RESUMEN
An experimental design methodology was applied to study the effects of temperature, pH, biomass dose, and stirring speed on copper removal from aqueous solutions by Aspergillus terreus in a biosorption batch system. To identify the effects of the main factors and their interactions on copper removal efficiency and to optimize the process, a full 2(4) factorial design with central points was performed. Four factors were studied at two levels, including stirring speed (50-150 min(-1)), temperature (30-50°C), pH (4-6) and biosorbent dose (0.01-0.175 g). The main factors observed were pH and biomass dose, along with the interactions between pH and biomass, and stirring speed. The optimal operational conditions were obtained using a response surface methodology. The adequacy of the proposed model at 99% confidence level was confirmed by its high adjusted linear coefficient of determination (R(Adj)(2)=0.9452). The best conditions for copper biosorption in the present study were: pH 6, biosorbent dose of 0.175 g, stirring speed of 50 min(-1) and temperature of 50°C. Under these conditions, the maximum predicted copper removal efficiency was 68.52% (adsorption capacity of 15.24 mg/g). The difference between the experimental and predicted copper removal efficiency at the optimal conditions was 4.8%, which implies that the model represented very well the experimental data.
Asunto(s)
Aspergillus/metabolismo , Cobre/aislamiento & purificación , Contaminantes Químicos del Agua/aislamiento & purificación , Biomasa , Concentración de Iones de Hidrógeno , Microbiología Industrial/métodos , Modelos Teóricos , Soluciones/química , TemperaturaRESUMEN
The use of etoposide (VP-16) for stem cell mobilization has been reported as a significant risk factor for the development of therapy-related myelodysplasia/therapy-related AML (tMDS/tAML) after transplantation. We compared the safety and effectiveness of VP-16+G-CSF (VP+G) to G-CSF alone for PBPC mobilization in patients with non-Hodgkin's lymphoma and Hodgkin's lymphoma who underwent autologous transplantation at the Cleveland Clinic and Ohio State University. In the VP+G group, median total CD34+ cells collected were 9.34 × 10(6) per kg (range 0.97-180.89), with 42% of all patients having adequate (2 × 10(6) cells per kg) CD 34+ collection after 2 days of apheresis compared with a median in the G-CSF group of 3.83 × 10(6) per kg (range, 0.72-50.38), with only 16% patients having adequate collection after 2 days (P<0.001). tMDS/tAML occurred in 15 patients (2.3%) in the VP+G and in 12 patients (3.8%) receiving G-CSF alone. (P=0.62). Increased number of days of apheresis was associated with the risk of tMDS/tAML (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.30, P<0.001). Priming regimen was not a significant variable for relapse-free survival or OS. The addition of etoposide significantly improves the effectiveness of mobilization at the cost of an increased incidence of neutropenic fever though with no mortalities. There is no evidence of increased incidence of tMDS/tAML in patients receiving VP+G compared with those mobilized with G-CSF alone.
