RESUMEN
Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T/metabolismo , Anciano , Citocinas/sangre , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
There is little data comparing the activity and toxicity of donor lymphocyte therapy with granulocyte (G)-CSF-mobilized cells (G-donor lymphocyte infusion (DLI)) with the conventionally collected DLI (C-DLI) after allogeneic blood or marrow transplantation. We retrospectively evaluated 67 patients to compare the efficacy and toxicity of GCSF-mobilized DLI with C-DLI in the treatment of relapse of malignant disease or poor donor engraftment post transplant. We assessed clinical outcomes that may represent the immunological outcome of DLI. The median OS was 210 days (range 3-2436 days), 291 days (range 17-1491 days) in the G-DLI group (15 patients) and 207.5 days (range 3-2436 days) in the C-DLI group (52 patients). The median PFS time was 72 days (range 8-1491 days) in the G-DLI group vs 82 days (range 1-2436 days) in the C-DLI group. Rates of post DLI GVHD and improvement in donor engraftment were similar in the G-DLI and C-DLI groups. We conclude that G-DLI appears to have similar therapeutic activity to that seen with C-DLI, and where such cells are available they may be substituted for conventional donor lymphocytes.
Asunto(s)
Supervivencia de Injerto/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Transfusión de Linfocitos/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Humanos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenAsunto(s)
Nucleótidos de Adenina/administración & dosificación , Antineoplásicos/administración & dosificación , Arabinonucleósidos/administración & dosificación , Ciclosporina/administración & dosificación , Supervivencia de Injerto/efectos de los fármacos , Neoplasias Hematológicas/terapia , Inmunosupresores/administración & dosificación , Trasplante de Células Madre de Sangre Periférica , Clofarabina , Femenino , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Trasplante HomólogoAsunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Sirolimus/uso terapéutico , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Efecto Injerto vs Tumor , Haplotipos , Humanos , Linfoma/terapia , Oncología Médica/métodos , Persona de Mediana Edad , Riesgo , Células Madre , Resultado del TratamientoRESUMEN
Granulocyte colony-stimulating factor (G-CSF) critically affects all stages of granulopoiesis by activating a signaling cascade initiated by dimerization of its receptor (G-CSFR). Five human G-CSFR isoforms have been identified (classes I-V). A quantitative polymerase chain reaction (Q-PCR) technique was used to examine the expression of these five isoforms in normal and leukemic myeloid cells. We demonstrated that neutrophils expressed predominantly the class I isoform and low levels of class IV isoform (IV/I = 0.037 +/- 0.005). No expression of the class II, class III, or class V isoform was detected. In contrast, all AML cell lines and acute myelogenous leukemia (AML) patient samples expressed increased relative amounts of the class IV isoform (IV/I = 0.047-0.350). When compared to normal immature myeloid cells, as represented by the CD34+ fraction of adult bone marrow (ABM) cells, three of eight AML cell lines and three of six AML patient samples expressed significantly increased levels of the class IV isoform relative to class I. This suggests that the increase in the relative expression of the class IV isoform seen in a considerable portion of AML cell samples is related to their leukemic phenotype. Given the inability of the class IV G-CSFR to drive myeloid maturation, the relative increase in class IV expression in AML cells may contribute to their aberrant response to G-CSF.
