RESUMEN
Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4-6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080-2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065-2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.
Asunto(s)
Melfalán/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Agonistas Mieloablativos/efectos adversos , Estomatitis/inducido químicamente , Acondicionamiento Pretrasplante/efectos adversos , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Glucosa Oxidasa/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Enfermedades Renales/complicaciones , Lactoperoxidasa/uso terapéutico , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Modelos Teóricos , Muramidasa/uso terapéutico , Agonistas Mieloablativos/administración & dosificación , Valor Predictivo de las Pruebas , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estomatitis/epidemiología , Estomatitis/etiología , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/efectos adversosRESUMEN
We evaluated the risk factors for infection of 367 consecutive myeloma patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT). Examination of bone marrow iron stores (BMIS) prior to ASCT was used to evaluate body iron stores. Other variables included age, sex, active smoking, myeloma remission status, severity of mucositis and duration of severe neutropenia post-ASCT (<100 absolute neutrophils counts (ANC)/microl). Median age was 56 years; 61% of patients were males. 140 episodes of severe infections occurred in 116 patients, including bacteremia (73), pneumonia (40), severe colitis (25) and bacteremia with septic shock (two). The infection incidence per 1,000 days at risk was 45.2. Pre-ASCT risk factors for severe infection by univariate analysis were increased BMIS (OR=2.686; 95% CI 1.707-4.226; P<0.0001), smoking (OR=1.565; 95% CI 1.005-2.437; P=0.0474) and male gender (OR=1.624; 95% CI 1.019-2.589; P=0.0414). Increased BMIS (OR=2.716; 95% CI 1.720-4.287; P<0.0001) and smoking (OR=1.714; 95% CI 1.081-2.718; P=0.022) remained significant by multivariate analysis. Duration of ANC <100 micro/l (OR=1.129; 95% CI 1.039-1.226; P=0.0069 and OR=1.127; 95% CI 1.038-1.224; P=0.0045 by both univariate and multivariate analysis, respectively) was the only post-ASCT risk factor for infection. Increased pre-transplant BMIS and smoking are significant predictors of severe infection after myeloablative chemotherapy followed by ASCT in myeloma patients.
Asunto(s)
Infecciones/epidemiología , Sobrecarga de Hierro/complicaciones , Mieloma Múltiple/terapia , Trasplante de Células Madre/efectos adversos , Talidomida/uso terapéutico , Análisis de Varianza , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Humanos , Sobrecarga de Hierro/etiología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Análisis MultivarianteRESUMEN
The duration of neutropenia (absolute neutrophil count (ANC) < or = 100/microl) identifies cancer patients at risk for infection. A test that precedes ANC > or = 100/microl would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid engraftment and hence a recovering marrow. We evaluated the IRF as predictor of marrow recovery among 90 myeloma patients undergoing their first and second (75 patients) melphalan-based autologous stem cell transplantation (Mel-ASCT). The time to IRF doubling (IRF-D) preceded ANC > or = 100/microl in 99% of patients after the first Mel-ASCT by (mean+/-s.d.) 4.23+/-1.96 days and in 97% of the patients after the second Mel-ASCT by 4.11+/-1.95 days. We validated these findings in a group of 117 myeloma patients and 99 patients with various disorders undergoing ASCT with different conditioning regimens. We also compared the time to hypophosphatemia and to absolute monocyte count > or = 100/microl to the time to ANC > or = 100/microl. These markers were reached prior to this ANC end point in 55 and 25% of patients but were almost always preceded by IRF-D. We conclude that the IRF-D is a simple, inexpensive and widely available test that can predict marrow recovery several days before ANC> or = 100/microl.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Neutropenia/terapia , Neutrófilos/patología , Recuento de Reticulocitos/métodos , Estudios de Cohortes , Humanos , Cinética , Mieloma Múltiple/diagnóstico , Valor Predictivo de las Pruebas , Recuperación de la Función , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
PURPOSE: Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM). PATIENTS AND METHODS: The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome. RESULTS: One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET. CONCLUSION: In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.
Asunto(s)
Fluorodesoxiglucosa F18 , Artropatías/diagnóstico por imagen , Mieloma Múltiple/diagnóstico por imagen , Radiofármacos , Infecciones de los Tejidos Blandos/diagnóstico por imagen , Tomografía Computarizada de Emisión , Adulto , Anciano , Antibacterianos/uso terapéutico , Femenino , Humanos , Artropatías/microbiología , Masculino , Registros Médicos , Persona de Mediana Edad , Mieloma Múltiple/microbiología , Estudios Retrospectivos , Infecciones de los Tejidos Blandos/microbiología , Factores de TiempoRESUMEN
Optimal regimens for the treatment of invasive fungal infections have yet to be defined, and these life-threatening conditions are one of the leading causes of treatment failure in patients with cancer. A substantial body of preclinical work points in the direction of using cytokines as immunomodulators of the multiple deficiencies involved in the progression of fungal infections in neutropenic and nonneutropenic cancer patients. These deficiencies include not only the easily recognized deficiencies in cell quantity but also subtle deficiencies of cell function. Four cytokines (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon gamma) show promise as adjuvant therapy for proven fungal infections in this setting, although clinical experience is still limited. As an additional approach, the concept of white blood cell transfusions has been revived by the use of granulocyte colony-stimulating factor and promises to be helpful in the setting of neutropenia.
