RESUMEN
Human herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in lesions of multicentric Castleman's disease (MCD). We have identified a major gamma-herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vIL-6) shares functional properties with endogenous IL-6 proteins and that both vIL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8' BCBL cell line. Low amounts of constitutive vIL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vIL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cytokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.
Asunto(s)
ADN Viral/genética , Herpesvirus Humano 8/genética , Interleucina-6/genética , Proteínas Inflamatorias de Macrófagos/genética , Secuencia de Aminoácidos , Quimiocina CCL4 , Humanos , Datos de Secuencia Molecular , ARN Mensajero/análisis , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
Seventy-four consecutive patients with high-risk acute lymphoblastic leukemia (ALL) were given cyclophosphamide (CY; 50 mg/kg on each of 4 days) plus total body irradiation (TBI; 300 rad on each of 4 days) followed by a human leukocyte antigen (HLA)-identical allogeneic bone marrow transplant (BMT). Eighteen patients in first complete remission (CR1), 36 in CR2, 16 in CR3, and four in CR4 were transplanted. Patients in CR1 were transplanted 1 to 8 months (median, 3 months) after attaining CR. All 18 patients in CR1 had one or more poor risk factors: age more than 18 (N = 17), initial leukocyte count greater than or equal to 20,000 (N = 11), Ph 1 chromosome (N = 2), delay in attaining CR more than 6 weeks (N = 8), or extramedullary disease (N = 1). Of those transplanted in CR2, 72% had relapsed on therapy. The 5-year event-free survival (EFS) rates for patients transplanted in CR1, CR2, and CR3 are 42%, 43%, and 25%, respectively, at median follow-up times of 57, 54, and 72 months, respectively. Children aged less than 18 years transplanted in CR2 have a 5-year EFS rate of 54%. All CR4 patients died early after transplant. The actuarial probability of relapse is 20%, 26%, and 48% for those transplanted in CR1, CR2, and CR3, respectively. Although there was substantial transplant-associated mortality, it decreased over the decade of the study (P = .01). This study indicates that BMT offers an attractive alternative to postremission chemotherapy in patients in CR1 with poor prognostic factors and in patients in second remission.
Asunto(s)
Trasplante de Médula Ósea , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adolescente , Adulto , Factores de Edad , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Distribución de Chi-Cuadrado , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Recuento de Leucocitos , Masculino , Análisis Multivariante , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkin's disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad de Hodgkin/terapia , Leucemia Mieloide Aguda/cirugía , Adolescente , Adulto , Busulfano/uso terapéutico , Terapia Combinada , Ciclofosfamida/uso terapéutico , Ciclosporinas/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/etiología , MasculinoRESUMEN
Patients with Hodgkin's disease who have failed two or more chemotherapy regimens or who have relapsed after an initial chemotherapy-induced remission of less than 12 months are seldom cured with conventional salvage therapies. We studied the effect of high-dose cytoreductive therapy followed by bone marrow transplantation in 50 such patients with relapsed Hodgkin's disease. Twenty-one patients with histocompatibility locus antigen (HLA)-matched donors had allogeneic marrow transplants, one patient received marrow from an identical twin, and 28 patients without a matched donor received autologous grafts purged with 4-hydroperoxycyclophosphamide. Busulfan plus cyclophosphamide was the preparative regimen for the 25 patients who had received extensive prior irradiation, and the other 25 patients received cyclophosphamide plus total body irradiation. The overall actuarial probability of event-free survival at 3 years was 30%, with a median follow-up of 26 months. The event-free survival following transplantation was influenced by the number of chemotherapy failures and the patient's response to conventional salvage therapy prior to transplant. The 16 patients who were transplanted at first relapse, while still responsive to standard therapy, had a 64% actuarial probability of event-free survival at 3 years. Age, presence of extranodal disease, preparative regimen, and type of graft (autologous v allogeneic) were not significant prognostic factors. The majority of transplant-related deaths were from interstitial pneumonitis; inadequate pulmonary function, multiple prior chemotherapy regimens, and prior chest irradiation all appeared to increase the transplant-related mortality. These results suggest a role for marrow transplantation in a subset of patients with relapsed Hodgkin's disease who are unlikely to be otherwise cured but are still responsive to conventional-dose cytoreductive therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Enfermedad de Hodgkin/terapia , Recurrencia Local de Neoplasia/terapia , Análisis Actuarial , Adolescente , Adulto , Niño , Terapia Combinada , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/cirugía , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Probabilidad , PronósticoRESUMEN
This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.