Asunto(s)
Leucemia Mieloide Aguda/metabolismo , ARN Mensajero/análisis , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Adulto , Diferenciación Celular , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Leucemia Mieloide Aguda/patología , Reacción en Cadena de la Polimerasa , Células Tumorales CultivadasRESUMEN
BACKGROUND: Sweet's syndrome (SS), acute febrile neutrophilic dermatosis, has been linked to hematologic malignancies and presents with characteristic edematous dermal plaques. Peripheral blood neutrophilia is frequently seen in association with SS and is one of the diagnostic criteria. OBJECTIVE: To report the clinical, laboratory, and hematologic data of four patients with myeloid leukemia who developed SS after chemotherapy. Three of these patients were neutropenic. METHODS: A retrospective study of four patients with SS and hematologic malignancies was undertaken. Three patients had de novo acute myelogenous leukemia and one was in the acute blast crisis of chronic myelogenous leukemia. RESULTS: Sweet's syndrome was not originally suspected in these patients because of the low peripheral white blood cell counts caused by chemotherapy. All of the patients presented with fevers, arthralgias, and an eruption. They had been treated with antibiotics because of a presumed infection. Once the correct diagnosis was made and oral prednisolone was started, a rapid response followed. CONCLUSIONS: Sweet's syndrome should be considered in the differential diagnosis when acute myeloid leukemic patients develop skin lesions and unexplained fevers regardless of the peripheral blood counts.
Asunto(s)
Síndrome de Sweet/diagnóstico , Síndrome de Sweet/etiología , Enfermedad Aguda , Adulto , Antineoplásicos/uso terapéutico , Biopsia , Diagnóstico Diferencial , Erupciones por Medicamentos/diagnóstico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutropenia/complicaciones , Neutropenia/patología , Prednisolona/uso terapéutico , Estudios Retrospectivos , Piel/patología , Síndrome de Sweet/tratamiento farmacológicoRESUMEN
To determine the incidence and prognostic significance of thrombocytopenia among hemophiliacs, we analyzed clinical and hematologic data from the Multicenter Hemophilia Cohort study. Nineteen percent of HIV-infected subjects had thrombocytopenia (platelet count of <100,000/mm3) noted at least once, compared to 3% of HIV-uninfected subjects. For HIV-infected subjects, the prevalence of thrombocytopenia rose in the first 5 years after seroconversion and was twice as common in subjects age >35 years compared to younger subjects. The risk increased after an AIDS-defining illness, particularly among older subjects, nearly one-half of whom had thrombocytopenia within 1 year after AIDS. When adjusted for age and CD4-positive lymphocyte counts, thrombocytopenia was associated with an increased risk of death [relative risk (RR) 1.7, 95%CI = 1.2-2.3] but with little change in the risk of progression to AIDS (RR = 1.2, 95%CI = 0.8-1.7). Treatment with zidovudine was associated with a decreased risk of thrombocytopenia (RR = 0.5, 95%CI = 0.3-0.7). Although 59 HIV-infected subjects died of hemorrhage, only 11 (19%) of the 59 had a reported platelet count of <50,000/mm3, and only 2 (3%) of the deaths were temporally associated with thrombocytopenia. Thus, the risk of death was increased for thrombocytopenic HIV-infected hemophiliacs but this was not explained by an increased risk of developing AIDS and was rarely associated with death from bleeding.
Asunto(s)
Seropositividad para VIH/complicaciones , Hemofilia A/complicaciones , Trombocitopenia/epidemiología , Adolescente , Adulto , Niño , Estudios de Cohortes , Seropositividad para VIH/fisiopatología , Hemofilia A/fisiopatología , Humanos , Persona de Mediana Edad , Prevalencia , Pronóstico , Trombocitopenia/etiología , Trombocitopenia/fisiopatologíaRESUMEN
OBJECTIVE: To compare the safety and activity of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced human immunodeficiency virus (HIV) infection who had received zidovudine. DESIGN: A multicenter, randomized, double-blind, three-arm, 24-week study with a blinded extension through at least 52 weeks. SETTING: 21 sites in the United States, Canada, and Puerto Rico. PATIENTS: 254 patients who had received zidovudine (median duration of previous therapy, 20 months) and had absolute CD4+ cell counts of 100 to 300 cells/mm3. INTERVENTIONS: Patients were randomly assigned to receive one of three regimens: 150 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (low-dose lamivudine group); 300 mg of lamivudine twice daily plus 200 mg of zidovudine three times daily (high-dose lamivudine group); or 0.75 mg of zalcitabine plus 200 mg of zidovudine three times daily (zalcitabine group). MEASUREMENTS: Immunologic activity was assessed primarily by changes