Asunto(s)
Etopósido/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma/terapia , Neoplasias Primarias Secundarias/etiología , Adolescente , Adulto , Anciano , Antineoplásicos Fitogénicos/uso terapéutico , Etopósido/efectos adversos , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Movilización de Célula Madre Hematopoyética/efectos adversos , Humanos , Leucemia/etiología , Linfoma/tratamiento farmacológico , Linfoma/cirugía , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Factores de Riesgo , Adulto JovenAsunto(s)
Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Hemorragia/inducido químicamente , Inmunotoxinas/efectos adversos , Alveolos Pulmonares/efectos de los fármacos , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales Humanizados , Gemtuzumab , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Alveolos Pulmonares/patología , Inducción de Remisión , Trasplante de Células Madre , Esteroides/uso terapéutico , Factores de TiempoRESUMEN
SUMMARY: To reduce relapse following allogeneic transplantation for AML, intensification of high-dose busulfan/cyclophosphamide using additional agents has been investigated but with few reported comparisons. We compared an intensified regimen of etoposide (60 mg/kg), busulphan (14 mg/kg), and cyclophosphamide (120 mg/kg) (BuCyVP) with BuCy2 in 237 AML patients. No significant difference in overall outcome was observed following BuCyVP (n=127) or BuCy2 (n=110). The 5-year survival was 27.3 and 30.1% following BuCyVP and BuCy2, respectively (P=0.48). Similarly, the 5-year cumulative incidence of relapse (CIR) was 28.3 and 34.8% with BuCyVP and BuCy2 (P=0.45), respectively. On multivariable analysis, patients transplanted in CR1 (P=0.002) and from related donors (P=0.013) had longer survival, while disease status at transplant was the only factor predicting CIR (P=0.002). In a separate analysis of CR1 patients (n=56), there was no significant difference in survival (P=0.37) or CIR (P=0.87) between the two regimens. However, for more advanced disease, there was a trend towards less relapse with BuCyVP (P=0.08), which was balanced by a higher cumulative incidence of transplant-related deaths (P=0.03) compared to BuCy2, resulting in similar survival. Overall, our results do not support the use of the more intensive BuCyVP regimen over BuCy2 in either early or more advanced disease AML patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide/terapia , Enfermedad Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Busulfano/administración & dosificación , Causas de Muerte , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Femenino , Enfermedad Injerto contra Huésped , Humanos , Leucemia Mieloide/complicaciones , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The use of VP-16 for stem cell mobilization has been cited as a significant risk factor for the development of therapy-related myelodysplasia/leukemia (tMDS/tAML) following autologous transplantation. The present study analyzed a large cohort of patients who underwent autotransplantation following stem cell mobilization with VP-16 and radiation-free preparation in order to determine the risk of tMDS/tAML. The estimated incidence of 9.9% at 7 years suggests that in the absence of TBI, VP-16 priming is not associated with an increased incidence of tMDS/tAML.
Asunto(s)
Etopósido/toxicidad , Leucemia/inducido químicamente , Defectos del Tubo Neural/inducido químicamente , Trasplante de Células Madre de Sangre Periférica/métodos , Adolescente , Adulto , Anciano , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/terapia , Etopósido/administración & dosificación , Femenino , Movilización de Célula Madre Hematopoyética/efectos adversos , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Incidencia , Linfoma/complicaciones , Linfoma/terapia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/inducido químicamente , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Probabilidad , Trasplante AutólogoRESUMEN
Age >or=50 years has been reported to be an adverse risk factor for allogeneic BMT, and consequently many of these patients are either not transplanted or treated on nonmyeloablative protocols. To study if older patients perform poorly relative to younger adults following myeloablative allogeneic transplants, we compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50 years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35 (range 18-49) years for older and younger patients, respectively. Patients were low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia, or NHL in remission or sensitive relapse at the time of transplantation. All others were high-risk. In patients with low-risk disease, there was no significant difference in overall survival (OS) between older and younger adults (P=0.64), while older patients tended to have a shorter OS among high-risk patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95% CI, 50-69%) for older and younger patients with low-risk disease, respectively. The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%) for high-risk patients. In low-risk patients, the incidence of acute and chronic graft-versus-host disease, and treatment-related mortality were similar in older and younger patients, while older patients experienced more treatment-related deaths by day 100. On multivariable analysis, age >or=50 years was a significant adverse factor only when high-risk patients were considered. We conclude that when radiation-free conditioning is used, age >or=50 years is not a significant adverse risk factor for allogeneic BMT in patients with low-risk disease, and that such patients should not be excluded from conventional myeloablative approaches until the efficacy of nonmyeloablative transplantation is better established.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Células Madre , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/fisiología , Adolescente , Adulto , Factores de Edad , Femenino , Estudios de Seguimiento , Humanos , Leucemia/terapia , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre/mortalidad , Análisis de Supervivencia , Factores de Tiempo , Trasplante Homólogo/mortalidad , Resultado del Tratamiento , Irradiación Corporal TotalRESUMEN
