RESUMO
The principal aim of our study was to investigate whether patients transplanted more than 20 years ago for ß-thalassemia major had a different health-related quality of life (HRQoL) compared with the general population. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) were received from 109 ex-thalassemia patients who underwent hematopoietic stem cell transplantation (HSCT) during the 1980s and 1990s. Adjusted comparisons were performed separately for patient age at HSCT and the presence or absence of graft-versus-host disease (GVHD). Sociodemographic and clinical variables were also analyzed. The median age of our cohort at HSCT and the time of the survey was 12 years (range, 1-36) and 34 years (range, 21-48), respectively, with a median follow-up age of 22.8 years (range, 11.7-30.3). Statistical analysis of data collected more than 20 years after HSCT showed that the long-term HRQoL of ex-thalassemia patients was very similar to that of the general population. Clinical meaningful differences were only found for the general health (GH) scale (-8.9; 95% CI, -15.0 to 2.7, P = .005). Mental health, education level, employment status, marital status, living arrangements, and birth rate were compatible with normal living patterns. The development of GVHD and older age at transplantation were important impairing factors. Additional analyses performed to evaluate HRQoL in an age-sex-matched cohort of 124 patients receiving conventional treatment of ß-thalassemia revealed poorer outcomes compared with the cohort of transplanted patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Talassemia beta/cirurgia , Adulto , Estudos Transversais , Coleta de Dados , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/psicologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Tempo , Adulto JovemRESUMO
Bone marrow transplantation (BMT) performance can be limited by a lack of ideal donors, and the role of alternative donor hematopoietic cell transplantation in thalassemia is not well established. Here we used a new treatment protocol (Pc 26.1) in 16 thalassemia patients to perform BMT using phenotypically HLA-identical or 1-antigen-mismatched relatives (related donors [RDs]). We compared these results with HLA-matched sibling (matched sibling donors [MSDs]) BMT in 66 patients. The entire RD group and 88% of MSD group had sustained engraftment. Rejection incidence was 0% in the RD and 12% (95% confidence interval [95% CI], 6%-21%) in MSD groups (P = .15), with respective thalassemia-free survival probabilities of 94% (95% CI, 63%-99%) and 82% (95% CI, 70%-89%) (P = .24). Transplant-related mortality was 6% (95% CI, 1%-26%) in the RD group and 8% (95% CI, 3%-16%) in the MSD group (P = .83). The intensified new protocol was not associated with increased nonhematologic toxicity. The present data show that the Pc 26.1 preparative regimen allows thalassemia patients to safely undergo BMT from RDs who are not HLA-matched siblings, with transplant outcomes similar to patients with MSD grafts.
Assuntos
Transplante de Medula Óssea/métodos , Teste de Histocompatibilidade , Histocompatibilidade , Talassemia/terapia , Adolescente , Líquido Amniótico , Transplante de Medula Óssea/mortalidade , Criança , Pré-Escolar , Família , Feminino , Rejeição de Enxerto/mortalidade , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Lactente , Masculino , Estudos Prospectivos , Taxa de Sobrevida , Talassemia/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Busulfan (Bu) is an integral part of conditioning regimens for patients with sickle cell anemia (SCA) undergoing transplantation. Patients with SCA might predispose to transplant-related neurological and pulmonary toxicities due to pre-existing disease-related cerebrovascular and lung injury. Bu therapy appears to be an important contributing factor in this context. PROCEDURE: We studied the pharmacokinetics of intravenous Bu and clinical outcomes of 36 children with SCA undergoing bone marrow transplantation. Most patients had pre-existing organ system damage. Busulfan was administered every 6 hr for 4 days with pharmacokinetic-guided dose adjustment to target a conservative area under the concentration versus time curve (AUC) range of 900-1,350 µMol*min. RESULTS: We found that the first-dose Bu clearance was significantly higher (P < 0.0005) than the subsequent daily clearance, which remained unchanged during the following days. After the first-dose, 69% of patients achieved the target range. We adapted a new dose-adjustment strategy targeting exposures to the lower end (900 µMol*min) of the AUC range after the first dose of Bu to avoid unnecessary dose increases on subsequent days due to differences in clearance. This strategy enabled most patients to maintain the AUC within therapeutic range following dose adjustments. CONCLUSIONS: Differences in Bu clearance after the first-dose and subsequent daily doses in patients with SCA should be considered for pharmacokinetic-guided dose adjustment. Conservative AUC range and targeting exposures to the lower end of the range after the first dose was associated with negligible toxicity, and high engraftment and sickle cell-free survival rates.
Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/farmacocinética , Condicionamento Pré-Transplante/métodos , Adolescente , Aloenxertos , Anemia Falciforme/mortalidade , Bussulfano/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Agonistas Mieloablativos/efeitos adversos , Estudos Prospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: Immunomagnetic cell selection (ICS) cells is increasingly used in allogeneic hematopoietic transplantation in order to reduce the T cells quantity. The aim of this study was to evaluate an protocol based on Ficoll method before ICS. STUDY DESIGN AND METHODS: The automated procedure was compared with the standard method. In the group 1 the cell processing involves the extraction of the buffy-coat by Ficoll before incubation with antibodies. This procedure was performed with the Sepax S-100 device. The efficacy of this automated procedure was compared with the group 2. In this group, the cell washing and the incubation were performed through the standard method. The CD34+ cells collected by apheresis (HPC-A) were selected with ICS. RESULTS: The results obtained after Ficoll procedure, showed a total nucleated cells (TNCs) and CD34+ cells recovery of 85.73% (75.90-90.63; SD 4.25) and 79.31% (51.77-112.31; SD 18.40), respectively. The TNC and CD34+ cells recovery after the pre-incubation washing performed through the standard method, was 75.54% (38.36-97.76; SD 22.5) and 61.51% (30.87-81.79; SD 19.3), respectively. The CD34+ cells recovery after ICS was 79% (51.77-100; SD 18.40) and 44% (15.57-88.24; SD 25.91) in the group 1 and the group 2, respectively. This difference was statistically significant (p=0.001). CONCLUSION: The efficacy of the ICS which resulted to be higher in the group 1 compared to the group 2. Overall, our data suggest that the Ficoll procedure before incubation is suitable for the clinical routine in the ICS for haploidentical transplantation in patients affected by thalassemia.
Assuntos
Anemia , Antígenos CD34/sangue , Transplante de Células-Tronco Hematopoéticas , Separação Imunomagnética , Leucaférese , Leucócitos/metabolismo , Adolescente , Adulto , Anemia/sangue , Anemia/patologia , Anemia/terapia , Feminino , Humanos , Separação Imunomagnética/instrumentação , Separação Imunomagnética/métodos , Leucaférese/instrumentação , Leucaférese/métodos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
We prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 microMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.
