Asunto(s)
Teorema de Bayes , Mortalidad , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Medición de RiesgoRESUMEN
This is a prospective study designed to determine the toxicity, efficacy and antileukemic effect of high-dose cytosine arabinoside (ara-C), cyclophosphamide and total body irradiation (TBI) as a myeloablative regimen prior to allogeneic bone marrow transplantation for patients with hematologic malignancies. Fifty-eight patients with hematologic malignancies were treated with cyclophosphamide, high-dose ara-C and total body irradiation (TBI) followed by allogeneic bone marrow transplantation. Fifty patients had good prognosis disease and eight had poor prognosis disease. Cyclosporine and short-course methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. The conditioning regimen consisted of ara-C 3000 mg/m2 twice a day x six doses on days -7, -6, and -5; cyclophosphamide 1800 mg/m2 on days -4 and -3; and TBI 1400 cGy midline dose at 5 cGy/min in eight total fractions administered twice a day on days -4, -3, -2, and -1. The bone marrow was infused on day 0 (zero). Toxicity related to the conditioning regimen was comparable to that reported with other conditioning regimens, except for diarrhea which appears to be more frequent. The actuarial survival at 1 year was 69% (58-82) and at 5 years was 54% (42-69) with the numbers in parentheses representing the 95% confidence interval of the Kaplan-Meier estimate. After a median follow-up of 28 months, 31 of 58 (53%) patients are alive without evidence of disease. Only four of the 58 patients (7%) have relapsed. Cyclophosphamide, ara-C and TBI is a safe and effective myeloablative regimen for patients with leukemia. The overall relapse rate in our study was 7% with a median follow-up of 28 months and appears to be lower than relapse rates reported in other series. This is probably due to the added antileukemic effect of ara-C. This regimen should be compared with other myeloablative regimens in a controlled study.
Asunto(s)
Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Citarabina/uso terapéutico , Leucemia/terapia , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Adolescente , Adulto , Niño , Preescolar , Ciclofosfamida/efectos adversos , Citarabina/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Leucemia/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Trasplante HomólogoRESUMEN
The utility of serum Aspergillus antigen in invasive aspergillosis was determined by identifying patients with >50 ng/mL Aspergillus carbohydrate antigen by ELISA. Patients were identified from a university hospital over a 65-month period. Nineteen patients with antigenemia had proven invasive aspergillosis, 16 had probable invasive aspergillosis, and 14 had an indeterminate diagnosis. There were 5 patients with false-positive results. Antigen levels were higher in disseminated infection than in invasive pulmonary aspergillosis (median levels, 500 and 121 ng/mL, respectively). Survival also correlated with antigenemia. Serial samples were obtained from 31 of 35 patients with proven or probable invasive aspergillosis. Fifteen of 19 patients with rising or persistent antigenemia died, whereas only 1 of 12 patients who cleared antigenemia died. Higher antigen levels were useful in predicting disseminated disease, and the course of antigenemia correlated with clinical outcome. Antigen detection may be a useful addition in the management of invasive aspergillosis.
Asunto(s)
Antígenos Fúngicos/análisis , Aspergilosis/diagnóstico , Aspergillus/inmunología , Carbohidratos/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , PronósticoRESUMEN
Bone marrow transplantation is characterized by a prolonged period of humoral immunodeficiency in which many patients have abnormal circulating B-cell subsets, and oligoclonal and monoclonal gammapathies. In this study we examine B-cell precursor reconstitution in the post-transplantation marrow. Within 1 month after transplantation there is a marked increase in the percentage of immature B cells (to 80% of marrow lymphocytes), which can persist for more than 1 year. The increase in B-cell precursors is seen in both adults and children and appears to be independent of age. These cells have a normal precursor B-cell surface antigenic phenotype (CD19+, CD10+, CD20 negative to dim) and generally express very little CD34. No monoclonal or oligoclonal immunoglobulin gene rearrangements are detected in these cells, which enables them to be easily distinguishable from common precursor B-cell acute lymphocytic leukemia lymphoblasts.