Therapeutic options for patients with Hodgkin's disease who relapse after high-dose chemotherapy with autologous stem cell support are limited. Salvage chemotherapy is not curative, and allogeneic stem cell transplantation in this setting is associated with mortality rates of 40-65%. We report our institution's experience with second autologous transplants in this patient population. Five patients (median age 36) with relapsed Hodgkin's disease underwent a second autologous stem cell transplant at a median of 66 months after first transplant. Four patients received CBV, and one patient received BuCy as conditioning. Neutrophil and platelet engraftment occurred by days +10 and +16, respectively. All patients achieved a complete response, and no relapses have occurred after a median follow-up of 42 months. All four patients who received CBV developed interstitial pneumonitis, and two patients died of pulmonary complications 37 and 48 months following second transplant. Three patients remain alive and disease-free 41, 42 and 155 months after second transplant. These data indicate that second autologous transplantation should be considered for selected patients who relapse after a prolonged response to first autologous transplant. However, BCNU pneumonitis is the major toxicity in patients who have undergone previous mantle radiation and received busulfan with first transplant.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Causas de Muerte , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/mortalidad , Enfermedad de Hodgkin/mortalidad , Humanos , Cinética , Masculino , Recurrencia , Inducción de Remisión , Terapia Recuperativa , Trasplante Autólogo/métodosRESUMEN
Long-term outcome was analyzed in 28 patients transplanted between 1989 and 1992 following busulfan and cyclophosphamide and who had busulfan levels studied. While there was no significant correlation of busulfan levels with diagnosis, patients who had received extensive prior chemotherapy had a significantly higher area under the curve (AUC; P = 0.02) and maximum busulfan levels (Cmax; P = 0.03). High AUC was associated with the development of hepatic veno-occlusive disease (P = 0.03) and with early transplant-related mortality (P = 0.06). No significant correlation of busulfan levels with relapse, late non-relapse death, late complications, nor event-free survival was detected.
Asunto(s)
Antineoplásicos Alquilantes/toxicidad , Busulfano/toxicidad , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Adolescente , Adulto , Antineoplásicos Alquilantes/sangre , Antineoplásicos Alquilantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Área Bajo la Curva , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Busulfano/sangre , Busulfano/farmacocinética , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Humanos , Estudios Longitudinales , Acondicionamiento Pretrasplante/efectos adversos , Resultado del TratamientoRESUMEN
Results in 164 patients who underwent allogeneic marrow transplantation following busulfan and cyclophosphamide over a 15 year period were analyzed. Age (median 37, range 14-66 years) did not significantly affect the incidence of graft-versus-host disease (GVHD), but patients who received methotrexate with cyclosporine had a significantly lower incidence (P = 0.002) of chronic GVHD compared to those who received methylprednisolone with cyclosporine. Hepatic veno-occlusive disease (VOD) occurred less frequently in chronic phase patients (P = 0.002) and in those transplanted shortly after diagnosis (P = 0.001). Five year leukemia-free survival (LFS) for the entire group was 49% (95% CI 41-57%). For 102 patients who underwent transplantation in chronic phase, results were significantly improved by transplantation at a short interval following diagnosis, particularly within 3 months (P = 0.01), by the use of methotrexate and not corticosteroids for GVHD prevention (P = 0.03), and by use of HLA-identical sibling donors (P = 0.01). Age was not a significant adverse prognostic factor and transplantation was successfully performed in individuals up to age 66. Allogeneic transplantation in CML, including older patients and those with unrelated donors, can be most safely and effectively performed shortly after diagnosis.
Asunto(s)
Trasplante de Médula Ósea , Busulfano/administración & dosificación , Ciclofosfamida/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Trasplante de Médula Ósea/efectos adversos , Causas de Muerte , Femenino , Proteínas de Fusión bcr-abl/análisis , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Trasplante HomólogoRESUMEN
After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.