in absolute CD4+ cell counts; virologic activity was assessed by changes in plasma HIV RNA levels as measured by reverse transcriptase polymerase chain reaction. Safety of the treatment regimens was assessed through the reporting of adverse events. RESULTS: 78% of patients completed 24 weeks of study treatment, and 63% of patients completed 52 weeks of study treatment. Changes in absolute CD4+ cell counts were significantly better for the low-dose and the high-dose lamivudine groups than for the zalcitabine group (median changes at 52 weeks were +42.5 cells/mm3 in the low-dose lamivudine group, +23.33 cells/mm3 in the high-dose lamivudine group, and -29.58 cells/mm3 in the zalcitabine group). Suppression of plasma HIV RNA levels was similar for all groups (median changes at 52 weeks were -0.48 log10 copies/mL in the low-dose lamivudine group, -0.51 log10 copies/mL in the high-dose lamivudine group, and -0.39 log10 copies/mL in the zalcitabine group). No significant differences in safety were seen among the three regimens, although the low-dose lamivudine regimen appeared to be better tolerated than the others. CONCLUSIONS: In patients with HIV infection who had previously received zidovudine, 150 mg of lamivudine plus zidovudine resulted in greater immunologic evidence of benefit than did 0.75 mg of zalcitabine plus zidovudine and was better tolerated than 300 mg of lamivudine plus zidovudine.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Zalcitabina/análogos & derivados , Zalcitabina/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Antivirales/efectos adversos , Biopterinas/análogos & derivados , Biopterinas/sangre , Recuento de Linfocito CD4 , Método Doble Ciego , Quimioterapia Combinada , Femenino , VIH/genética , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/inmunología , Humanos , Lamivudine , Masculino , Neopterin , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Zalcitabina/efectos adversos , Zidovudina/efectos adversos , Microglobulina beta-2/metabolismoRESUMEN
Although CD4 positive lymphocyte counts are important predictors of clinical events in persons infected with human immunodeficiency virus (HIV), little is known about their predictive value for survival. We analyzed CD4 counts obtained regularly since 1983 with regard to survival in a multicenter cohort study of 921 HIV-infected hemophiliacs of whom 177 have died. Dates of seroconversion were determined from stored serum samples. Cumulative mortality and actuarial survival rates were calculated from the first time the mean of two consecutive CD4 counts decreased from levels of > 500 to 200-499, 100-199, 50-99, and < 50 cells/microliter. The death rate per 100 patient years of observation was 0.87 (95% CI 0.27, 1.47) for those with CD4 counts of > 500 cells/microliter and increased progressively to 26.23 (95% CI 21.29, 31.17) for those with CD4 counts of < 50/microliter. HIV-related deaths occurred in 50 of 58 who died with CD4 counts of < 300/microliter compared to 0 of 6 who died with CD4 counts of > 500/microliter. The median CD4 count most proximal to death was 39.5 (range, 1-945). The 10-year actuarial estimate of survival from seroconversion was 77.3 +/- 2% for 546 persons who seroconverted at age > or = 18 years compared to 90.5 +/- 2% for 375 persons who seroconverted at age < 18. Survival decreased at each CD4 level to a median of 27 months at CD4 counts of < 50/microliter. At each CD4 level, younger patients survived longer than older patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Linfocitos T CD4-Positivos , Infecciones por VIH/mortalidad , Hemofilia A/complicaciones , Adolescente , Adulto , Factores de Edad , Causas de Muerte , Estudios de Cohortes , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Hemofilia A/inmunología , Hemofilia A/mortalidad , Humanos , Recuento de Leucocitos , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Congenital afibrinogenemia is a rare disorder with unusual clinical manifestations. The disease is inherited as an autosomal recessive trait and consanguinity is common among affected families. Clinical manifestations range from minimal bleeding to catastrophic hemorrhage. Congenitally afibrinogenemic patients seem to be peculiarly susceptible to spontaneous rupture of the spleen. Coagulation tests which depend on clot formation as an end point may be infinitely prolonged and abnormalities of platelet function are usually present. The diagnosis is established by demonstrating trace or no immunoreactive fibrinogen. The disease is caused by markedly reduced or absent synthesis of fibrinogen by liver cells, but the genetic defect remains unknown. Bleeding episodes can be effectively treated with cryoprecipitate. Purified virally inactivated fibrinogen concentrates have been used in Europe and may soon be widely available.