Asunto(s)
Linfocitos B/citología , Células de la Médula Ósea , Trasplante de Médula Ósea , Células Madre Hematopoyéticas/citología , Adolescente , Adulto , Antígenos CD/análisis , Linfocitos B/inmunología , Southern Blotting , Médula Ósea/inmunología , Niño , Preescolar , Células Clonales , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Reordenamiento Génico de Cadena Pesada de Linfocito B , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunofenotipificación , Lactante , Cinética , Masculino , Persona de Mediana Edad , Neprilisina/análisisAsunto(s)
Antineoplásicos/farmacología , Trasplante de Médula Ósea , Hematopoyesis/efectos de los fármacos , Inmunosupresores/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Busulfano/análogos & derivados , Busulfano/farmacología , Carmustina/farmacología , Hematopoyesis/efectos de la radiación , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Melfalán/farmacología , Irradiación Corporal TotalRESUMEN
Wiskott-Aldrich Syndrome (WAS) is a sex-linked disease characterized by immunodeficiency and thrombocytopenia. Supportive treatment of this disease is inadequate and bone marrow transplantation has been reported to result in excellent survival. The long-term follow-up of 8 male patients who received bone marrow transplantation for the WAS is reported here. All of these patients received ablative preparative treatment consisting of ATS (antithymocyte serum), cytoxan and either busulfan or TBI (total body irradiation). Bone marrow was transplanted from an HLA-matched donor. Seven of eight of these male patients have had excellent engraftment of their transplant and now have adequate lymphocyte and platelet function. In addition, they have had good growth and development. This suggests that ablative preparative treatment followed by early bone marrow transplantation from an HLA-matched donor is a highly successful therapy for this congenital disease.
Asunto(s)
Trasplante de Médula Ósea , Síndrome de Wiskott-Aldrich/cirugía , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Lactante , Masculino , Síndrome de Wiskott-Aldrich/inmunologíaRESUMEN
Twenty-three patients with primary myelodysplasia (MDS) or secondary myelodysplasia/acute nonlymphocytic leukemia (MDS/ANLL) were treated with allogeneic or syngeneic bone marrow transplantation (BMT). Only one patient was in a chemotherapy-induced hematologic remission. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, cyclosporine, or T-cell depletion using one of two anti-CD5 monoclonal antibodies. For patients with primary MDS, the median age was 19 years (range, 11 to 41 years) and the actuarial disease-free survival was 56% +/- 21% (median follow-up, 2 years; range, 0.8 to 5 years). There were three graft failures (two with autologous recovery) and two early deaths. Outcome appeared to be related to French-American-British (FAB) classification. For patients with secondary MDS/ANLL, the median age was 28 years (range, 3 to 16 years) and the actuarial disease-free survival was 27% +/- 13% (median follow-up, 5 years; range, 2.5 to 8.5 years). There were no graft failures, two relapses, and four early deaths. The presence of marrow fibrosis per se did not predict for graft failure (P = .21); however, the use of T-cell depleted marrow in patients with marrow fibrosis resulted in graft failure in three of five individuals. Our results suggest that in patients with primary MDS or secondary MDS/ANLL, BMT should be considered early in the course of the disease, and that attempts at inducing a remission prior to BMT appeared to be unnecessary. In MDS patients with marrow fibrosis, T-cell depletion should be avoided.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mieloide Aguda/cirugía , Síndromes Mielodisplásicos/cirugía , Análisis Actuarial , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Estudios de Evaluación como Asunto , Femenino , Supervivencia de Injerto , Humanos , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Inducida por Radiación/etiología , Leucemia Inducida por Radiación/mortalidad , Leucemia Inducida por Radiación/cirugía , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/mortalidad , Mielofibrosis Primaria/complicaciones , Traumatismos por Radiación/etiología , Traumatismos por Radiación/mortalidad , Traumatismos por Radiación/cirugía , Radioterapia/efectos adversos , Tasa de Supervivencia , Linfocitos TAsunto(s)
Trasplante de Médula Ósea , Trasplante de Médula Ósea/métodos , Desarrollo Embrionario y Fetal , Feto , Enfermedades Hematológicas/cirugía , Humanos , Síndromes de Inmunodeficiencia/cirugía , Recién Nacido/crecimiento & desarrollo , Errores Innatos del Metabolismo/cirugía , Donantes de TejidosRESUMEN