Asunto(s)
Trasplante de Médula Ósea , Ciclosporina/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/administración & dosificación , Metotrexato/administración & dosificación , Tacrolimus/administración & dosificación , Enfermedad Aguda , Administración Oral , Adolescente , Adulto , Niño , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Prognostic factors in 42 patients aged 11 to 62 (median 46) years, with myelodysplastic syndrome (MDS) or after leukemic transformation, who underwent allogeneic marrow transplantation between 1984 and 1999 were analyzed. Thirty-six had advanced disease morphology; 19 had leukemic transformation. Twenty-nine received a preparative regimen of BuCy2 and 13 busulfan 14 mg/kg, etoposide 50 mg/kg and cyclophosphamide 120 mg/kg. Severe hepatic veno-occlusive disease (VOD) occurred in three patients all of whom received anti-leukemic chemotherapy prior to transplantation. Fifteen patients (36%) died from early transplant-related complications; nine patients relapsed. The estimated 4 year disease-free survival (DFS) was 35% (95% CI 26-44%). Older age was the most significant adverse prognostic factor. Patients with leukemic transformation who underwent early transplantation had significantly better DFS than those treated first with chemotherapy (P = 0.002). Delayed toxicity was rare in these patients; no late relapses occurred. Bone Marrow Transplantation (2000) 25, 1219-1222.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Trasplante de Médula Ósea , Busulfano/administración & dosificación , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Leucemia/terapia , Síndromes Mielodisplásicos/terapia , Adulto , Niño , Terapia Combinada , Humanos , Leucemia/fisiopatología , Persona de Mediana Edad , Síndromes Mielodisplásicos/fisiopatología , Pronóstico , Trasplante HomólogoRESUMEN
The purpose of the study was to determine the toxicities and effectiveness of a novel preparative regimen of busulfan (Bu) 14 mg/kg, etoposide 50 or 60 mg/kg, and cyclophosphamide (Cy) 120 mg/kg in non-Hodgkin's lymphoma (NHL) and to analyze results using doses based on different body weight parameters and the two different etoposide doses. Three hundred and eighty-two patients aged 16 to 72 underwent first autologous transplantation with mobilized peripheral blood progenitor cells between August 1992 and December 1998 at either of two transplant centers. Mucositis was the most common toxicity. Hepatic toxicity was the most common life-threatening toxicity; severe hepatic VOD occurred in 11 patients (2.9%). Ten patients (2.6%) died from treatment-related toxicity. The 3-year progression-free survival (PFS) for the entire group was 46.9% (95% CI, 40.5-53.3%). Elevated LDH, resistance to chemotherapy, and intermediate/aggressive histology were significant adverse prognostic factors. For patients in sensitive first relapse PFS was 47.0% (95% CI, 37-57%). Neither etoposide dose nor body weight parameter utilized significantly affected outcome. In conclusion, the novel preparative regimen of Bu, etoposide and Cy results in a low incidence of treatment-related mortality and is effective in the treatment of patients with NHL. Bone Marrow Transplantation (2000) 25, 1243-1248.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Busulfano/administración & dosificación , Busulfano/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Humanos , Linfoma no Hodgkin/patología , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
Patients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML). In the subset of patients with SCN that progresses to AML, acquired mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) have been detected that result in the expression of truncated forms of the G-CSF receptor (G-CSFR) protein. G-CSFR truncation mutants from these patients transduce hyperproliferative growth responses. In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (delta716) confers resistance to apoptosis and prolongs cell survival through a mechanism involving Akt, a downstream target of PI3-kinase. G-CSF stimulation of cells expressing the G-CSFR truncation mutant induces sustained activation of Akt and prolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enhanced cell survival. Extension of cell survival allowing for sufficient time for the acquisition of additional oncogenic events may represent an important mechanism by which G-CSFR mutations contribute to leukemogenesis. These data provide further insight into the pathophysiologic contribution of G-CSFR mutations to AML. (Blood. 2000;95:2132-2137)
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/fisiología , Leucemia Mieloide Aguda/genética , Mutación , Neutropenia/congénito , Proteínas Serina-Treonina Quinasas , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Animales , Apoptosis/genética , Western Blotting , Proteínas Portadoras/metabolismo , Línea Celular , Supervivencia Celular/genética , Activación Enzimática , Ratones , Neutropenia/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Pruebas de Precipitina , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Recombinantes/metabolismo , Transducción de Señal , Factores de Tiempo , Proteína Letal Asociada a bclRESUMEN
Acquired mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) occur in a subset of patients with severe congenital neutropenia (SCN) who develop acute myelogenous leukemia (AML). These mutations affect one allele and result in hyperproliferative responses to G-CSF, presumably through a dominant-negative mechanism. Here we show that a critical domain in the G-CSFR that mediates ligand internalization is deleted in mutant G-CSFR forms from patients with SCN/AML. Deletion of this domain results in impaired ligand internalization, defective receptor downmodulation, and enhanced growth signaling. These results explain the molecular basis for G-CSFR mutations in the pathogenesis of the dominant-negative phenotype and hypersensitivity to G-CSF in SCN/AML.
