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Explotaciones Pesqueras , Anomalías Maxilomandibulares/etiología , Perciformes/anomalías , Columna Vertebral/anomalías , Alimentación Animal/análisis , Animales , Australia , Dieta/veterinaria , Larva/crecimiento & desarrollo , Perciformes/crecimiento & desarrollo , Estimulación Luminosa , Columna Vertebral/crecimiento & desarrollo , TemperaturaRESUMEN
Long-term survival of chronic myeloid leukaemia (CML) patients transplanted in chronic phase with a replete marrow have been described previously. The same success has not been achieved with patients in more advanced stages of the disease. We describe a CML patient who received an allogeneic bone marrow transplantation in accelerated phase. Cytogenetic and molecular analysis confirmed donor chimaerism, and the absence of the BCR-ABL mRNA. Almost 12 years post-transplant relapse was noted. Cytogenetic analyses showed a complex evolving karyotype. These findings are correlated with the longitudinal molecular analysis utilising real-time and VNTR PCR.
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Trasplante de Médula Ósea/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Quimera por Trasplante/genética , Adolescente , Resultado Fatal , Proteínas de Fusión bcr-abl/genética , Efecto Injerto vs Tumor , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Recurrencia Local de Neoplasia , ARN Mensajero/análisis , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Trasplante HomólogoAsunto(s)
Transformación Celular Neoplásica/genética , Leucemia Mieloide/genética , Enfermedad Aguda , Femenino , Reordenamiento Génico , Genes abl/genética , Genes bcl-2/genética , Humanos , Leucemia Mieloide/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genéticaRESUMEN
Autografting following high-dose conditioning is being increasingly offered to breast cancer sufferers, without due regard to the reinfusion of malignant cells. We sought to determine if a breast cancer cell line could be successfully purged from peripheral blood stem cell (PBSC) harvests using a ligand-toxin molecule directed to heregulin-activated erbB receptors. Initial experiments demonstrated no reduction in hemopoietic colony-forming ability in the presence of ligand toxin (2 nM). Breast cancer cell lines which demonstrated differing sensitivities to the ligand toxin were subsequently seeded into stem cell collections and incubated with 2 nM ligand-toxin. One cell line, ZR-75-1, was completely sensitive to the ligand toxin in this mixture; a second, MDB-MA-361, was more profoundly sensitive to the ligand toxin in the presence of the PBSC, whereas a third was unaffected by the toxin. These results suggest purging may indeed be possible in the PBSC of breast cancer patients, but the parameters that define sensitivity are as yet unknown.
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Receptores ErbB/metabolismo , Exotoxinas/farmacología , Glicoproteínas/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , División Celular/efectos de los fármacos , Separación Celular , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Receptor ErbB-4 , Proteínas Recombinantes de Fusión/farmacología , Células Tumorales CultivadasRESUMEN
Preclinical studies with the murine anti-CD48 antibody, mHuLym3 (IgG2a) have shown it to be a potentially useful therapeutic reagent in the treatment of human leukaemia and lymphoma. For clinical use, humanised antibodies can have a number of advantages over their original murine version, including mediation of higher effector cell function with human cells, longer serum half-life and lower immunogenicity. In this study, we have produced a mouse/human chimeric HuLym3 antibody (cHuLym3) where the murine antibody constant regions have been replaced with human constant regions. We report the production and preclinical characterisation of the antibody, cHuLym3, with potent in vitro and in vivo antitumour activity. The genes encoding the variable heavy and light chains were amplified by the polymerase chain reaction, sequenced and cloned into eukaryotic expression vectors containing the human light- and heavy-chain constant regions (kappa and IgG1). The chimeric and murine HuLym3 antibodies had similar cell-binding specificity and affinity. In the human Raji cell severe combined immunodeficient mouse model the i.v. injection of cHuLym3 and mHu-Lym3 produced similar antitumour responses. Doses of cHuLym3 and mHuLym3 (100 microg) on days 1, 2 and 4 after i.v. Raji cell injection produced a 40% longer time to hind-leg paralysis than when a control antibody was used. cHuLym3 had more potent activity than mHuLym3 in antibody-dependent cellular cytotoxicity (ADCC) assays in vitro, with human peripheral blood mononuclear cells as effectors. Up to 60% specific cell lysis was observed with cHuLym3 in ADCC assays. These properties suggest that anti-CD48 antibodies may be useful in the treatment of a number of diseases including lymphoid leukaemias and lymphoma.