The clinical pathologic syndrome of graft-versus-host disease (GVHD) is usually a sequela of bone marrow transplantation. This disorder occurs as a result of recognition by engrafted donor-derived lymphocytes of "foreign" recipient transplantation antigens. GVHD may also result from engraftment of lymphocytes from other sources, including (1) transfusion of lymphocytes containing blood components, (2) transplacental maternal fetal transfusion, and (3) passive transfer of lymphocytes in solid organ transplantation. The recipients are usually severely immunodeficient and thus incapable of rejecting the transfused lymphocytes. This syndrome may, however, also develop in immunologically competent patients receiving blood products from individuals with histocompatibility antigens not recognized as foreign.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Reacción a la Transfusión , Diagnóstico Diferencial , Relación Dosis-Respuesta Inmunológica , Humanos , Transfusión de Leucocitos , Factores de Riesgo , Rayos UltravioletaRESUMEN
The proliferation and differentiation of donor hematopoietic progenitor cells in bone marrow transplantation (BMT) recipients is influenced by hematopoietic growth factors, which could derive from either T cells or adherent stromal bone marrow cells, or both. In this study of 20 BMT recipients, we asked whether T lymphocytes arising from donor bone marrow grafts were able to express normal levels of granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA, and to secrete normal levels of soluble GM-CSF in response to the mitogen phytohemagglutinin. We have found that T cells obtained up to 18 months following BMT express little or no PHA-induced GM-CSF message. T cell GM-CSF secretion in response to PHA is also reduced or absent. This T cell GM-CSF defect was observed in all patients studied, whether or not donor bone marrows had undergone T cell depletion. This defect likely reflects a broader deficit in mitogen-induced lymphokine production. This defect likely contributes to BMT recipients' blunted responses to infections, and contributes to graft failure in T cell-depleted transplants.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Factores Estimulantes de Colonias/biosíntesis , Sustancias de Crecimiento/biosíntesis , Linfocitos T/metabolismo , Adolescente , Adulto , Células Cultivadas , Niño , Preescolar , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Interleucina-3/biosíntesis , ARN Mensajero/análisis , Linfocitos T/trasplanteRESUMEN
Serial serum protein electrophoreses were performed on 60 patients undergoing allogeneic and syngeneic bone marrow transplantation (BMT). More than 50% of patients (31 of 60) developed transient oligoclonal and monoclonal gammopathies that appeared an average of 84 days posttransplantation (range 27 to 336 days) and persisted an average of 175 days (range 14 to 652 days). Immunofixation analysis revealed 82% of the M components to be of the immunoglobulin G (IgG) type and 18% to be IgM; 56% were kappa and 44% were lambda. A strong correlation between development of graft versus host disease (GVHD) and appearance of M components was observed (73% incidence in GVHD patients v 27% in non-GVHD patients, P = .0003). Two of the three syngeneic graft recipients also developed monoclonal gammopathies. Evidence of oligoclonal circulating B-cell populations was found in 68% of patients posttransplantation by flow cytometric B-cell clonal excess assay. No correlation of recovery of particular B- or T-lymphocyte subsets and development of M components was seen. The development of transient oligoclonal and monoclonal gammopathies after transplantation may be a ubiquitous finding reflecting recapitulation of early B-cell ontogeny.
Asunto(s)
Linfocitos B/patología , Trasplante de Médula Ósea/patología , Hipergammaglobulinemia/etiología , Gammopatía Monoclonal de Relevancia Indeterminada/etiología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Trastornos Linfoproliferativos/etiología , Factores de TiempoRESUMEN
Cytotoxic T lymphocytes have been implicated as the effector cell mediating graft rejection following human allogeneic bone marrow transplantation. We have studied a BMT patient who rejected haploidentical T cell-depleted marrow. In vitro studies demonstrated that the circulating lymphocytes were CD3+ and CD8+, of recipient origin, and exhibited selective cytotoxicity against donor-specific class I major histocompatibility complex antigens. Cytotoxicity was inhibited by monoclonal antibodies directed against CD3, CD8, CD2, and lymphocyte function-associated antigen-1 on the T cell, and against MHC class I proteins on the target cell. Furthermore, these circulating cells inhibited the in vitro growth and differentiation of enriched donor bone marrow progenitor cells, an inhibition that was partially reversed by anti-CD3 MAb. Donor-specific recipient-derived CTL may mediate resistance to engraftment, and CTL activity may be inhibited by a number of MAb. The implications of these findings for host preparation and treatment are discussed.
