Assuntos
Produtos Biológicos/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Aprovação de Drogas/legislação & jurisprudência , Descoberta de Drogas/legislação & jurisprudência , Terapia Genética/legislação & jurisprudência , Regulamentação Governamental , Europa (Continente) , HumanosRESUMO
We wanted to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) may result in long-term survival in patients with solid cancer. HSCT was performed in 61 patients with solid cancer: metastatic renal carcinoma (n = 22), cholangiocarcinoma (n = 17), colon carcinoma (n = 15), prostate cancer (n = 3), pancreatic adenocarcinoma (n = 3), or breast cancer (n = 1). Liver transplantation was performed for tumor debulking in 18 patients. Median age was 56 years (range, 28 to 77). Donors were either HLA-identical siblings (n = 29) or unrelated (n = 32). Conditioning was nonmyeloablative (n = 23), reduced (n = 36), or myeloablative (n = 2). Graft failure occurred in 13 patients (21%). The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 47%, and that of chronic GVHD was 32%. Treatment-related mortality was 21%. At 5 years cancer-related mortality was 63%. Currently, 6 patients are alive, 2 with renal cell carcinoma, 1 with cholangiocarcinoma, and 3 with pancreatic carcinoma. Eight-year survival was 12%. Risk factors for mortality were nonmyeloablative conditioning (HR, 2.95; P < .001), absence of chronic GVHD (HR, 3.57; P < .001), acute GVHD of grades II to IV (HR, 2.90; P = .002), and HLA-identical transplant (HR, 5.00; P = .03). With none of these risk factors, survival at 6 years was 50% (n = 6). Long-term survival can be achieved in some patients with solid cancer after HSCT.
Assuntos
Adenocarcinoma/terapia , Neoplasias dos Ductos Biliares/terapia , Neoplasias da Mama/terapia , Neoplasias do Colo/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Renais/terapia , Neoplasias Pancreáticas/terapia , Neoplasias da Próstata/terapia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos , Metástase Neoplásica , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.
Assuntos
Carcinogênese , Proliferação de Células , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Técnicas de Cultura de Células , Diferenciação Celular/genética , Humanos , Células-Tronco Mesenquimais/metabolismoRESUMO
AIMS: Risk factors for disease relapse are remaining tumor or leukemic cells or mixed chimerism (MC) following allogeneic hematopoietic stem cell transplantation. Donor lymphocyte infusion (DLI) after stem cell transplantation can contribute to complete donor chimerism and graft-versus-tumor/leukemia effect. We evaluate cytokine secretion at the single-cell level using ELISpot in relation to DLI effect on disease response. PATIENTS & METHODS: Blood samples were collected from four patients with solid tumors and four with hematological malignancies before DLI, and 1 and 3 weeks after DLI. Tumor response was evaluated according to the international Response Evaluation Criteria In Solid Tumors (RECIST) method. Indications for DLI were stable disease or MC and/or progressive disease in solid tumors, and molecular or early relapse, or MC in hematological malignancies. ELISpot was performed for TNF-α, IFN-γ, IL-12, IL-4, IL-10 and IL-13 cytokines. RESULTS: Depending on the disease response, patients were divided into two groups: responders and nonresponders. Responders were patients who achieved partial response (one renal cell cancer) or stable disease (one prostate cancer) or clinical remission (two acute myeloid leukemia). Patients who relapsed, progressed or rejected the graft were the nonresponders. DLI rescued the renal cell cancer patient, who has partial response, and two acute myeloid leukemia patients, who are in clinical remission. Patients who responded tended to have a higher expression of TNF-α, IFN-γ, IL-12 and IL-10 than those who did not respond. CONCLUSIONS: DLI can act when the patients' mononuclear cells have normal or increased capacity to produce TNF-α, IFN-γ, IL-12 and IL-10. Assessment of these cytokines may be useful to predict those patients who will respond to DLI therapy.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva , Transfusão de Linfócitos , Quimerismo , ELISPOT , Humanos , Imunoterapia Adotiva/métodos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Transfusão de Linfócitos/efeitos adversos , Transfusão de Linfócitos/métodos , Doadores de Tecidos , Quimeras de Transplante , Transplante Homólogo/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HCT) allowed the existence of an allogeneic cell-mediated antitumor effect in metastatic colorectal cancer (mCRC) to be explored. We report on 39 patients with progressing mCRC treated with different RIC regimens in a multicenter clinical trial of the European Bone Marrow Transplantation Group. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (15%), and partial response (PR) in 2 (5%). All patients engrafted (median donor T cell chimerism of 90% at day +60). Transplant-related morbidities were limited. Grades II-IV acute graft-versus-host disease (aGVHD) occurred in 14 patients (35%) and chronic GVHD (cGVHD) in 9 patients (23%). Transplant-related mortality occurred in 4 patients (10%). The best tumor responses were: 1 complete response (CR) (2%), 7 PR (18 %), and 10 SD (26%), giving an overall disease control in 18 of 39 patients (46%). Allogeneic HCT after RIC is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. The study of an allogeneic cell based therapy in less advanced patients is warranted.