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Anticuerpos Antineoplásicos/uso terapéutico , Antígenos CD/inmunología , Antineoplásicos/uso terapéutico , Linfoma/terapia , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/genética , Secuencia de Bases , Antígeno CD48 , Clonación Molecular , Genes de Inmunoglobulinas , Humanos , Inmunidad Celular , Región Variable de Inmunoglobulina , Inmunoterapia , Ratones , Datos de Secuencia Molecular , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)
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Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Análisis Actuarial , Adolescente , Adulto , Niño , Ciclosporina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Prueba de Histocompatibilidad , Humanos , Inmunosupresores/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Donadores Vivos , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Análisis Multivariante , Núcleo Familiar , Sistema de Registros , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
OBJECTIVE: Based on animal studies and anecdotal case reports, high-dose therapy and autologous blood stem cell rescue have been proposed as an experimental treatment for severe, refractory rheumatoid arthritis (RA). This study aimed to establish the toxicity of this treatment and obtain preliminary efficacy data upon which to base future clinical trials. METHODS: Two cohorts of 4 patients who fulfilled criteria for severe, active, treatment-resistant RA were recruited into a dose-escalation study of cyclophosphamide (CYC) (100 mg/kg or 200 mg/kg) followed by unmanipulated peripheral blood stem cell rescue. Patient treatment was managed according to a standard supportive care protocol. Disease-modifying drugs were discontinued before treatment, but corticosteroids were maintained and later tapered where possible. Patients' conditions were assessed using World Health Organization toxicity criteria and standard parameters for rheumatic disease. RESULTS: Dose-dependent differences in hematologic toxicity were observed between cohorts 1 and 2, although toxicity was similar for other systems and was most significant in the gastrointestinal system. Patients in cohort 1 had only transient responses to therapy, lasting 2-3 months. Substantial improvements were sustained beyond 17-19 months in cohort 2, including steroid-independent disease remission for 1 patient, although the procedure did not completely abolish disease activity. CONCLUSION: High-dose CYC and unmanipulated autologous blood stem cell rescue has acceptable dose-dependent toxicity in severe, treatment-resistant RA, and 200 mg/kg of CYC induces substantial clinical responses. Refinement of this intensive approach might include further intensification of the preparation regimen, graft manipulation, and posttransplant immunomodulation.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/terapia , Ciclofosfamida/uso terapéutico , Adulto , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Estudios de Cohortes , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Movilización de Célula Madre Hematopoyética/efectos adversos , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVES: Autologous haemopoietic stem cell transplantation (HSCT), which carries defined risks of early treatment-related mortality (TRM), has recently been proposed as an experimental therapy for severe rheumatoid arthritis (RA). The aim of this study was to establish whether the risks of this approach are acceptable to patients with RA and whether risk taking related to disease-associated or personal/social parameters. METHODS: A standard gamble questionnaire was used to determine the acceptable risk of mortality for a potentially curative procedure in patients with RA aged <70 yr. Additional data collected included age, sex, duration of RA, number of second-line agents, domestic and workforce information, and self-assessed disability. RESULTS: The 53 patients (age range 24-69 yr, 39 female, 14 male, disease duration 2-43 yr) interviewed were prepared to accept a broad range of treatment-related mortality in order to be returned to normality off all drugs (median 5%, range 0-50%). Risk taking was significantly related to degree of disability measured by the disability section of the Health Assessment Questionnaire (HAQ; P = 0.001) and negatively related to age (P = 0.04), although only HAQ score maintained significance on multivariate analysis. Using linear regression, we were able to determine that current TRM of autologous HSCT in Australia (3.3%) would be acceptable to patients with HAQ scores of >0.44 (84% of our sample), but allogeneic HSCT (with a TRM of 13.1%) would be acceptable only to severely disabled patients with HAQ scores of >2.45 (4% of our sample), assuming the procedure to be curative. CONCLUSION: Along with previous studies, these results suggest that, if long-term efficacy can be proven, then the risks of autografting may be acceptable to most patients with RA, particularly those with significant disability.
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Artritis Reumatoide , Trasplante de Células Madre Hematopoyéticas , Adulto , Anciano , Artritis Reumatoide/mortalidad , Artritis Reumatoide/psicología , Artritis Reumatoide/terapia , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/terapia , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Participación del Paciente , Medición de Riesgo , Asunción de Riesgos , Encuestas y CuestionariosRESUMEN
High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 microg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 x 10(6)/kg, P = 0.03) and CD34+ cells (2.7 v 5.8 x 10(6)/kg, P = 0.003). However, there were increased proportions of CD14+ cells (P = 0.006) and CD14+ CD15+ cells (the phenotype of previously described 'abnormal' myeloid cells, P = 0.002) in the RA PBSCH which translated into 3.5- and 7-fold increases respectively on a per CD34+ cell basis. There were no differences in T-cell activation status as judged by proportions of CD4+ and CD8+ expressing CD45RA, CD45RO, HLA-DR and CD28 (RA PBSCH, n = 7, donor PBSCH, n = 5, P = 0.2-0.7). Phytohaemagglutinin responses determined fluorocytometrically with induction of CD69 expression were reduced in CD4+ and CD8+ cells following filgrastim administration in 3/3 RA patients tested. Compared with bone marrow as a potential source of CD34+ cells, PBSCH contained 11-fold more T cells (P < 0.0005), 8-fold more B cells (P < 0.0005) and 4-fold more monocytes (P = 0.02). In short-term methylcellulose culture there were no differences in colony counts (CFU-GM, CFU-GEMM, BFU-E) per CD34+ cell from PBSCH from RA patients (n = 11) and healthy donors (n = 10). Long-term culture initiator cells were cultured successfully from cryopreserved PBSCH from RA patients (n = 9). In conclusion, PBSCH from RA patients differed significantly in composition from normal individuals, but in vitro studies support normal stem and progenitor cell function. Changes in T-cell function occur during mobilization in RA patients. This work provides reassurance for the use of PBSCH as haematological rescue and baseline data for clinical trials of graft manipulation strategies in patients with RA.