Asunto(s)
Protocolos Clínicos , Inmunoterapia Adoptiva/métodos , Leucemia Linfoide/terapia , Timidina Quinasa/genética , Estudios de Evaluación como Asunto , Vectores Genéticos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfocitos/citología , Linfocitos/metabolismo , Selección de Paciente , Inducción de Remisión/métodos , Simplexvirus/enzimología , Timidina Quinasa/metabolismoRESUMEN
Of 386 patients with allogeneic bone marrow transplants (BMT) treated during a 9-year interval, 166 developed interstitial pneumonitis (IP). Idiopathic and cytomegalovirus (CMV) IP constituted 90% of the 113 cases in which tissue was examined. Risk factors for IP overall were acute graft-versus-host disease (AGVHD), remote transplant date, the diagnosis of leukemia, and GVHD prophylaxis with agents other than cyclosporine. Risk factors for CMV IP were pre-transplant CMV seropositivity, CMV excretion, age greater than 10 years, AGVHD, GVHD prophylaxis with agents other than cyclosporine, and a remote transplant date. Patients transplanted for aplastic anemia were at lower risk for idiopathic IP than those transplanted for leukemia. The incidence of IP in patients given busulfan plus cyclophosphamide was equivalent to that in patients receiving cyclophosphamide plus total body irradiation. The incidence of idiopathic IP remained constant over this 9-year period while CMV IP declined significantly.
Asunto(s)
Trasplante de Médula Ósea , Fibrosis Pulmonar/etiología , Adulto , Instituciones Oncológicas , Infecciones por Citomegalovirus/etiología , Análisis Factorial , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresores/uso terapéutico , Masculino , Maryland , Fibrosis Pulmonar/epidemiología , Factores de Riesgo , Estadística como AsuntoRESUMEN
A virus-specified thymidine kinase appears to be a general requirement for herpes virus susceptibility to the antiviral effect of acyclovir. Surprisingly, mouse cytomegalovirus (MCMV), which does not encode for a thymidine kinase, is exquisitely sensitive to the drug both in vitro and in vivo. The drug is active against the virus in the absence of a cellular thymidine kinase and the antiviral activity is not diminished in the presence of excess thymidine or a variety of nucleosides and deoxynucleosides. Thus, a thymidine phosphorylation pathway is not required for the drug's activation of this infection. The enzyme system responsible for phosphorylation of the drug has not been identified. Mouse cytomegalovirus mutants resistant to the drug have been isolated, indicating that the antiMCMV effect results from selective inhibition of viral replication rather than indirectly through toxicity to the host cell. Eight resistant mutants appear to be in the same complementation group and seven of the mutants demonstrate coresistance to phosphonoacetic acid, a marker for the DNA polymerase locus of herpes viruses. The evidence to date indicates that the MCMV DNA polymerases is the final site of action of the drug. Investigations of the antiMCMV activity of acyclovir should provide insights into the antiviral effects of this drug and other nucleoside analogs in other herpes virus infections in which the virus does not code for a thymidine kinase (for example, human cytomegalovirus and Epstein-Barr virus).
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Guanina/análogos & derivados , Aciclovir , Animales , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/enzimología , Resistencia a Medicamentos , Femenino , Guanina/farmacología , Guanina/uso terapéutico , Ratones , Ratones Endogámicos A , Mutación , Ácido Fosfonoacético/farmacología , Timidina Quinasa/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
Acyclovir, a new antiherpetic agent, was administered for 18 days to 10 recipients of bone marrow transplants as a part of a double-blind, randomized, placebo-controlled trial assessing its prophylactic efficacy and safety. Renal glomerular function diminished over the time of the study in the 10 acyclovir-treated and 10 placebo-treated patients. The decline in glomerular filtration rate (GFR) did not differ significantly between the two groups and is unlikely to be associated with acyclovir. The pharmacokinetics of acyclovir is expected to be altered by a change in GFR since glomerular filtration is probably the major process involved with the excretion of acyclovir. Such an alteration was seen as an increase over time of both peak (one hour after the end of an infusion) and trough (immediately before a dose) plasma acyclovir concentrations. Although peak and trough acyclovir concentrations rose from 8.5 to 15.8 microM and from 1.7 to 4.1 microM, respectively, these rises are fully attributable to the decreases in GFR seen in both drug- and placebo-treated groups. The placebo-controlled and blinded nature of this trial allows an assessment of the effects of acyclovir on a battery of hematologic, renal, and hepatic tests. The only adverse effects observed that statistically differed in the acyclovir-treated group compared with controls were the rises in SGOT (53.2 +/- (SEM) 19.9 versus 3.1 +/- 12.2) and SGPT (59.7 +/- 15.3 versus 12.3 +/- 13.8).