Assuntos
Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Talassemia/metabolismo , Talassemia/terapia , Adolescente , Adulto , Sequência de Bases , Bussulfano/farmacologia , Criança , Pré-Escolar , Primers do DNA/genética , Intervalo Livre de Doença , Monitoramento de Medicamentos , Feminino , Genótipo , Glutationa Transferase/genética , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Lactente , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Estudos Prospectivos , Talassemia/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
Fetomaternal microchimerism suggests immunological tolerance between mother and fetus. Thus, we performed primary hematopoietic stem cell transplantation from a mismatched mother to thalassemic patient without an human leukocyte antigen-identical donor. Twenty-two patients with thalassemia major were conditioned with 60 mg/kg hydroxyurea and 3 mg/kg azathioprine from day -59 to -11; 30 mg/m(2) fludarabine from day -17 to -11; 14 mg/kg busulfan starting on day -10; and 200 mg/kg cyclophosphamide, 10 mg/kg thiotepa, and 12.5 mg/kg antithymocyte globulin daily from day -5 to -2. Fourteen patients received CD34(+)-mobilized peripheral blood and bone marrow progenitor cells; 8 patients received marrow graft-selected peripheral blood stem cells CD34(+) and bone marrow CD3/CD19-depleted cells. T-cell dose was adjusted to 2 x 10(5)/kg by fresh marrow cell addback at the time of transplantation. Both groups received cyclosporine for graft-versus-host disease prophylaxis for 2 months after transplantation. Two patients died (cerebral Epstein-Barr virus lymphoma or cytomegalovirus pneumonia), 6 patients reject their grafts, and 14 showed full chimerism with functioning grafts at a median follow-up of 40 months. None of the 14 patients who showed full chimerism developed acute or chronic graft-versus-host disease. These results suggest that maternal haploidentical hematopoietic stem cell transplantation is feasible in patients with thalassemia who lack a matched related donor.
Assuntos
Antígenos CD34/metabolismo , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/prevenção & controle , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico , Linfócitos T , Talassemia/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Viabilidade , Citometria de Fluxo , Sobrevivência de Enxerto/imunologia , Antígenos HLA/metabolismo , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Mães , Projetos Piloto , Reação em Cadeia da Polimerase , Estudos Prospectivos , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND AIMS: Immunomagnetic cell selection (ICS) of CD34(+) cells is being used increasingly in allogeneic transplantation in order to reduce T-cell quantity. The aim of this study was to evaluate an automated washing protocol before immunomagnetic selection. METHODS: The automated method was compared with a conventional washing procedure. In the study group the cell processing using the automated procedure, both before and after antibody incubation, was performed with a Sepax S-100 device. The efficacy of the automated procedure was compared with the control group, where washing were performed using a standard method. RESULTS: The results obtained after pre-incubation washing performed using the automated system showed a total nucleated cell (NC) and CD34(+) cell recovery of 84.87% (71.80-105, SD 8.62; range, standard deviation) and 83.45% (47-109, SD 16.12), respectively. The NC and CD34(+) cell recovery after the pre-incubation washing cycle was performed using the standard method was 75.54% (38.36-97.76, SD 22.5) and 61.51% (30.87-81.79, SD 19.3), respectively. The CD34(+) cell recovery after ICS was 51.27% (13.77-98.82, SD 24.97) and 48.89% (15.57-88.24, SD 25.91) for group 1 and group 2, respectively. The average purity in group 1 was 86.46% (67.4-96.10, SD 13.07) and in group 2 84.97% (58.1-97.8, SD 15.58). CONCLUSIONS: The efficacy of the ICS led to an optimal purity without affecting cell recovery, which was higher in group 1. Overall, our data suggest that the automated method is suitable for washing hematopoietic progenitor cell apheresis (HPC-A) concentrates before immunomagnetic cell selection in daily clinical routines.
Assuntos
Antígenos CD34/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas , Separação Imunomagnética , Adolescente , Adulto , Remoção de Componentes Sanguíneos , Técnicas de Cultura de Células , Feminino , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Separação Imunomagnética/instrumentação , Separação Imunomagnética/métodos , Masculino , Pessoa de Meia-Idade , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: Persistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit - erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow. DESIGN AND METHODS: The donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit - erythroid colonies singly picked out after 14 days of incubation. RESULTS: The proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit - erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. Conclusions Our results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.