Asunto(s)
Eliminación de Gen , Leucemia Mieloide Aguda/genética , Neutropenia/congénito , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Secuencia de Aminoácidos , Animales , Unión Competitiva , Células COS , División Celular , Electroforesis en Gel de Poliacrilamida , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Técnicas de Inmunoadsorción , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Neutropenia/genética , Fenotipo , Receptores de Factor Estimulante de Colonias de Granulocito/química , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , TransfecciónRESUMEN
We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Ciclosporina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Tacrolimus/uso terapéutico , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Niño , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Histocompatibilidad , Humanos , Hiperglucemia/inducido químicamente , Hipertensión/inducido químicamente , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Incidencia , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Núcleo Familiar , Recurrencia , Análisis de Supervivencia , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Activation of both positive and "negative" or anti-proliferative signals has emerged as a common paradigm for regulation of cell growth through cell surface receptors that regulate immune responses. SHP-1 and -2 and the novel 5'-inositol phosphatase SHIP have recently been shown to function as growth inhibitory molecules in immune receptor signaling. In the current study, we have identified distinct regions in the granulocyte colony-stimulating factor receptor (G-CSFR) distal to the conserved box 2 motif necessary for mitogenesis, which exert positive and negative influences on growth signaling in Ba/F3 pro-B lymphoid cells. The region spanning amino acids 682 to 715 mediates activation of phosphatidylinositol 3'(PI3)-kinase. Activation of PI3-kinase leads to inhibition of apoptosis, promotion of cell survival, and enhanced proliferative responses to G-CSF. We show that the region of 98 amino acids in the distal tail of the class I G-CSFR down-modulates proliferative signaling, not only in myeloid cell lines, as previously reported, but also in Ba/F3 cells. This same region recruits SHIP to the signaling cascade through a mechanism involving Shc, with the formation of Shc/SHIP complexes. Our data suggest a model in which PI3-kinase and SHIP coordinately regulate growth signaling through the G-CSFR.
Asunto(s)
División Celular , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Tirosina Fosfatasas/fisiología , Receptores de Factor Estimulante de Colonias de Granulocito/fisiología , Apoptosis , ADN/biosíntesis , Activación Enzimática , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Receptores de Eritropoyetina/fisiología , Receptores de Factor Estimulante de Colonias de Granulocito/análisis , Receptores de Factor Estimulante de Colonias de Granulocito/química , TransfecciónRESUMEN
The granulocyte colony-stimulating factor receptor (G-CSFR) critically regulates granulopoiesis. Defects in G-CSFR expression due to targeted disruption of the G-CSFR gene or the genes for the transcription factors C/EBPalpha and PU.1 result in decreases in hematopoietic progenitor cell numbers and neutropenia. Mutations in the G-CSFR gene disrupt its normal signaling functions and appear to contribute to leukemogenesis. Acquired mutations in the G-CSFR resulting in truncation of the distal cytoplasmic region that mediates maturation and growth arrest signaling have been reported in patients with severe congenital neutropenia (SCN) and acute myelogenous leukemia (AML). A role for G-CSFR mutations in the pathogenesis of other disorders is speculated. This review will summarize the current state of knowledge of the G-CSFR and its role in disorders of granulopoiesis.