Asunto(s)
Antivirales/sangre , Guanina/análogos & derivados , Herpes Simple/prevención & control , Aciclovir , Antivirales/efectos adversos , Recuento de Células Sanguíneas , Trasplante de Médula Ósea , Evaluación de Medicamentos , Tasa de Filtración Glomerular , Guanina/efectos adversos , Guanina/sangre , Humanos , Riñón/fisiología , Hígado/fisiologíaRESUMEN
BACKGROUND: Cytomegalovirus (CMV) has been associated with the development of chronic allograft rejection. Attempts to delineate pathogenetic mechanisms for this association have characteristically used well-established laboratory strains for in vitro investigation and rodent strains for in vivo studies. There is substantial genetic heterogeneity not only among different laboratory strains, but also between laboratory strains and clinical isolates, and genetic differences between human and animal strains are profound. Given these genetic differences, one would anticipate differences in biological activity between strains. METHODS: Vascular endothelial cells were infected with two laboratory strains of CMV (Towne and AD-169) as well as two individual clinical CMV isolates, after genetic typing with six segments of the genome (including early and late genes). mRNA expression coding for a panel of mesenchymal growth factors was studied using quantitative reverse transcription, polymerase chain reaction. Major histocompatibility complex (MHC) expression was investigated using flow cytometry. RESULTS: There was substantial genetic variability between clinical and laboratory isolates. There did not appear to be differences in overall infectivity by the different strains as determined by expression of immediate-early antigen at 24 hours (5-10% of endothelial cells positive for immediate-early. Two growth factors, platelet-derived growth factor-A and basic fibroblast growth factor were augmented by one of the two clinical strains of CMV (Clin 2) (P=0.0091 and P=0.0018, respectively). Transforming growth factor -alpha and insulin-like growth factor expression were significantly reduced by both clinical strains and AD-169. Two other growth factors, heparin-binding epidermal growth factor and transforming growth factor-beta were not altered by infection with any strain. No strain altered MHC class II expression. MHC class I expression was increased with one of the two clinical strains (Clin 1, P=0.0006) and decreased by AD-169 (P=0.0016). Clin 2 and Towne had no effect on MHC class I expression. CONCLUSIONS: These data demonstrate that the genetic heterogeneity of CMV is associated with differences in transplant-relevant biologic activity even among clinical isolates. The relationship between CMV and chronic rejection may be difficult to determine given the heterogeneous nature of this complex virus.
Asunto(s)
Infecciones por Citomegalovirus/patología , Citomegalovirus/genética , Citomegalovirus/patogenicidad , Endotelio Vascular/fisiología , Endotelio Vascular/virología , Sustancias de Crecimiento/genética , Trasplante de Corazón/patología , Antígenos Virales/genética , Aorta , Células Cultivadas , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/etiología , Cartilla de ADN , Factor 2 de Crecimiento de Fibroblastos/genética , Variación Genética , Humanos , Factor de Crecimiento Derivado de Plaquetas/genética , Reacción en Cadena de la Polimerasa , Complicaciones Posoperatorias/virología , ARN Mensajero/genética , Somatomedinas/genética , Especificidad de la Especie , Factor de Crecimiento Transformador alfa/genética , Trasplante HomólogoRESUMEN
Interstitial pneumonitis (IP) occurred in 20 of 143 (14%) patients who received cytoreductive therapy followed by autologous bone marrow transplantation (BMT) as treatment for malignancy. IP occurred at a median onset time of 41 days (5 to 624 days). All but three of the episodes were fatal. Of the thirteen cases in which tissue was examined, half were idiopathic; the remainder were due to various infectious agents. The actuarial incidences of idiopathic (7%) and CMV IP (2%) in these marrow autograft recipients were lower than the incidences of idiopathic (19%) and CMV IP (17%) in comparably treated recipients of allogeneic BMT (P less than or equal to 0.001 for both comparisons).