Assuntos
Anemia Falciforme/terapia , Transplante de Medula Óssea , Núcleo Celular/patologia , Quimerismo , Eritrócitos/patologia , Hemoglobinopatias/etiologia , Talassemia beta/terapia , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Doadores de Tecidos , Adulto Jovem , Talassemia beta/complicaçõesRESUMO
To analyze immunohematologic reconstitution, particularly of natural killer (NK) cells, we evaluated 13 ß-thalassemia patients after 20 and 60 days and 1 year posttransplantation with T cell-depleted HLA-haploidentical stem cells. We assessed lymphocyte and bone marrow (BM) progenitor cell phenotype and differentiation capacity, spontaneous BM cytokine production, stromal cells, and stromal cell interleukin (IL)-7 production. A reduced clonogenic capability manifested at day +20. Patients had significantly lower CD4(+) T cells versus controls, mainly in the CD45RA(+)CD62L(+) subset. NKs were among the first lymphocytes to repopulate the peripheral blood. At day +60, an increase in primitive BM progenitor cells paralleled small increases in CD4(+), naïve CD4(+), and thymic naïve Th cells. A significant increase in CD4(+) and CD8(+) markers paralleled an increase in CD3â»CD16(+) NKs, especially with full engraftment. In patients with stable mixed chimerism we observed very low levels of CD3(+) donor chimerism early after transplant that increased over time, but a stable population of high donor NK cells, suggesting a role of these cells on donor engraftment. Stromal cells secreted less IL-7 and displayed "macrophage-like" morphology. Patients initially manifested impaired stem/progenitor cell growth and differentiation capacity in parallel with altered T cell homeostasis and a reduced T cell naïve compartment. We hypothesize that T cell compartment damage partly arises from altered new T cell production from the hematopoietic stem/progenitor cells under stromal cytokine influence. NNK subset analysis might be useful for determining transplant outcome.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade Materno-Fetal , Depleção Linfocítica , Linfócitos/citologia , Linfócitos T/citologia , Talassemia beta/terapia , Linfócitos B/citologia , Células Sanguíneas/citologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Contagem de Células , Criança , Pré-Escolar , Quimera/sangue , Ensaio de Unidades Formadoras de Colônias , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Interleucina-2/metabolismo , Interleucina-7/metabolismo , Células Matadoras Naturais/citologia , Doadores Vivos , Contagem de Linfócitos , Mães , Células Estromais/citologia , Células Estromais/metabolismo , Subpopulações de Linfócitos T/citologia , Transplantes , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Little is known about late-onset hemorrhagic cystitis (HC) in children, its relationship to BK virus, and treatment with cidofovir (CDV) following hematopoietic stem cell transplantation (HSCT). We prospectively investigated BK virus reactivation in children who underwent HSCT from a matched related donor for thalassemia or sickle cell anemia following busulfan-cyclophosphamide-based conditioning regimens and analyzed risk factors for development of HC and its treatment with CDV. Grade 2-4 HC occurred in 30 patients with a cumulative incidence of 26% (95% confidence interval [CI] = 18%-34%). The cumulative incidences of BK viruria and viremia were 81% (95% CI = 69%-89%) and 28% (95% CI = 18%-40%), respectively. Multivariate analysis revealed that use of antithymocyte globulin (ATG) (hazard ratio [HR] = 10.5; P = .001), peak BK viruria >100,000 copies/mL (HR = 6.2; P = .004), and grade II-IV acute graft-versus-host disease (HR = 5.3; P = .007) were predictive factors for HC. Nineteen patients with HC were given CDV at 1.5 mg/kg/day 3 times a week, or 5 mg/kg/week. The median duration of therapy was 27 days (range, 21-180 days), and a median of 9 doses were given (range, 6-22). All patients had a complete clinical response (CCR), and 69% had a microbiological response at 4 weeks. Eleven patients with BK virus-related HC receiving supportive care also had CCR. The median duration of HC in these patients was similar to that in patients treated with CDV. None of the patients with HC cleared BK viruria when CCR was achieved. We conclude that late-onset HC is more prevalent in children with sustained high BK viruria who are treated with ATG or who develop graft-versus-host disease. Randomized clinical trials are urgently needed to better define the role of CDV in treating BK virus-related HC.