Asunto(s)
Granulocitos/citología , Leucopoyesis/fisiología , Receptores de Factor Estimulante de Colonias de Granulocito/fisiología , Animales , Humanos , Leucemia Mieloide Aguda/genética , Neutropenia/genética , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Relación Estructura-ActividadRESUMEN
PURPOSE: We analyzed the safety and effectiveness of high-dose etoposide (2 g/m2) followed by granulocyte colony-stimulating factor (G-CSF) as a peripheral-blood progenitor cell (PBPC) mobilization regimen and assessed extent of tumor reduction in patients with breast cancer, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). PATIENTS AND METHODS: One hundred sixty-nine consecutive patients who eventually underwent PBPC transplantation received treatment with high-dose etoposide (2 g/m2) followed by daily G-CSF (5 microg/kg). RESULTS: This mobilization method was effective in nearly all patients. No patients died of mobilization-related complications. A 50% reduction in tumor size was seen in 19% of assessable patients with breast cancer, 44% of those with NHL, and 38% of those with HD. Hematopoietic recovery (HR) following transplantation occurred in all patients. Patients with > or = 4 x 10(6) CD34+ cells/kg engrafted with neutrophils at a median of 9 days after transplant and patients with at least 1.2 x 10(6) CD34+/CD33- cells/kg achieved platelet recovery at a median of 15 days. CONCLUSION: Etoposide plus G-CSF is an effective and safe method for mobilization of PBPCs. Etoposide is an effective agent in tumor reduction in NHL and HD and is less effective in breast cancer. The substantially lower incidence of prior exposure to this agent compared with cyclophosphamide favors its use.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Etopósido/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Enfermedad de Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Recolección de Muestras de Sangre , Neoplasias de la Mama/terapia , Criopreservación , Etopósido/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Humanos , Inmunofenotipificación , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana EdadRESUMEN
Activation of the granulocyte colony-stimulating factor receptor (G-CSFR) induces rapid tyrosine phosphorylation of multiple intracellular substrates in proliferating cells and nonproliferating, terminally differentiated neutrophils. The kinases that couple ligand binding to tyrosine phosphorylation of cellular substrates by the G-CSFR with activation of specific functional programs are largely unknown. In this study, we examined early signaling events in proliferating and terminally differentiated cells following G-CSF stimulation to determine whether identical signaling cascades are activated. In murine Ba/F3 cells transfected with the human G-CSFR and NFS-60 cells constitutively expressing the murine G-CSFR, G-CSF induced tyrosine phosphorylation and activation of Jak1, Jak2, and Tyk2. Tyrosine phosphorylation of Stat3 and, to a lesser extent, Stat1 was also detected following G-CSF stimulation. Using a mitogenically incompetent human G-CSFR mutant in which Pro639 and Pro641 were substituted by alanine, the box 1 PDP motif was found to be required for activation of Jak kinases, tyrosine phosphorylation of the G-CSFR, and recruitment of Stat proteins. Notably, no activation of Jak1, Jak2, Tyk2, Stat1, or Stat3 was observed in neutrophils following G-CSF stimulation. In addition, there was no detectable activation in neutrophils of the recently cloned Jak3 kinase, which has been reported to be expressed at high levels as myeloid cells undergo terminal neutrophilic maturation. These results indicate a lack of involvement of Jak kinases in signaling by the G-CSFR in neutrophils, and suggest utilization of alternative signal transduction pathways distinct from those in proliferating cells. Activation of the Jak-Stat pathway correlates with proliferative signaling by the G-CSFR and requires the membrane-proximal box 1 PXP motif, which is conserved in members of the cytokine receptor superfamily.