Asunto(s)
Trasplante de Médula Ósea , Leucemia/terapia , Linfoma/terapia , Fibrosis Pulmonar/etiología , Adolescente , Adulto , Niño , Preescolar , Infecciones por Citomegalovirus/complicaciones , Femenino , Humanos , Masculino , Factores de Riesgo , Virosis/complicacionesRESUMEN
PURPOSE: MRL/Mp-lpr/lpr mice (MRL/lpr) spontaneously develop lacrimal gland inflammatory lesions and are a model for the human disease Sjögren's syndrome. Therapy with monoclonal antibodies (mAb) to CD4 ameliorates the autoimmune renal, vasculitic, and intraocular inflammatory lesions in MRL/lpr mice. The effect of anti-CD4 mAb therapy on lacrimal gland immunopathology was evaluated. METHODS: From 1 to 5 months of age, MRL/lpr mice were treated with weekly intraperitoneal injections of 2 mg anti-CD4 mAb, after which they were killed and their lacrimal glands were removed for histologic evaluation and immunocytochemistry. Control mice were administered weekly intraperitoneal injections of either saline or normal rat immunoglobulin. RESULTS: Anti-CD4 mAb treatment produced no reduction in lacrimal gland inflammation but did change its morphology. In control mice, there were multiple sharply delineated foci of inflammatory cells in the lacrimal gland, whereas in anti-CD4 mAb-treated mice, there was a more diffuse inflammation surrounding ill-defined foci that spread throughout the gland. Immunocytochemistry revealed that in control mice, lesions were composed predominantly of CD4+ T cells, but in anti-CD4 mAb-treated mice, CD8+ T cells predominated. CONCLUSIONS: Although anti-CD4 mAb therapy of MRL/lpr mice eliminated autoimmune renal disease, autoantibody formation, and ocular inflammatory disease, it had a paradoxic effect on lacrimal gland lesions. Lacrimal gland lesions in the anti-CD4 mAb-treated mice were not decreased, but they had a different morphology and a different immunocytochemical profile.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/terapia , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedades del Aparato Lagrimal/terapia , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Autoanticuerpos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Femenino , Glomerulonefritis/inmunología , Glomerulonefritis/terapia , Técnicas para Inmunoenzimas , Inyecciones Intraperitoneales , Aparato Lagrimal/inmunología , Aparato Lagrimal/patología , Aparato Lagrimal/virología , Enfermedades del Aparato Lagrimal/inmunología , Enfermedades del Aparato Lagrimal/patología , Ratones , Ratones MutantesRESUMEN
Angiographic studies have demonstrated that perfusion balloon percutaneous transluminal coronary angioplasty (PTCA) may result in modestly improved luminal gains and fewer major dissections than conventional balloon PTCA. However, intracoronary ultrasound (ICUS), which is more sensitive than angiography in evaluating the incidence, extent, and severity of dissection, was not used. We randomized 48 patients with 54 coronary stenoses to conventional or perfusion balloon PTCA. Four 2-minute inflations were permitted with conventional balloon PTCA. Two 10-minute inflations were allowed with perfusion balloon PTCA. Quantitative coronary angiography and ICUS were performed before and after treatment. In-hospital clinical events were recorded. Conventional and perfusion balloon PTCA achieved similar improvements in lumen diameter (1.25+/-0.51 vs 1.28+/-0.51 mm) and reductions in percent stenosis (-45+/-21% vs -44+/-15%) by quantitative coronary angiography. Comparable gains in lumen diameter (0.62+/-0.39 vs 0.50+/-0.38 mm) and lumen area (2.70+/-1.96 vs 2.05+/-1.52 mm2) were observed on ICUS. Angiography demonstrated similar rates of any dissection (36% vs 21%) and major dissection (12% vs 7%). ICUS identified a similar incidence of any dissection (60% vs 76%) and type II dissection (52% vs 62%). The relative dissection area was also similar (9.2+/-5.6% vs 7.8+/-5.8%). One conventional balloon patient experienced postprocedural chest pain. No patient in either group died, or had myocardial infarction, abrupt closure, or urgent revascularization.