Assuntos
Anemia Falciforme/complicações , Cistite/etiologia , Citosina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Organofosfonatos/uso terapêutico , Infecções por Polyomavirus/tratamento farmacológico , Talassemia/complicações , Adolescente , Adulto , Anemia Falciforme/terapia , Vírus BK , Criança , Pré-Escolar , Cidofovir , Cistite/tratamento farmacológico , Cistite/virologia , Citosina/uso terapêutico , Hemorragia , Humanos , Incidência , Lactente , Pessoa de Meia-Idade , Infecções por Polyomavirus/etiologia , Estudos Prospectivos , Talassemia/terapia , Infecções Tumorais por Vírus , Adulto JovemRESUMO
BACKGROUND AIMS: Immunomagnetic CD34(+) cell selection (ICS) is utilized in autologous and allogeneic transplants. In the first case it is used to reduce the neoplastic contamination of concentrates, while in the second case it is needed to carry out a T-depletion of cell concentrates in order to reduce the incidence of graft-versus-host disease (GvHD) in patients who have undergone haplo-identical transplants. METHODS: The efficacy of CliniMACS technology, after reduction of platelet contamination, incubation of monoclonal antibodies (MAb) and successive washings of concentrates, performed in 16 ICS using the standard method without reducing platelet content, was compared with the use of the automated system CytoMate, which was carried out in 46 ICS. RESULTS: In the group of ICS carried out after automatic manipulation, a significant statistical difference in purity was noted (91.39% versus 83.57, P = 0.017) compared with the group of ICS carried out with the standard procedure. The same significant difference was noted in relation to the remaining percentages of CD3(+) and CD19(+) cells (2.31% versus 5.68%, P = 0.012, and 1.58% versus 2.71%, P = 0.014, respectively). Recovery of CD34+ cells overlapped in the two groups (70.49% versus 68.39%, P = 0.774). CONCLUSIONS: Immunomagnetic selection carried out using the automated procedure was more efficient, producing a purer sample, more efficient T-depletion and optimal reduction of B cells, without influencing cell recovery. Furthermore, conforming to good manufacturing practice (GMP) guidelines, the entire procedure with CytoMate took place in a contamination-controlled environment.
Assuntos
Antígenos CD34/imunologia , Plaquetas/fisiologia , Separação Imunomagnética/métodos , Transplante de Células-Tronco/métodos , Talassemia beta/cirurgia , Adolescente , Adulto , Automação/métodos , Linfócitos B/citologia , Linfócitos B/imunologia , Plaquetas/citologia , Contagem de Células , Criança , Pré-Escolar , Contaminação de Equipamentos/prevenção & controle , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/fisiopatologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucaférese , Masculino , Pessoa de Meia-Idade , Linfócitos T/citologia , Linfócitos T/imunologia , Condicionamento Pré-Transplante , Adulto Jovem , Talassemia beta/imunologia , Talassemia beta/fisiopatologiaRESUMO
Infection with human polyomaviruses BKV and JCV is asymptomatic, and lifelong and widespread, among the general population. However, in the setting of immunosuppression, secondary to medications or viral infection, for example, with HIV, reactivation can occur and result in severe disease. In this study, stool specimens from 31 patients with hematological disorders (25 transplanted and 6 non-transplanted) were examined prospectively to determine whether the novel polyomaviruses KIV and WUV reactivated and were excreted in the gastrointestinal tract. Reactivation was correlated with the appearance of gastrointestinal and respiratory symptoms. Of the 31 patients examined, KIV and WUV were detected in 13 transplanted patients as single infection or in combination with BKV, cytomegalovirus (CMV), and adenovirus (Adv). Because of frequent co-infections, a clear correlation between novel polyomaviruses and clinical symptoms could not be established. There was no correlation between demographic variables and detection of KIV and WUV. Phylogenetic analysis of the small t-antigen gene of KIV and WUV isolates showed that the novel polyomaviruses identified in feces clustered with those identified in the respiratory tract suggesting an oral-fecal transmission of these viruses. The novel polyomaviruses KI and WU may have a pathogenic role in immunocompromised patients.