Asunto(s)
Trasplante de Médula Ósea , Rechazo de Injerto , Linfocitos T Citotóxicos/inmunología , Adolescente , Anticuerpos Monoclonales/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Células Cultivadas , Citotoxicidad Inmunológica , Humanos , MasculinoRESUMEN
Hematologic engraftment following bone marrow transplantation requires not only pluripotent stem cells but also functioning accessory cells whose trophic factors support the proliferation and differentiation of stem cells and progenitors to mature blood cells. To better understand the regulation of hematopoiesis following transplantation, we studied hemopoietic accessory cell function in bone marrow transplant recipients 3 weeks to 10 months following transplantation. In general, hematopoietic accessory cell function was decreased following bone marrow transplantation. Sequential fractionation of accessory cells demonstrated that adherent cells often produced near-normal functional burst-promoting activity (BPA) and granulocyte-macrophage colony-stimulating activity (GM-CSA), but Fc receptor-positive (Fc+) cells and T cells uniformly produced greatly reduced BPA and GM-CSA, as compared to transplant donor cells. This cellular deficiency was corrected by soluble burst-promoting activity and granulocyte-macrophage colony-stimulating activity and so appeared to be due to the failure of accessory cells to produce trophic hormones. Limiting-dilution analysis (LDA) for proliferating T-cell precursors demonstrated a greatly reduced frequency in phytohemagglutinin-responsive cells, supporting the role of deficient hematopoietic growth factor production by activated T cells in transplant recipients. This hemopoietic accessory cell defect may thus reflect more generalized lymphocyte dysfunction in these patients. Hematopoiesis following bone marrow transplantation appears to rely upon growth factors released by accessory cells in the adherent layer.
Asunto(s)
Células Presentadoras de Antígenos/fisiología , Trasplante de Médula Ósea , Células Madre Hematopoyéticas/fisiología , Adolescente , Adulto , División Celular , Fraccionamiento Celular , Niño , Preescolar , Femenino , Humanos , Masculino , Células Madre/citología , Linfocitos T/citología , Linfocitos T Colaboradores-Inductores , Donantes de TejidosRESUMEN
We have studied the effect of removing donor T cells by treatment with the monoclonal antibody Leu-1 and complement before marrow transplantation on the regeneration of functionally competent T lymphocytes in the blood at selected times after transplant. Using sensitive limiting-dilution methods that allow us to enumerate helper, cytotoxic, and proliferating T lymphocyte precursors, we report that regeneration of a functional T cell compartment is more severely impaired for the first 180 days after transplantation in those patients given T cell-depleted bone marrow than in recipients of untreated marrow. After this first 6 months, however, patients given T cell-depleted bone marrow had blood T cell frequencies comparable to those observed in patients given untreated marrow. Diminished frequencies of reactive T cells in recipients of depleted marrow could leave them more susceptible to infection or to the recurrence of neoplastic cells.
Asunto(s)
Trasplante de Médula Ósea , Depleción Linfocítica , Linfocitos T/citología , Células de la Médula Ósea , División Celular , Humanos , Periodo Posoperatorio , Linfocitos T/fisiología , Linfocitos T Citotóxicos/citología , Factores de TiempoRESUMEN
Differences in the expression of Leu-1 (CD5) define two populations of recovering B cells after human marrow transplantation, Leu-1+ and Leu-1- B cells. The Leu-1+ B cells were polyclonal, of donor origin, and did not express detectable interleukin 2 receptor. Leu-1+ B cells generally appeared 2-4 wk after marrow grafting and often preceded the recovery of Leu-1- B cells. Acute and chronic graft vs. host disease (GvHD) resulted in the recovery of significantly fewer Leu-1+ B cells, whereas Leu-1- B cells were only decreased in acute GvHD. Multivariate analysis showed no significant effect of age, disease, prednisone or azathioprine, or ex vivo treatment of the marrow with anti-Leu-1 and complement on recovery of Leu-1+ and Leu-1- B cells, independent of the effects of GvHD. Leu-1+ B cells are a major lymphocyte population posttransplant. They may reflect a stage of differentiation of normal B cells or a separate B cell lineage.