Asunto(s)
Angioplastia Coronaria con Balón , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/terapia , Ultrasonografía Intervencional , Angioplastia Coronaria con Balón/mortalidad , Angiografía Coronaria , Enfermedad Coronaria/mortalidad , Estudios Cruzados , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Sensibilidad y Especificidad , Resultado del Tratamiento , Ultrasonografía Intervencional/mortalidadRESUMEN
Since June 1977 eight patients with acute leukemia and three with chronic myelogenous leukemia (CML) have undergone cytoreductive therapy prior to a second allogeneic or syngeneic bone marrow transplantation (BMT). The median age was 24 years (range 7-49 years) and the median time to second BMT was 495 days (range 122-1887 days). Prompt hematopoietic recovery was documented in 11/11 patients and verified by cytogenetic analysis in 7/11. Early death (less than 100 days) was the result of sepsis in one, veno-occlusive disease in one and interstitial pneumonitis in two. Of seven patients who survived beyond 1 year, two patients subsequently died, one as a result of acute respiratory failure and one of leukemia relapse. Five are currently disease-free at 8+, 20+, 42+, 49+ and 72+ months after the second BMT. In this patient population which is at high risk for resistant disease and treatment-related toxicity, a second preparative therapy and BMT may offer a durable disease remission with tolerable toxicity.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/cirugía , Leucemia Mieloide Aguda/cirugía , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adolescente , Adulto , Niño , Estudios de Evaluación como Asunto , Femenino , Enfermedad Injerto contra Huésped , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Cuidados Preoperatorios , ReoperaciónRESUMEN
Hepatic veno-occlusive disease (HVOD) and interstitial pneumonitis (IP) are both widely regarded as toxicities of intensive cytoreductive therapy, but their association has not been previously examined. Risk factors for IP were evaluated in 154 patients given intensive cytoreductive therapy followed by allogeneic bone marrow transplantation during a 2 1/2 year period. IP occurred in 68 patients; HVOD occurred in 39. The actuarial incidence of IP in patients with VOD was 71% and 45% in those without VOD (p = 0.0002). In multivariate analysis, the diagnosis of hematologic malignancy (p less than 0.001), the occurrence of HVOD (p less than 0.01), and pretransplant CMV seropositivity (p less than 0.02) were significantly associated with IP. The individual relative risks for IP of presence to absence of these factors was 4.5 for the diagnosis of hematologic malignancy, 2.1 for HVOD, and 1.9 for CMV seropositivity. Pulmonary veno-occlusive disease (PVOD), a previously rare observation, was noted at autopsy in 1/5 (20%) patients with HVOD alone, 6/20 (30%) patients with IP alone, and 10/14 (71%) of patients with both HVOD and IP. The association of HVOD and IP is supportive of the concept that toxic effects of cytotoxic therapy have a major role in pathogenesis of HVOD and IP.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea , Enfermedad Veno-Oclusiva Hepática/complicaciones , Leucemia/terapia , Enfermedades Pulmonares/complicaciones , Fibrosis Pulmonar/complicaciones , Antineoplásicos/efectos adversos , Enfermedad Veno-Oclusiva Hepática/epidemiología , Humanos , Enfermedades Pulmonares/epidemiología , Fibrosis Pulmonar/epidemiología , Traumatismos por RadiaciónRESUMEN
We have performed univariate and multivariate analysis to determine the factors that affect the kinetics of neutrophil and platelet recovery in 546 recipients of T cell-depleted (TCD) marrow allografts. All patients received marrow depleted of mature CD3(+) T cells by complement-mediated lysis using T(10)B(9)-1A3 (n = 489) or Muromonab-Orthoclone OKT3 (n = 57) monoclonal antibodies. Neutrophil engraftment to 0.5 x 10(9)/1 and platelet engraftment to 20 x 10(9)/l were assessed as endpoints. Factors significantly affecting neutrophil or platelet engraftment in the univariate analysis included patient age, T cell dose, anti-thymocyte globulin use, gender, diagnosis at transplant, CMV serostatus, HLA mismatch, CD34 cell dose (n = 249), and growth factor use and type. These variables were included in the multivariate Cox proportional hazards regression model. The results showed that a faster rate of neutrophil engraftment was independently associated with CD34(+) cell dose > or = 5 x 10(6)/kg and most strongly with growth factor administration. Faster platelet engraftment was associated with transplantation for chronic leukemia, CD34(+) cell dose > or = 2 x 10(6)/kg, an HLA matched related donor, and the absence of growth factor use. G-CSF had a higher relative risk (RR) of enhancing neutrophil engraftment than GM-CSF and significantly delayed platelet engraftment. The combined use of G-CSF + GM-CSF was similar to G-CSF alone. The enhancing effect of G-CSF for neutrophil recovery was most striking for patients who engrafted to 0.5 x 10(9)/1 at or before day 12 (RR = 9.5, P < 0.0001) compared to patients who received no growth factor. Conversely, the delaying effect of G-CSF on platelet engraftment was strongest for patients engrafting on or before day 25 (RR = 0.4, P = 0.0004). Of the independent variables affecting engraftment kinetics in recipients of TCD marrow allografts only growth factor, and to a limited extent, CD34(+) cell dose can be controlled by the clinician. A higher CD34(+) cell dose enhances the rate of both neutrophil and platelet engraftment whereas for G-CSF the benefits of myeloid growth factor use in enhancing neutrophil recovery may be partly offset by a delay in platelet engraftment.