Assuntos
Fezes/virologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Infecções por Polyomavirus/virologia , Polyomavirus/isolamento & purificação , Adenoviridae/isolamento & purificação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise por Conglomerados , Citomegalovirus/isolamento & purificação , DNA Viral/química , DNA Viral/genética , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , Polyomavirus/classificação , Polyomavirus/genética , Análise de Sequência de DNA , Adulto JovemAssuntos
Hemoglobina Fetal/biossíntese , Transplante de Células-Tronco Hematopoéticas , Adolescente , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/transplante , Anemia Falciforme/sangue , Anemia Falciforme/terapia , Pré-Escolar , Feminino , Hemoglobina Fetal/análise , Rejeição de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Resultado do Tratamento , Regulação para Cima , Talassemia beta/sangue , Talassemia beta/terapiaRESUMO
BACKGROUND: Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood. DESIGN AND METHODS: The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor. RESULTS: Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro. CONCLUSIONS: Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.
Assuntos
Quimerismo , Células Eritroides , Transplante de Células-Tronco Hematopoéticas , Linfócitos T Reguladores/transplante , Talassemia/cirurgia , Criança , Pré-Escolar , Células Eritroides/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interleucina-10/imunologia , Masculino , Linfócitos T Reguladores/imunologia , Talassemia/genética , Talassemia/imunologia , Transplante HomólogoRESUMO
An adult patient affected by beta(0)-thalassemia major underwent allogeneic bone marrow transplant (BMT) from a matched related donor. Forty days after transplant, allogeneic engraftment failure and autologous beta(0)-thalassemic bone marrow recovery were documented. Red blood cell transfusions were required until 118 days post-transplant. Thereafter, the haemoglobin (Hb) levels stabilized over 11.8 gr/dl throughout the ongoing 34-month follow-up, abolishing the need for transfusion support. The Hb electrophoresis showed 100% Hb Fetal (HbF). This unexplained case suggests full HbF production may occur in an adult patient with beta(0)-thalassemia major.
Assuntos
Transplante de Medula Óssea , Hemoglobina Fetal/biossíntese , Rejeição de Enxerto/sangue , Talassemia beta/sangue , Adolescente , Humanos , Talassemia beta/genética , Talassemia beta/cirurgiaRESUMO
Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with thalassemia. Current results of transplantation in patients aged less than 17 years from matched related donors offer 80% to 87% probability of cure according to risk classes. Adult thalassemics treated with myeloablative conditioning continue to have inferior results because of their advanced stage of disease. With the introduction of high-resolution tissue typing techniques transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients who could not benefit from transplantation because of lack of matched family donor. Although limited number of patients treated, results of transplant from unrelated matched donors are comparable to those obtained using sibling donors. Graft failure or rejection remains a significant cause of transplant failure in patients with thalassemia making difficult to perform reduced intensity conditioning regimens. Mixed chimerism is a common phenomenon after transplantation and is a risk factor for rejection. Ex-thalassemics still carry the clinical complications acquired during years of transfusion and chelation therapy. Longer follow-up and management of these complications in ex-thalassemics are essential.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Talassemia/terapia , Adolescente , Criança , Pré-Escolar , Teste de Histocompatibilidade , Humanos , Lactente , Quimeras de Transplante , Transplante Homólogo/métodosRESUMO