Asunto(s)
Citocinas/uso terapéutico , Micosis/tratamiento farmacológico , Neoplasias/complicaciones , Neutropenia/tratamiento farmacológico , Infecciones Oportunistas/tratamiento farmacológico , Adyuvantes Inmunológicos/uso terapéutico , Factores Estimulantes de Colonias/uso terapéutico , Humanos , Interferón gamma/uso terapéutico , Transfusión de Leucocitos , Micosis/inmunología , Neoplasias/inmunología , Neoplasias/microbiología , Infecciones Oportunistas/inmunologíaRESUMEN
We studied the potential of multidimensional flow cytometry to evaluate the frequency and maturation/activation status of dendritic cells in minimally manipulated peripheral blood mononuclear cell preparations (i.e., only separated on Ficoll-Hypaque) of normal donors and cancer patients. A rare subset of HLA-DR+ leukocytes (less than 1% mononuclear cells) was detected in blood of normal donors that displayed all the features of dendritic cells: these cells had high forward-light-scatter characteristics and coexpressed CD4, CD86 and CD54 surface antigens, but lacked the lineage-associated surface markers of T cells, B cells, monocytes, granulocytes or NK i.e. they were CD3-, CD19-, CD20-, CD14-, CD11b-, CD16-, CD56-). These physical and phenotypic properties were virtually identical to those of immunomagnetically sorted leukocytes characterized as dendritic-cells on the basis of morphology, phenotype and high stimulatory activity in allogeneic mixed-lymphocyte cultures. Using this flow-cytometric approach we observed that the frequency of dendritic cell-like cells in peripheral blood mononuclear cell specimens of cancer patients receiving chemotherapy alone or those recovering from stem cell transplantation was significantly lower than that of normal individuals (mean +/- SE: 0.36 +/- 0.05%, 0.14 +/- 0.06%, and 0.75 +/- 0.04% respectively). Multidimensional flow-cytometric analysis of dendritic cells might represent an important new tool for assessing immunocompetence, and for monitoring the effects of therapeutic regimens on the immune system.
Asunto(s)
Células Dendríticas/citología , Leucocitos Mononucleares/citología , Células Dendríticas/fisiología , Estudios de Factibilidad , Citometría de Flujo/métodos , Humanos , Separación Inmunomagnética , Leucocitos Mononucleares/fisiología , Luz , Fenotipo , Valores de Referencia , Dispersión de RadiaciónRESUMEN
Lymphocytes comprise up to 30% of the cells present in human bronchoalveolar lavage fluid and thus could participate in host response to infectious Aspergillus fumigatus conidia. We have examined the possibility that lymphocytes might play a role during early infection by either damaging the fungus or interfering with adherence. When incubated with A. fumigatus conidia for 20 h, highly purified 5-day-old lymphocytes activated with either IL-2 or phytohaemagglutinin, but not untreated lymphocytes, were consistently able to reduce residual fungal biomass as estimated by a metabolic assay. T lymphocytes, but not NK cells, appeared to be responsible for this activity. Lymphocytes bound both A. fumigatus conidia and hyphae, and the antifungal activity of the lymphocytes required direct lymphocyte fungus contact. In a separate set of experiments using release of 51Cr from 51Cr-loaded fungi as an estimate of fungal damage, lymphocyte-induced loss of fungal biomass was found to be due to loss of fungal adherence rather than to direct fungal damage. The detached hyphae were also found to be metabolically intact and to have normal morphology by electron microscopy. These data demonstrate that IL-2- and phytohaemagglutinin-activated lymphocytes exhibit a contact-dependent ability to reduce adherence of germinating conidia of A. fumigatus to a surface.
Asunto(s)
Aspergillus fumigatus/fisiología , Activación de Linfocitos , Linfocitos/microbiología , Aspergillus fumigatus/inmunología , Aspergillus fumigatus/ultraestructura , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Adhesión Celular , Células Cultivadas , Humanos , Interleucina-2/fisiología , Linfocitos/inmunología , Linfocitos/ultraestructura , FitohemaglutininasRESUMEN
The response of human peripheral blood mononuclear cells (MNC) to Aspergillus fumigatus in vitro was evaluated. In studies of the proliferative response of MNC from 18 healthy donors to heat-killed A. fumigatus conidia, 15 displayed a significant response, with a stimulation index (SI) between 4 and 193. In contrast, all donors displayed a positive response to Candida albicans blastoconidia (SI ranged from 10 to 224). Despite the variability in reactivity to A. fumigatus conidia, the response of a particular individual was stable when retested over periods of 1-2 weeks. Supernatant from cocultures of A. fumigatus conidia with MNC contained increased levels of interferon-gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin (IL)-2, compared with unstimulated cells, but not IL-10 or IL-4. In addition, A. fumigatus induced lymphocyte surface expression of adhesion/activation-associated molecules. These results suggest that lymphocytes may contribute to host defense against Aspergillus by generating a Th1-type response.