Asunto(s)
Trasplante de Médula Ósea , Supervivencia de Injerto , Depleción Linfocítica , Adolescente , Adulto , Anciano , Análisis de Varianza , Antígenos CD34/fisiología , Donantes de Sangre , Plaquetas/citología , Niño , Preescolar , Estudios de Cohortes , Femenino , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Sustancias de Crecimiento/farmacología , Enfermedades Hematológicas/mortalidad , Enfermedades Hematológicas/terapia , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Estudios Retrospectivos , Factores de Riesgo , Linfocitos T , Factores de TiempoRESUMEN
Between 1984 and 1991 24 patients with severe aplastic anemia (SAA) were transplanted with HLA identical sibling donor BM. The overall long-term survival was 79 +/- 8%. The average age was 21 years (range 4-53 years) and the median pre-transplant disease duration was 35 days (range 12-2998 days). Over one-half (15 of 24) of the patients had received > 10 units of blood product transfusions prior to BMT. The pre-transplant conditioning regimen consisted of 200 mg/kg cyclophosphamide (CY). Cyclosporine (CYA) was administered from 2 days prior to BMT and continued for 6-12 months. Two of the 24 patients failed to achieve primary engraftment (FTE). One of these patients had autologous recovery of BM function and is alive and well. Five of the 22 patients who engrafted failed to sustain engraftment (FTSE). Of these, three are alive and well following a second BMT or marrow boost. Only 1 of the 22 patients who engrafted had clinically significant (i.e. Stage II-IV) acute GVHD. No patient developed chronic GVHD. Our results indicate that BMT following a regimen consisting of CY with the continuous use of CYA in the post-transplant period is well tolerated and associated with excellent long-term survival. The high incidence of secondary graft instability (i.e. FTSE), however, suggests that future studies should focus on post-transplantation immunomodulation.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Ciclosporina/uso terapéutico , Adolescente , Adulto , Anemia Aplásica/mortalidad , Niño , Preescolar , Terapia Combinada , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Twenty patients with poor prognosis non-Hodgkin's lymphoma received regimens which employed cyclophosphamide and total body irradiation followed by autologous bone marrow rescue. There were two toxic deaths. All 10 patients with residual disease prior to treatment achieved a complete remission. Ten patients survive disease free from 1.4 to 9.5 years and median survival exceeds 2.9 years. The actuarial 3-year disease-free survival is 50%. Treatment with cyclophosphamide and total body irradiation followed by autologous bone marrow infusion is an effective salvage regimen for poor prognosis lymphoma. Durable long-term remissions can be achieved.
Asunto(s)
Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Linfoma no Hodgkin/terapia , Adolescente , Adulto , Niño , Preescolar , Humanos , Pronóstico , Irradiación Corporal TotalRESUMEN
Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple/terapia , Linfocitos T , Adulto , Antígenos CD34/análisis , Terapia Combinada , Ciclofosfamida/uso terapéutico , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Metilprednisolona/uso terapéutico , Acondicionamiento Pretrasplante , Trasplante Autólogo , Irradiación Corporal TotalRESUMEN
Cutaneous sclerodermalike changes are a well-documented manifestation of chronic cutaneous graft-vs-host reaction. We describe a patient with chronic cutaneous graft-vs-host reaction who developed vesicles and bullae on sclerodermoid skin 18 months after bone marrow transplantation. The vesicles and bullae were subepidermal in location by light microscopy and were associated with dilated lymphatics and a sparse perivascular mononuclear cell infiltrate. No deposition of immunoreactants was seen by immunofluorescent microscopy. Electron microscopy confirmed the presence of a subepidermal blister beneath an intact basement membrane zone and surrounded by marked dermal edema. We postulate that localized lymphedema may play a role in the development of these vesicles and bullae.