0.84 [95%CI, 0.48-1.47]), or NRM (HR = 1.28 [95%CI, 0.66-2.46]). In summary, transplant outcomes for RRAL were comparable in the HID-HSCT and non-HID-HSCT groups. HID-HSCT using very low-dose ATG and mPSL for RRAL may be a viable alternative to non-HID-HSCT.


Assuntos
Soro Antilinfocitário/administração & dosagem , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Depleção Linfocítica , Metilprednisolona/administração & dosagem , Adolescente , Adulto , Idoso , Aloenxertos , Ciclofosfamida/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Recidiva
5.
Ann Hematol ; 99(1): 167-179, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31828376

RESUMO

The optimal rabbit anti-thymocyte globulin (rATG) graft-versus-host disease (GVHD) prophylaxis regimen in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. In this prospective study, we used low-dose rATG for GVHD prophylaxis in patients or donors aged ≥ 40 years with hematological malignancies receiving MSD-PBSCT. rATG was administered to 40 patients at an intravenous dose of 5 mg/kg divided over day 5 and day 4 before graft infusion. No graft failure occurred. Median times to leukocyte engraftment and platelet engraftment were 11.0 days and 13.9 days. The cumulative incidence of grades 2-4 and grades 3-4 acute GVHD at day +100 was 30.0% and 2.6%. The 2-year cumulative incidence of extensive chronic GVHD and severe chronic GVHD was 11.4% and 14.7%. 93.5% (29/31) of patients had discontinued immunosuppressive medication within 3 years after transplantation. The 2-year cumulative incidence of transplant-related mortality (TRM) and relapse was 14.0% and 22.6%. The cumulative incidence of cytomegalovirus reactivation, Epstein-Barr virus reactivation, and fungal infection was 22.3%, 12.9%, and 12.5%. Kaplan-Meier estimates for overall survival, disease-free survival, and GVHD-free and relapse-free survival 3 years after transplantation were 68.9%, 68.9%, and 54.0%. rATG for GVHD prophylaxis is tolerable and efficacious at a 5 mg/kg total dose administered over 2 days (days -5 to -4) in patients receiving allogeneic MSD-PBSCT.


Assuntos
Soro Antilinfocitário/administração & dosagem , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco de Sangue Periférico , Irmãos , Doadores de Tecidos , Adulto , Idoso , Células Alógenas , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
6.
Ann Hematol ; 98(11): 2579-2591, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31628517

RESUMO

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores de Calcineurina/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Incidência , /etiologia , Japão/epidemiologia , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Neutrófilos , Contagem de Plaquetas , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
7.
Expert Opin Drug Metab Toxicol ; 15(10): 803-811, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31595800

RESUMO

Introduction: Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplantation (HSCT); therefore, the prevention of GVHD is important for a successful treatment. Tacrolimus (Tac), a calcineurin inhibitor, has been widely used for the prophylaxis of GVHD in HSCT recipients. Areas covered: This review introduces phase II/III of clinical trials related with Tac's roles in the prevention of GVHD in HSCT. Furthermore, we discuss the normal ranges of Tac concentrations, pharmacogenetics, and drug interactions of Tac, as well as its side effects in adult HSCT recipients. Expert opinion: A series of studies has established the efficacy and safety of Tac alone or in combination with other agents in HSCT. However, successful administration of Tac is complicated by its narrow therapeutic window, inter-patient pharmacokinetic variability, and a spectrum of undesirable side effects. It is necessary to maintain concentrations of Tac within the desired ranges for GVHD prophylaxis. Moreover, various factors contribute to significant variability in Tac pharmacokinetics, including drug interactions and genomic variation.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Tacrolimo/administração & dosagem , Adulto , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacocinética , Interações de Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Farmacogenética , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética
8.
BMC Med ; 17(1): 156, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31401973