Assuntos
Neoplasias Colorretais/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total , Adulto JovemRESUMO
Explorative knowledge of cellular and molecular mechanisms of immune function and regulation has provided optimism in developing cancer immunotherapy. However, three decades of experimental and clinical investigations to offer powerful immunotherapeutic strategies against solid tumors, with the possible exception of monoclonal antibody-targeted therapies, have not succeeded in significantly prolonging patient survival. Nonspecific immune approaches, including cytokine-based therapies and allogeneic hematopoietic stem cell transplantation, have so far produced consistent, although limited, results. In this review, we present the developments of cell transfer-based strategies that, in preclinical studies, have demonstrated potential efficacy, but have only established tumor regression in limited numbers of patients. The key to success demands creative combinations of tumor antigens, adjuvance, gene modification and various administration strategies in the development of cell-based therapies together with other cancer-treatment principles, often in a stepwise 'space-rocket-type' approach. Combined efforts of several scientific disciplines, such as tumor biology and immunology, as well as cell and gene research in transplantation, will open new venues. New regulation for clinical trials with advanced therapy medicine products to ensure patient safety will be highlighted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer , Imunoterapia Adotiva , Neoplasias/tratamento farmacológico , Animais , Antígenos de Neoplasias/genética , Ensaios Clínicos como Assunto , Citocinas/imunologia , Citocinas/uso terapêutico , Humanos , Epitopos Imunodominantes/imunologia , Imunoterapia Adotiva/tendências , Neoplasias/imunologia , Transgenes/genética , Evasão TumoralRESUMO
The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.
Assuntos
Neoplasias Colorretais/terapia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/metabolismo , Transfusão de Linfócitos , Células T Matadoras Naturais/metabolismo , Neoplasias/terapia , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Citotoxicidade Imunológica , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/transplante , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Células T Matadoras Naturais/transplante , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/fisiopatologia , Carga Tumoral/imunologiaRESUMO
Allogeneic transplantation of hematopoietic cells from an HLA-compatible donor has been used to treat hematologic malignancies. Allogeneic transplantation not only replaces the marrow affected by the disease, but exerts an immune graft-versus-tumor (GVT) effect mediated by donor lymphocytes. The development of nonmyeloablative conditioning regimens before allogeneic transplantation has allowed this therapy to be used in elderly and disabled patients. An allogeneic GVT effect is observed in a proportion of patients with renal, breast, colorectal, ovarian, and pancreatic cancer treated with allogeneic transplantation. In general, the tumor response is associated with the development of acute and chronic graft-versus-host disease. Further improvements will depend on the identification of the antigen targets of GVT, and on reduction of the toxicity of the procedure. Targeted therapies may complement the immune effect of allogeneic transplantation. We present updated results from the literature and data recently placed on file at the European Bone Marrow Transplantation Solid Tumors Working Party.
Assuntos
Efeito Enxerto vs Tumor , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/terapia , Transplante HomólogoRESUMO
BACKGROUND: Following different types of conditioning, allogeneic hematopoietic stem cell transplantation produces a graft-versus-tumor effect in patients with solid tumors. We performed a non-randomized study comparing low intensity conditioning with reduced intensity conditioning after stem cell transplantation to demonstrate the graft-versus-tumor effect. DESIGN AND METHODS: Allogeneic stem cell transplantation was performed in 48 patients with metastatic renal cell cancer (n=17), colo-rectal cancer (n=15), non-metastatic advanced primary liver cancer after orthotopic liver transplantation (n=11), and other solid tumors (n=5). Tumor response was determined based on the international response evaluation criteria for solid tumors (RECIST). RESULTS: No significant difference in the incidence of graft rejection was found between the low intensity conditioning and reduced intensity conditioning groups. Engraftment occurred earlier in the low intensity conditioning group than in the reduced intensity conditioning group (median 0 vs. 16 days, respectively; p<0.001). Complete donor chimerism in B cells occurred earlier after low intensity conditioning than after reduced intensity conditioning (median 28 vs. 97 days, respectively; p<0.001). No significant difference in the incidence of tumor response was found between groups receiving the different types of the conditioning. The most favorable tumor response rate was found in patients who received donor lymphocyte infusions and developed chronic graft-versus-host disease (75% vs. 34%, p=0.003). The best graft-versus-tumor effect was demonstrated in patients with advanced primary liver cancer who had previously undergone liver transplantation (p=0.018). Patients receiving reduced intensity conditioning had a tendency to better overall survival compared to the low intensity conditioning group (30% vs. 17%, p=0.005). CONCLUSIONS: Adjuvant cell therapy with donor lymphocyte infusion may augment the graft-versus-tumor effect of chronic graft-versus-host disease. Patients with limited tumor load are indicated for allogeneic stem cell transplantation and reduced intensity conditioning may be favorable compared to low intensity conditioning.