BACKGROUND: Bone marrow transplantation (BMT) for class 3 patients with thalassemia is challenging due to high rates of graft rejection and transplant-related mortality. Since the first studies of BMT in the late 1980s, a number of conditioning regimens have been designed to improve outcomes, but with suboptimal results. Here we report the outcome of transplantation in class 3 patients using a modified protocol. METHODS: Sixty-three patients between 5 and 16.7 years of age with class 3 thalassemia received HLA-matched sibling BMT following either the original protocol (26 patients) or the modified protocol (37 patients). Both regimens comprised preconditioning cytoreduction with hydroxyurea and azathioprine starting at -45 days pretransplant, and fludarabine from days -16 to -12. Conditioning was performed with busulfan and cyclophosphamide (original protocol) or with busulfan, thiotepa, and cyclophosphamide (modified protocol). RESULTS: The 2 groups showed similar patient demographics. At day 0, the degree of cytoreduction (lymphopenia, neuthropenia, and thrombocytopenia) achieved by the modified protocol was greater than the original protocol. The incidence of graft failure/rejection was significantly higher in the original group (15%; 95% confidence interval [95% CI], 5-32%) compared with the modified group (0%) (P = 0.014). The respective 5-year thalassemia-free survival rates were 73% (95% CI, 51-86%) and 92% (95% CI, 77-97%) (P = 0.047). Both groups showed similar incidences of grades II to IV acute graft-versus host disease. Modified protocol did not increase nonhematological toxicity or infectious complications. CONCLUSIONS: The modified treatment protocol effectively and safely prevented graft failure/rejection and significantly increased thalassemia-free survival of class 3 patients with thalassemia.
Assuntos
Transplante de Medula Óssea/métodos , Antígenos HLA/imunologia , Histocompatibilidade , Doadores Vivos , Irmãos , Talassemia/cirurgia , Adolescente , Fatores Etários , Transplante de Medula Óssea/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Teste de Histocompatibilidade , Humanos , Imunossupressores/administração & dosagem , Incidência , Estimativa de Kaplan-Meier , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Cidade de Roma/epidemiologia , Talassemia/diagnóstico , Talassemia/genética , Talassemia/imunologia , Fatores de Tempo , Condicionamento Pré-Transplante , Resultado do TratamentoRESUMO
INTRODUCTION: Several DNA polymorphisms have been associated with high production of fetal hemoglobin (HbF), although the molecular basis is not completely understood. In order to identify and characterize novel HbF-associated elements, we focused on five probands and their four families (from Egypt, Iraq and Iran) with thalassemia major (either ß(0)-IVSII-1 or ß(0)-IVSI-1) and unusual HbF elevation (>98 %), congenital or acquired after rejection of bone marrow transplantation, suggesting an anticipated favorable genetic background to high HbF expression. METHODS: Patient recruitment, genomic DNA sequencing, western blotting, electrophoretic mobility shift assays, surface plasmon resonance (SPR) biospecific interaction analysis, bioinformatics analyses based on docking experiments. RESULTS: A polymorphism of the Aγ-globin gene is here studied in four families with ß(0)-thalassemia (ß(0)-IVSII-1 and ß(0)-IVSI-1) and expressing unusual high HbF levels, congenital or acquired after rejection of bone marrow transplantation. This (GâA) polymorphism is present at position +25 of the Aγ-globin genes, corresponding to a 5'-UTR region of the Aγ-globin mRNA and, when present, is physically linked in chromosomes 11 of all the familiar members studied to the XmnI polymorphism and to the ß(0)-thalassemia mutations. The region corresponding to the +25(GâA) polymorphism of the Aγ-globin gene belongs to a sequence recognized by DNA-binding protein complexes, including LYAR (Ly-1 antibody reactive clone), a zinc-finger transcription factor previously proposed to be involved in down-regulation of the expression of γ-globin genes in erythroid cells. CONCLUSION: We found a novel polymorphism of the Aγ-globin gene in four families with ß(0)-thalassemia and high levels of HbF expression. Additionally, we report evidence suggesting that the Aγ-globin gene +25(GâA) polymorphism decreases the efficiency of the interaction between this sequence and specific DNA binding protein complexes.