RESUMO

BACKGROUND: The optimal dose of rabbit antithymocyte globulin (ATG, ImtixSangstat) minimizing infections without increasing graft-versus-host disease (GVHD) is unknown in T cell-replete, G-CSF-primed haploidentical hematopoietic stem cell transplantation (haplo-HSCT). METHODS: Four hundred and eight patients were enrolled in this multicenter study to evaluate the effect of 7.5 mg/kg and 10.0 mg/kg rabbit ATG on viral infections and GVHD prophylaxis after haplo-HSCT. The primary endpoint was EBV DNAemia within 1 year posttransplantation. RESULTS: The 1-year incidence of EBV DNAemia was 20.7% (95% confidence interval, 15.4-26.5) and 40.0% (33.3-46.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (P < 0.001). The 100-day cumulative incidence of grade II to IV aGVHD was 27.1% (21.1-33.4) and 25.4% (19.6-31.5) in the 7.5 mg/kg and 10.0 mg/kg ATG groups, respectively (P = 0.548). The 2-year incidence of chronic GVHD was 34.6% (27.8-41.4) and 36.2% (29.1-43.2) in the 7.5 mg and 10.0 mg groups (P = 0.814). The 1-year incidence of CMV DNAemia was 73.4% (67.2-79.4) and 83.4% (77.5-87.9) in the 7.5 mg/kg and 10.0 mg/kg groups (P = 0.038). The 3-year overall survival posttransplantation was 69.5% (63.2-75.8) and 63.5% (56.2-70.8), and the disease-free survival was 62.2% (55.3-69.1) and 60.3% (53.0-67.6) in the 7.5 mg/kg and 10.0 mg/kg groups, respectively (OS: P = 0.308; DFS: P = 0.660). The counts of EBV- and CMV-specific cytotoxic T cells (CTLs) were higher in the 7.5 mg/kg group than in the 10.0 mg/kg group early posttransplantation. CONCLUSIONS: Compared with 10.0 mg/kg, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in haplo-HSCT, probably by affecting EBV- and CMV-specific CTLs. TRIAL REGISTRATION: clinicaltrials.gov, NCT01883180 . Registered 14 June 2013.


Assuntos
Soro Antilinfocitário/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/administração & dosagem , Adolescente , Adulto , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/prevenção & controle , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle
9.
Adv Clin Exp Med ; 28(9): 1223-1228, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430069

RESUMO

BACKGROUND: Unmanipulated haploidentical stem cell transplantation (haploSCT) with post-transplant cyclophosphamide is an option for patients with advanced hematologic malignancies. It offers a platform both for non-major histocompatibility complex-restricted alloimmunity due to killer-like immunoglobulin receptor (KIR)-mediated mechanisms of natural killer lymphocyte regulation and for classical T-cell mediated antileukemic effects. OBJECTIVES: The devastating long-term sequelae after total body irradiation (TBI) in children are encouraging omission of irradiation techniques in pediatric stem cell transplantations (SCT). MATERIAL AND METHODS: Five children, 4 with acute leukemia and 1 with hemophagocytic lymphohistiocytosis, aged from 1 to 10 years, underwent haploSCT with post-transplantation cyclophosphamide. In all children, the conditioning regimen consisted of chemotherapy without TBI. The graft material was bone marrow (BM) in 4 cases and peripheral blood stem cells in 1 case. Three out of 5 leukemic patients showed better KIR haplotype associated with augmented alloreactivity. RESULTS: Engraftment with complete donor chimerism was achieved in 4 patients, and 1 recipient died before leukocyte recovery. Three patients developed skin acute graft-versus-host-disease (aGvHD), 1 gut aGvHD and 1 liver aGvHD. In 2 recipients, chronic graft-versus-host-disease (cGvHD) was observed (1 limited and 1 extensive). The 4 engrafted patients were alive and in complete remission 3, 9, 32, and 36 months after transplantation. A T-cell count of 200 cells/uL was reached 90 days after haploSCT in all patients. CONCLUSIONS: HaploSCT with TBI-free protocols can be a viable option for heavily pretreated patients with advanced malignancies.