Assuntos
Transfusão de Linfócitos , Neoplasias/terapia , Transplante de Células-Tronco de Sangue Periférico , Quimeras de Transplante , Condicionamento Pré-Transplante , Adulto , Idoso , Linfócitos B/imunologia , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Taxa de Sobrevida , Fatores de Tempo , Quimeras de Transplante/imunologia , Transplante HomólogoRESUMO
Severe hemorrhagic cystitis (HC) may be a life-threatening complication in allogeneic stem cell transplantation (SCT). In order to improve the strategies for prophylaxis and treatment, we retrospectively analyzed data on patients who underwent SCT at our center from 1990 through 2005. Patients with HC were identified through our database and their medical charts were reviewed. Grades 2-5 and 3-5 HC developed in 109/834 patients (13.1%) and 27/834 patients (3.2%), respectively. The frequency of HC decreased over the time from 18.0% in 1990-1992 to 9.5% in 2002-2005 (p = 0.005). HC started on a median of 35 (0-166) days post-transplant and persisted for a median of 23 (2-270) days. Transplant-related mortality was 21% in patients without HC, 15% in those with HC of grade 2, 55% in those with grade 3, and 71% in patients with HC of grades 4-5 (p < 0.001). In multivariate analysis, the risk factors for HC were myeloablative conditioning, busulphan, cytomegalovirus infection, hematological malignancy, and acute graft-versus-host disease (aGVHD). With four risk factors, the risk of HC development was 31%. Risk factors for severe HC of grades 3-5 were aGVHD and bacteremia.
Assuntos
Bacteriemia/complicações , Cistite/etiologia , Doença Enxerto-Hospedeiro/complicações , Hemorragia/etiologia , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo/efeitos adversosRESUMO
BACKGROUND: The use of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic stem cell transplantation (HSCT) has increased over the past five years. PATIENTS: In this study, involving 137 patients, we compared the outcome after RIC in patients receiving grafts from matched unrelated donors (MUD; n=74) and sibling donors (n=63). The MUD and sibling groups were comparable regarding diagnosis, including solid tumors and hematological malignancies, and conditioning regimens. RESULTS: Engraftment was successful in most patients (88%), with no significant difference between MUD and sibling transplants. Cytomegalovirus (CMV) infection was more common in the MUD group (65%) than in the sibling group (46%) (P=0.04). No difference in severe acute graft-versus-host disease (GVHD) was found between the groups. However, the incidence of chronic GVHD was higher after sibling transplants. This was probably due to higher donor age in this group, since this was the only significant risk factor for chronic GVHD in multivariate analysis. The incidence of transplant related mortality (TRM) was significantly higher after MUD transplantation (40%) than after sibling transplantation (16%) (P<0.01). Because relapse/disease progression was more common after sibling transplantation, there was no significant difference in overall survival between the two groups. CONCLUSION: Using unrelated donors after RIC is feasible, but it resulted in more CMV infection and increased transplant-related mortality. Survival was comparable to that of sibling transplants.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Doença Aguda , Antifúngicos/uso terapêutico , Causas de Morte , Doença Crônica , Ciclosporina/uso terapêutico , Infecções por Citomegalovirus/epidemiologia , Rejeição de Enxerto/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Micoses/prevenção & controle , Irmãos , Transplante de Células-Tronco/mortalidade , Análise de Sobrevida , Doadores de Tecidos/estatística & dados numéricos , Transplante Homólogo , Falha de Tratamento , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. DESIGN AND METHODS: Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. RESULTS: The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p < 0.001), mismatch in Epstein-Barr virus (EBV) serology (p < 0.001) and splenectomy (p = 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. INTERPRETATION AND CONCLUSIONS: We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade/métodos , Transtornos Linfoproliferativos/epidemiologia , Esplenectomia , Infecções por Vírus Epstein-Barr/imunologia , Seguimentos , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Antígenos HLA-DR/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/imunologia , Humanos , Incidência , Transtornos Linfoproliferativos/imunologia , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Transplante Homólogo/imunologiaRESUMO
BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD). METHODS: We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors. RESULTS: Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma. CONCLUSION: MSC is a very promising treatment for severe steroid-resistant acute GVHD.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Mesenquimais , Adulto , Animais , Criança , DNA/análise , Feminino , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Imunoterapia , Mucosa Intestinal/fisiopatologia , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Projetos Piloto , Esteroides/uso terapêutico , Doadores de Tecidos , Resultado do TratamentoRESUMO
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders. METHODS: We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches. RESULTS: In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease. CONCLUSION: In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/terapia , Adolescente , Adulto , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA/imunologia , Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/complicações , Neoplasias/diagnóstico , Neoplasias/imunologia , Transplante Homólogo , Resultado do TratamentoRESUMO
Allogeneic hematopoietic stem cell transplantation (SCT) has recently been presented as promising immunotherapy against renal cell, colon, ovarian, breast, and primary liver cancer. Because clinical results demonstrate a variable effect on metastases, we studied whether there is an association between the clinical response and free cytokines in serum. Two patients with metastatic colorectal and 4 with renal cell cancer underwent allogeneic SCT. Conditioning included fludarabine (30 mg/m2) for 3 or 5 days, using sibling or matched unrelated donors, respectively, followed by 2 Gy total body irradiation (n=5) or cyclophosphamide (60 mg/kg) for 2 days (n=1). Antithymoglobuline (4 mg/kg) was given to patients with matched unrelated donors (n=3). Immunosuppression was cyclosporin A, combined with mycophenolate mofetil (n=5) or methotrexate (n=1). The tumor load was examined by computer tomography of the thorax and abdomen before and 3, 6, 9, and 12 months after SCT. Free cytokines in serum were analyzed using enzyme-linked immunosorbent assay. In each patient, the ratio between inflammatory (I) and anti-I cytokines was calculated. No statistical significance was found between the cytokine ratio in correlation to the tumor load according to international response evaluation criteria in solid tumors criteria. In contrast, tumor regression was found to correlate with dominating I cytokine levels in 5/7 occasions, compared with 1/12 of cases with anti-I cytokines using our local method focusing on metastases in lungs, lymph nodes, and liver (P=.01). Thus, an increased level of I cytokines possibly mirrors tumor killing induced by type 1 T-cell response. Furthermore, anti-I cytokines might inhibit cytotoxic cells from exerting the antitumor effect of allogeneic SCT.
Assuntos
Citocinas/sangue , Efeito Enxerto vs Tumor/imunologia , Transplante de Células-Tronco Hematopoéticas , Neoplasias/sangue , Idoso , Citocinas/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Estudos Retrospectivos , Células Th1/imunologia , Células Th1/patologia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Carga Tumoral/imunologiaRESUMO
The influence of BK-viruria, donor background, and conditioning on the development of hemorrhagic cystitis was examined in 90 allogeneic hematopoetic stem cell transplant patients, of whom 15 developed hemorrhagic cystitis. Thirty-two patients had related and 58 had unrelated donors, while 44 received full, and 46 received reduced intensity conditioning (RIC). BK-viruria was more common in patients with hemorrhagic cystitis than in those without (p<0.01), and hemorrhagic cystitis was less common in patients with related donors than in those with unrelated donors (p=0.02). Finally, hemorrhagic cystitis and BK-viruria were less common in patients receiving RIC, rather than full conditioning (p<0.01 and p<0.01, respectively).