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Artritis Reumatoide/sangre , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/fisiología , Adulto , Antígenos CD , Artritis Reumatoide/inmunología , Células Cultivadas , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunofenotipificación/métodos , Masculino , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
The value of the polymerase chain reaction (PCR) in the diagnosis of malignant disorders is well established. However, several factors such as sample type, storage conditions and extraction methodology affect the ability of the PCR to provide a diagnosis. We describe the use of a PCR-product-specific 'capture' oligo to overcome these potential problems. The detection of the captured product by standard ELISA technologies allowed a rapid colorimetric analysis to be performed removing the need for both gel electrophoresis and the performance of a nested PCR in order to reach a diagnosis. In a survey of 14 clinical samples this method was observed to be both more sensitive and specific than the PCR followed by gel electrophoresis.
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Médula Ósea/patología , Colorimetría , ADN de Neoplasias/genética , Ensayo de Inmunoadsorción Enzimática , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Células Madre Neoplásicas/química , Reacción en Cadena de la Polimerasa , Trasplante de Médula Ósea/patología , ADN de Neoplasias/análisis , Electroforesis en Gel de Poliacrilamida , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Sensibilidad y Especificidad , Células Tumorales CultivadasRESUMEN
We have evaluated the antitumor activity of a murine antibody (IgG2a) against the leukocyte antigen CD48. CD48 is expressed on T and B lymphocytes, monocytes, and a wide range of lymphoid malignancies. To assess the therapeutic potential of an anti-CD48 antibody, we established a reproducible model of human B-cell (Raji) leukemia/lymphoma in C.B17/scid mice, where untreated mice develop hind leg paralysis due to tumor engraftment. Using this model, the murine anti-CD48 antibody HuLy-m3 was shown to mediate a strong in vivo antitumor effect. Long-term survival (>1 year) of scid mice was obtained after treatment with three 200-microg i.v. doses of anti-CD48 antibody on days 0, 2, and 4 after i.v. injection of tumor cells. In contrast, mice treated with an isotype control antibody developed hind leg paralysis after 34 +/- 3 days. A strong antitumor response was still observed when a dose of 20 microg of HuLy-m3 antibody was used. During preclinical investigations, we also examined a number of properties of the CD48 antigen. CD48 is present at high levels on the surface of T and B cells, but most (>95%) CD34-positive cells do not express CD48. Anti-CD48 antibodies are maintained on the surface of antigen-positive cells for extended periods (>24 h). These properties suggest that anti-CD48 antibodies may be useful in the treatment of a number of diseases including lymphoid leukemias and lymphomas.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Linfoma de Células B/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Sitios de Unión , Antígeno CD48 , Humanos , Linfoma de Células B/patología , Ratones , Ratones SCID , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The bcr-abl chimeric gene is found in 95% of chronic myeloid leukemia (CML) patients and is thought to be seminal to the etiology of the disease. The possibility of using ribozymes to suppress bcr-abl gene expression and subsequently alter the malignant phenotype of hematopoietic cells may provide an alternative therapeutic approach to current regimens. A series of hammerhead ribozymes targeted to a b3a2 bcr-abl transcript has been developed and previously shown to be capable of cleaving the desired sequence with varying degrees of specificity. This study investigated the ex vivo effects of endogenous expression of these ribozymes in a CML cell line, K562. We demonstrated a 53% decrease in bcr-abl mRNA levels in a clone induced to express Rz8, compared with its uninduced control. Phenotypic analysis of this clone also revealed a 63% decrease in colony-forming ability and a 43% inhibition of cell proliferation following ribozyme expression. Morphologic analysis of cells showed there was a slight increase (2.5% to 15%) in the number of cells undergoing apoptosis. These results suggest that Rz8 was effective in suppressing bcr-abl gene expression within a cellular environment and altering the leukemic nature of a CML cell line.