Assuntos
Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Condicionamento Pré-Transplante , Irradiação Corporal Total
10.
Medicine (Baltimore) ; 98(29): e16498, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335716

RESUMO

RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT. PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT. DIAGNOSES: Two patients were diagnosed with ALL with high risk. INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT. OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively. LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Transplante Haploidêntico , Adulto , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Masculino , Doadores de Tecidos
11.
BioDrugs ; 33(4): 401-409, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31302863

RESUMO

Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune "reset" was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Escleroderma Sistêmico/terapia , Condicionamento Pré-Transplante/métodos , Ensaios Clínicos Controlados como Assunto , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Prospectivos , Escleroderma Sistêmico/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do Tratamento
12.
Transfus Apher Sci ; 58(4): 472-474, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31303512

RESUMO

Mogamulizumab (Mog), a humanized anti-CCR4 antibody, provides an important treatment option for relapsed/refractory adult T cell leukemia/lymphoma. However, administration of Mog before allogenic hematopoietic stem cell transplantation has been reported to be a risk factor for severe acute graft-versus-host disease (GVHD). The etiological hypothesis is Mogamulizumab may eradicate CCR4-positive regulatory T cells (Tregs). Theoretically, Treg homeostasis and course of GVHD can be affected by plasma exchange (PE) with decreasing plasma Mog concentration. Here, we present a case of severe acute GVHD after pretransplantation Mog, in which PE was performed for liver failure. As a result, plasma Mog concentration was decreased but it did not lead to the prompt elevation of Treg levels in peripheral blood and clinical responses of GVHD were limited to partial remission. Our case suggests that recovery of donor-derived Treg in the acute phase after HSCT is multifactorial and the single procedure of PE-based Mog depletion does not necessarily warrant the quick restoration of Treg homeostasis.


Assuntos
Anticorpos Monoclonais Humanizados , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Troca Plasmática , Linfócitos T Reguladores/imunologia , Doença Aguda , Aloenxertos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Feminino , Doença Enxerto-Hospedeiro/induzido quimicamente , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/terapia , Falência Hepática/imunologia , Falência Hepática/terapia , Pessoa de Meia-Idade
13.
Blood ; 134(12): 924-934, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31292117

RESUMO

Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Seleção do Doador/normas , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/normas , Doadores não Relacionados , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Seleção do Doador/métodos , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/normas , Humanos , Recém-Nascido , Sistema de Registros , Doadores não Relacionados/provisão & distribução
14.
Blood ; 134(11): 892-899, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31270102

RESUMO

The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.


Assuntos
Soro Antilinfocitário/administração & dosagem , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Tipagem e Reações Cruzadas Sanguíneas/efeitos adversos , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/efeitos adversos , Humanos , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Imunologia de Transplantes , Transplante Homólogo , Adulto Jovem
15.
Rinsho Ketsueki ; 60(6): 626-634, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281155

RESUMO

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for patients with hematological malignancies with donor selection being one of the most important decisions for its success. Several possible donor options have been available, including matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and HLA-haploidentical donor. A MRD remains the preferred donor option for optimal transplant outcomes with approximately 30% of the patients having such a donor. Therefore, the remaining 70% of patients require an alternative donor source. Although a MUD is considered to be the next preferred donor option following a MRD, searching for a MUD may delay transplantation for patients unlikely to have a MUD. UCB or HLA-haploidentical donors allow for shorter time to transplant but are associated with increased risk. Recently, T-cell-replete haploidentical transplantation using posttransplantation cyclophosphamide (PTCY) has been developed. This strategy dramatically reduces the risk of graft versus host disease (GVHD), while transplant outcomes after PTCY-based HLA-haploidentical stem cell transplantation seem to be equivalent to those after HLA-matched stem cell transplantation. Recent advances in GVHD prophylaxis may change the algorithm for donor selection.