Asunto(s)
Antígenos de Superficie/análisis , Linfocitos B/citología , Trasplante de Médula Ósea , Formación de Anticuerpos , Antígenos de Diferenciación de Linfocitos B , Diferenciación Celular , Citometría de Flujo , Enfermedad Injerto contra Huésped/inmunología , Humanos , Inmunoglobulina G/análisis , Factores de TiempoRESUMEN
A 28-yr-old woman with severe idiopathic aplastic anemia received an HLA-identical mixed lymphocyte culture nonreactive bone marrow transplant from her brother. In the months after successful engraftment, she developed cutaneous and hepatic graft-versus-host disease, associated with marked cholestatic jaundice. Despite a series of therapeutic maneuvers, cholestasis persisted but remained relatively stable over the ensuing 10 yr. However, serial liver biopsies revealed progressive biliary-type fibrosis culminating in cirrhosis. Subsequently, her clinical course deteriorated and she developed signs of hepatic failure, and ultimately died 10.5 yr after bone marrow transplantation. The evolution of chronic graft-versus-host disease to cirrhosis may be a limiting factor in the long-term survival of this group of bone marrow transplant recipients. The lack of correlation between the stable clinical or biochemical indices and the progressive hepatic disease underscores the need for sequential liver biopsies in patients with sustained liver function abnormalities after bone marrow transplantation.
Asunto(s)
Enfermedad Injerto contra Huésped/complicaciones , Cirrosis Hepática/etiología , Hígado/patología , Adulto , Anemia Aplásica/terapia , Biopsia , Trasplante de Médula Ósea , Femenino , Humanos , Cirrosis Hepática/patología , Factores de TiempoRESUMEN
Patients who undergo bone marrow transplantation are generally immunosuppressed with a dose of cyclophosphamide (CYA) which is usually calculated based on the patient's weight. At these high doses of CYA, serious cardiotoxicity may occur, but definitive risk factors for the development of such cardiotoxicity have not been described. Since chemotherapeutic agent toxicity generally correlates with dose per body surface area, we retrospectively calculated the dose of CYA in patients transplanted at our institution to determine whether the incidence of CYA cardiotoxicity correlated with the dose per body surface area. Eighty patients who were to receive CYA 50 mg/kg/d for four days as preparation for marrow grafting underwent a total of 84 transplants for aplastic anemia, Wiskott-Aldrich syndrome, or severe combined immunodeficiency syndrome. Fourteen of 84 (17%) patients had symptoms and signs consistent with CYA cardiotoxicity within ten days of receiving 1 to 4 doses of CYA. Six of the 14 patients died with congestive heart failure. The dose of CYA per body surface area was calculated for all patients and the patients were divided into two groups based on daily CYA dose: Group 1, CYA less than or equal to 1.55 g/m2/d; Group 2, CYA greater than 1.55 g/m2/d. Cardiotoxicity that was thought to be related to CYA occurred in 1/32 (3%) of patients in Group 1 and in 13/52 (25%) patients in Group 2 (P less than 0.025). Congestive heart failure caused or contributed to death in 0/32 patients in Group 1 v 6/52 (12%) of patients in Group 2 (P less than 0.25). There was no difference in the rate of engraftment of evaluable patients in the two groups (P greater than 0.5). We conclude that the CYA cardiotoxicity correlates with CYA dosage as calculated by body surface area, and that patients with aplastic anemia and immunodeficiencies can be effectively prepared for bone marrow grafting at a CYA dose of 1.55 g/m2/d for four days with a lower incidence of cardiotoxicity than patients whose CYA dosage is calculated based on weight. This study reaffirms the principle that drug toxicity correlates with dose per body surface area.