Assuntos
Vírus BK , Cistite/epidemiologia , Cistite/virologia , Transplante de Células-Tronco Hematopoéticas , Hemorragia/epidemiologia , Hemorragia/virologia , Infecções por Polyomavirus/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Urina/virologia , Adolescente , Adulto , Criança , Cistite/urina , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/urina , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/cirurgia , Infecções por Polyomavirus/urina , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo , Infecções Tumorais por Vírus/cirurgia , Infecções Tumorais por Vírus/urinaRESUMO
BACKGROUND AND OBJECTIVES: Cytomegalovirus (CMV) disease remains an important complication of allogeneic stem cell transplantation (SCT). We studied viral load kinetics and correlated the viral load and other transplant factors with the development of CMV disease. DESIGN AND METHODS: We studied 162 consecutive patients who were CMV seropositive or had CMV seropositive donors. Quantification of CMV DNA was performed by real-time polymerase chain reaction. RESULTS: CMV DNA detected was detected in 105 of the 162 patients. The mean peak viral loads were similar at first and subsequent reactivations. The serologic status of the donors and recipients prior to SCT significantly influenced the viral load. The cumulative incidence of CMV disease was 1.8% at 100 days and 6.3% at 365 days after SCT. The peak viral load were higher in patients who developed CMV disease than in patients without CMV disease (log10 3.5; SE +/- 0.26/200,000 cells vs. log10 2.7; SE +/- 0.09/200,000 cells; p=0.02). However, in multivariate analysis, only acute graft-versus-host disease (GVHD) grade II-IV and a graft from a CMV-negative donor to a CMV-positive patient were significant risk factors for CMV disease. In patients who required more than one course of pre-emptive therapy, acute GVHD and the rate of decrease in viral load during first pre-emptive therapy were significant risk factors for subsequent development of CMV disease. INTERPRETATION AND CONCLUSIONS: A decrease in viral load during pre-emptive therapy is an important factor for later development of CMV disease.
Assuntos
Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Incidência , Lactente , Pessoa de Meia-Idade , Infecções Oportunistas , Pré-Medicação , Fatores de Risco , Transplante Homólogo , Carga ViralRESUMO
BACKGROUND: The objective of this study was to identify prognostic factors for predicting survival in patients with advanced renal cell carcinoma (RCC) who had undergone an allogeneic stem cell transplantation after failure on immunotherapy. METHODS: The authors studied 70 patients with advanced RCC who underwent allogeneic transplantation with a fludarabine-based, reduced-intensity regimen. Ten parameters were analyzed at the time of transplantation for their power to predict survival. Clinical features were examined first univariately; then, variables that were correlated significantly with survival in the univariate analysis were included in a multivariate Cox regression model. RESULTS: Factors that were found to be associated significantly with limited survival were performance status, the number of metastatic sites, the presence of mediastinal metastasis, hemoglobin level, C-reactive protein (CRP) level, lactate dehydrogenase (LDH) level, and neutrophil counts. All these variables were included in a multivariate Cox regression model, and three were retained in the final model. Patients were classified according to the score estimated by the final Cox model in two groups (above or below the median value): The median survival was 3.5 months for patients who had a poor prognosis patients versus 23 months for patients who had a good prognosis. CONCLUSIONS: The current findings suggested that three easily available parameters (performance status, CRP level, and LDH level) could be used to stratify patients with advanced RCC who are candidates for allografting and to assist clinicians in decision-making and selection of an appropriate treatment program.
Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Transplante de Células-Tronco , Proteína C-Reativa/análise , Carcinoma de Células Renais/patologia , Humanos , Avaliação de Estado de Karnofsky , Neoplasias Renais/patologia , L-Lactato Desidrogenase/sangue , Prognóstico , Análise de Sobrevida , Transplante HomólogoRESUMO
The development of Epstein-Barr virus (EBV) associated lymphoproliferative disorder (PTLD) is related to EBV genome numbers in serum or plasma and B-cells, and the level of immunosuppression. EBV DNA viremia, defined as presence of EBV genomes in serum or plasma, is common in immunodeficiency. This survey of EBV viremia was performed by real-time polymerase chain reaction (PCR) on consecutive serum samples of 21 patients with acute (n = 3) or chronic liver disease (n = 18) during the first year after liver transplantation (LTX). Cytomegalovirus (CMV) DNA was analyzed with PCR in serum or leukocytes. The levels of EBV and CMV viremia were related to PTLD and the effect of different anti-rejection regimens. All patients were EBV-seropositive pre-LTX. In total, 24 of 152 (16%) samples from 10 of 21 (48%) individuals were EBV positive [five of 11 cyclosporin A (CsA); five of 10 tacrolimus treated cases]. EBV viremia was demonstrated in five of seven patients with OKT3 therapy. The number of EBV DNA positive samples was highest (26%) at 14 days after LTX. In the OKT3 treated groups, the medians of EBV DNA copy numbers were 1600/ml (range 230-7200) and 380/ml (range 120-860) in the CsA and tacrolimus patients, respectively (P < 0.02). One patient developed EBV lymphoma and another one EBV hepatitis 13 months and 24 days post-LTX, respectively. Both patients had received OKT3. Their EBV genome load was not significantly different from what was found in other patients. After ganciclovir therapy, EBV DNA was eradicated from serum in four of five patients for several months. EBV DNA load was not affected by CMV infection or disease. We conclude that presence of EBV in serum is a possible marker of an active infection and an early ganciclovir therapy may be beneficial. Quantification of EBV load offers the potential to implement pre-emptive interventions.