Assuntos
Seleção do Doador , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Algoritmos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Transplante Homólogo , Doadores não Relacionados
16.
Lancet Haematol ; 6(8): e409-e418, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31248843

RESUMO

BACKGROUND: Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting. METHODS: This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3-12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2-4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3-4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov, number NCT01231412. FINDINGS: Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31-60). The cumulative incidence of grade 2-4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17-35] in the triple-drug group vs 52% [41-63] in the standard group; HR 0·45 [95% CI 0·28-0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0-9) and 16% (8-24) in the triple-drug group and 16% (8-24) and 32% (21-43) in the standard group (HR 0·48 [0·26-0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78-93) in the triple-drug group and 70% in the standard group (60-80) and at 4 years it was 64% in the triple-drug group (54-75) and 46% in the standard group (34-57%; HR 0·62 [0·40-0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68-85) in the triple-drug group and 64% (53-74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49-70) and 41% in the standard group (30-53%; HR 0·64 [0·42-0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3-4 acute GVHD (2% [0-5] in the triple-drug group vs 8% [2-14] in the standard group; HR 0·55 [0·16-1·96]; p=0·36) and chronic GVHD (49% [39-59] in triple-drug group vs 50% [39-61] in the standard group; HR 0·94 [0·62-1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary. INTERPRETATION: Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center. FUNDING: National Institutes of Health.


Assuntos
Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Sirolimo/uso terapêutico , Idoso , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Antígenos HLA/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Recidiva , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Irradiação Corporal Total
17.
Nat Med ; 25(7): 1064-1072, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235963

RESUMO

Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.


Assuntos
Genes Codificadores dos Receptores de Linfócitos T , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Proteínas WT1/genética , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Transplante Homólogo
18.
Bull Cancer ; 106(6): 574-583, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-31060736

RESUMO

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for numerous malignant and non-malignant haematological diseases. A sustained engraftment of the donor stem cells is essential for transplant success and overall outcome. Graft failure is a rare but severe event after allogeneic hematopoietic stem cell transplantation. While different risk factors such as underlying disease, graft source or HLA matching have been found to be consistently associated with graft failure, other factors such as ABO mismatch graft-versus-host disease prophylaxis or infections, particularly viral reactivations, are more controversial. In this article, we review the different factors associated with graft failure.


Assuntos
Rejeição de Enxerto , Transplante de Células-Tronco Hematopoéticas , Aloenxertos , Incompatibilidade de Grupos Sanguíneos , Gerenciamento Clínico , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/prevenção & controle , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Incidência , Neutropenia/etiologia , Pancitopenia/etiologia , Fatores de Risco , Quimeras de Transplante
19.
Cell Mol Life Sci ; 76(17): 3323-3348, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31055643

RESUMO

Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues-adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn's disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Diferenciação Celular , Terapia Baseada em Transplante de Células e Tecidos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Via de Sinalização Wnt
20.
Orv Hetil ; 160(20): 774-779, 2019 May.
Artigo em Húngaro | MEDLINE | ID: mdl-31081358

RESUMO

The relationship between the gut flora and various diseases (obesity, diabetes mellitus, metabolic disorders, allergic and autoimmune diseases, inflammatory bowel diseases, liver failure, infections, certain neuropsychiatric disorders, tumors) has been highlighted in recent years. Depletion of microbiotics inhibits bone marrow healing. Infections and their antibiotic treatment may also affect hematopoiesis. Intestinal flora may also affect the severity of the graft-versus-host disease and may also play a role in the pathogenesis of immunthrombocytopenia through the T-regulator cells. The study summarizes the features of the gut flora, the effects of microbiotics on bone marrow healing, the course of infections, allogeneic bone marrow transplantation, graft-versus-host disease, lymphoma and the results of related research and therapeutic options. The authors briefly discuss the possible linkage between intestinal flora and immunthrombocytopenia and the effectiveness of the immunotherapy of tumors and its effect on the von Willebrand-factor synthesis. They draw attention on the importance of maintaining microbiotics diversity. Orv Hetil. 2019; 160(20): 774-779.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Sistema Digestório/microbiologia , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos
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