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Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , ARN Catalítico/metabolismo , ARN Mensajero/metabolismo , Proteínas de Fusión bcr-abl/biosíntesis , Humanos , Fenotipo , ARN/metabolismo , ARN Catalítico/genética , Transfección , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism. METHODS: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases. RESULTS: In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution. CONCLUSION: Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.
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Enfermedades Autoinmunes/cirugía , Adulto , Anemia Aplásica/inducido químicamente , Anemia Aplásica/fisiopatología , Anemia Aplásica/cirugía , Antirreumáticos/efectos adversos , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Trasplante de Médula Ósea , Femenino , Hematopoyesis/fisiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Estudios Longitudinales , Persona de Mediana Edad , Psoriasis/complicaciones , Radiografía , Recurrencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 microg/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 x 10(6)/kg CD34+ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34+ cells and CFU-GM. One patient in the 5 microg/kg/day group and two patients in the 10 microg/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 microg/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 microg/kg/day was more efficient with all patients (n = 5) achieving target CD34+ cell counts with a single leukapheresis (median = 2.8, range = 2.3-4.8 x 10(6)/kg, median CFU-GM = 22.1, range = 4.2-102.9 x 10(4)/kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 microg/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 microg/kg/day. However, on balance, 10 microg/kg/day remains the dose of choice in view of more efficient CD34+ cell mobilisation.
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Artritis Reumatoide/terapia , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Adulto , Estudios de Cohortes , Ensayo de Unidades Formadoras de Colonias , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/efectos adversos , Humanos , Leucaféresis , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Trasplante AutólogoRESUMEN
We report a patient who underwent allogeneic bone marrow transplantation from a sibling with longstanding untreated severe active rheumatoid arthritis. After 4 years of follow-up there is no evidence of adoptive transfer of rheumatoid arthritis to the recipient. This case, along with another recently reported case, provides reassurance that haemopoietic stem cell transplantation from a donor with systemic autoimmune disease may not necessarily result in adoptive transfer of the disease. All previous reports of transfer of autoimmunity in humans have been of organ-specific autoimmune diseases and we speculate that pathophysiological differences might account for why systemic autoimmune disease is not transferred.
Asunto(s)
Traslado Adoptivo , Artritis Reumatoide/inmunología , Trasplante de Médula Ósea , Médula Ósea/inmunología , Donantes de Tejidos , Adulto , Artritis Reumatoide/patología , Médula Ósea/patología , Femenino , Humanos , Trasplante HomólogoRESUMEN
Bone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome. We studied 1,305 recipients of HLA-identical sibling transplants for aplastic anemia between 1976 and 1992, reported to the IBMTR by 179 centers. We compared survival of transplants performed in three intervals (1976 through 1980 [n = 186], 1981 through 1987 [n = 648], and 1988 through 1992 [n = 471]) using Cox proportional hazards regression. Five-year survival (+/-95% confidence interval) increased from 48% +/- 7% in the 1976-1980 cohort to 66% +/- 6% in the 1988-1992 cohort (P < .0001). Risks of graft-versus-host disease (GVHD) and interstitial pneumonia decreased over time, but the risk of graft failure did not. Higher long-term survival resulted primarily from decreased mortality in the first 3 months posttransplantation. Late mortality risks were low and changed little over the intervals studied. In multivariate analysis, changes in transplantation strategies accounted for most but not all of the improved outcome. Use of cyclosporine to prevent GVHD was the most important factor. Changes in patient selection did not seem to explain improved survival. Survival after HLA-identical sibling bone marrow transplantations for aplastic anemia has improved since 1976. Changes in GVHD prophylaxis account for much of this improvement. Other changes may also operate.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea , Resultado del Tratamiento , Factores de Edad , Anemia Aplásica/mortalidad , Trasplante de Médula Ósea/mortalidad , Trasplante de Médula Ósea/fisiología , Estudios de Cohortes , Intervalos de Confianza , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/epidemiología , Prueba de Histocompatibilidad , Humanos , Terapia de Inmunosupresión/métodos , Enfermedades Pulmonares Intersticiales/epidemiología , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomonas exotoxin (PE) 40 fusion protein was constructed for potential use in the treatment of myeloid leukaemias, as a conditioning agent prior to allogeneic bone marrow transplantation or for ex vivo purging of malignant cells prior to autologous bone marrow transplantation. The GM-CSF-PE40 fusion protein successfully binds to the GM-CSF receptor and is capable of initiating a mitogenic signal similar to native GM-CSF in the GM-CSF-dependent TF1 cell line. The toxin component also appears to be fully functional as determined by an in vitro adenosine diphosphate-ribosylation assay. The GM-CSF-PE40 fusion protein, however, was not cytotoxic to a number of myeloid leukaemia cell lines. It is suggested that the mechanism of internalization of the GM-CSF receptor is not appropriate for the translocation of PE to the cytosol where it can fulfil its cytotoxic potential.