Assuntos
Hemoglobina Fetal/metabolismo , Polimorfismo de Nucleotídeo Único , Talassemia beta/genética , gama-Globinas/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 11/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Hemoglobina Fetal/genética , Humanos , Células K562 , Masculino , Linhagem , Talassemia beta/metabolismo , gama-Globinas/química , gama-Globinas/metabolismoRESUMO
Current regular blood transfusion programs and chelation treatment have considerably improved survival of patients with thalassemia, which resulted in a larger proportion of adult patients. However, disease- and treatment-related complications in these patients progress over time, causing severe morbidity and shortened life expectancy. Stem cell transplantation still remains the only cure currently available for patients with thalassemia. This study updates transplant outcomes in 107 adult patients with median age of 22 years (range, 17-35 years) who received bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical related donors between 1988 and 1996 (group A) and describes the results of BMT in 15 adult patients with median age of 21 years (range, 17-31 years) who were treated with a new treatment protocol (Protocol 26) between 1997 and 2003 (group B). The probability of survival, event-free survival, nonrejection mortality, and rejection for group A patients were 66%, 62%, 37%, and 4%, respectively, with a median follow-up of 12 years (range, 8.3-16.2 years). Group B patients treated with the new protocol had some improvement in thalassemia-free survival (67%) and lower transplant-related mortality (27%) than that of previous protocols. However, transplant-related mortality in these high-risk patients remains elevated. Current myeloablative BMT in adult patients is characterized by higher transplant-related toxicity due to an advanced phase of disease. Although this new approach to transplant adult patients with a reduced-dose intensity-conditioning regimen has improved thalassemia-free survival, transplant-related mortality in these high-risk patients remains elevated.
Assuntos
Transplante de Medula Óssea/estatística & dados numéricos , Talassemia/cirurgia , Adolescente , Adulto , Azatioprina/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/mortalidade , Bussulfano/administração & dosagem , Terapia por Quelação , Protocolos Clínicos , Terapia Combinada , Comorbidade , Desferroxamina/uso terapêutico , Intervalo Livre de Doença , Transfusão de Eritrócitos , Eritropoetina/administração & dosagem , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fatores de Crescimento de Células Hematopoéticas/administração & dosagem , Hemossiderose/epidemiologia , Hemossiderose/etiologia , Hemossiderose/terapia , Humanos , Hidroxiureia/administração & dosagem , Imunossupressores/administração & dosagem , Quelantes de Ferro/uso terapêutico , Tábuas de Vida , Cirrose Hepática/complicações , Masculino , Flebotomia , Complicações Pós-Operatórias/mortalidade , Análise de Sobrevida , Talassemia/complicações , Talassemia/tratamento farmacológico , Talassemia/mortalidade , Talassemia/terapia , Reação Transfusional , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Condicionamento Pré-Transplante/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Transplante Homólogo/estatística & dados numéricos , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
The b-thalassemias and sickle cell disorders are the most common genetic diseases worldwide. Although improvements in conservative treatment have considerably improved the prognosis of hemoglobinopathies, stem cell transplantation remains the only cure for thalassemia and sickle cell disease. Results of transplants in these diseases have steadily improved over the last two decades due to improvements in preventive strategies, effective control of transplant-related complications and development of new preparative regimens. High-resolution human leukocyte antigen (HLA) typing has enabled physicians to perform transplant from unrelated volunteer donors for thalassemia with results comparable with those obtained employing an HLA-identical sibling. Current understandings of stable mixed chimerism (MC) in patients with hemoglobinopathies provide a rationale for the use of less intensive conditioning regimens and future gene therapy. Despite recent advances in animal models, the clinical application of gene therapy for hemoglobinopathies is unlikely to be a reality for at least near future. With the advances in transplantation for thalassemia, all sickle cell disease patients should be offered stem cell transplantation with an human leukocyte antigen (HLA)-identical donor. This review focuses on the current status of stem cell transplantation for hemoglobinopathies.