Asunto(s)
Afibrinogenemia/congénito , Afibrinogenemia/terapia , Afibrinogenemia/fisiopatología , Diagnóstico Diferencial , Fibrinógeno/efectos adversos , Fibrinógeno/uso terapéutico , Humanos , IncidenciaRESUMEN
The objective of this prospective cohort study was to describe the natural history of hepatitis C virus (HCV) infection and the effect of human immunodeficiency virus (HIV) on the clinical manifestations of HCV liver disease. Two hundred twenty-three hemophiliacs were followed in a comprehensive care setting with periodic clinical and laboratory evaluations. Dates of HIV seroconversion were determined retrospectively from frozen sera. HCV assays were performed by a "second generation" four-antigen recombinant immunoblot assay (RIBA 2). Liver failure was found after a latency period of 10 to 20 years in 9% of multitransfused HCV-positive/HIV-positive adult hemophiliacs without an AIDS-defining opportunistic infection or malignancy. Lymphocytopenia, decreased CD4 counts, and, possibly, thrombocytopenia were associated with liver failure which appeared to be accelerated by HIV disease and its treatment. This form of severe liver disease is being seen with increasing frequency among multi-transfused persons with hemophilia who are coinfected with HCV and HIV.
Asunto(s)
Transfusión Sanguínea , Infecciones por VIH/fisiopatología , Hemofilia A/fisiopatología , Hepatitis C/fisiopatología , Adolescente , Adulto , Anciano , Linfocitos T CD4-Positivos , Niño , Preescolar , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Seropositividad para VIH/fisiopatología , Hemofilia A/complicaciones , Hepatitis C/complicaciones , Humanos , Fallo Hepático/etiología , Fallo Hepático/fisiopatología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios ProspectivosRESUMEN
A newly developed method for assaying 2', 5'-oligoadenylate (2, 5A) synthetase activity by polyacrylamide gel electrophoresis was applied to peripheral blood mononuclear cells (PBMC) from normal subjects, HIV-positive subjects, and renal cell carcinoma (RCC) patients. Sex differences were observed in 2, 5A synthetase activity of PBMC from normal young adults, males having eightfold higher activities of this enzyme than females. Moreover, compared to values for postmenopausal (PM) females receiving estrogen replacement, untreated PM females had higher activities. Collectively, these results suggest that estrogen downregulates 2, 5A synthetase activity. Activities of 2, 5A synthetase were investigated in two disease states associated with altered immune function. In one patient with AIDS-related Kaposi's sarcoma, interferon-alpha (IFN-alpha) therapy increased 2, 5A synthetase activity twofold. In addition, combined therapy with interleukin-2 (IL-2) and IFN-alpha increased 2, 5A synthetase activities in eight of nine patients with RCC. Therefore, in patients receiving immunotherapy with IL-2 and IFN-alpha, our new assay could contribute to evaluation of immune stimulation. In general, studies in vitro confirmed these observations; however, exposure of PBMC from RCC patients revealed that in vitro IL-2 failed to induce this enzyme activity as it did in PBMC from normal volunteers.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/metabolismo , Regulación Enzimológica de la Expresión Génica , Leucocitos Mononucleares/enzimología , Síndrome de Inmunodeficiencia Adquirida/enzimología , Adenosina Trifosfato/biosíntesis , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Linfocitos T CD4-Positivos , Antígenos CD8/biosíntesis , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/terapia , Regulación hacia Abajo , Electroforesis en Gel de Poliacrilamida , Terapia de Reemplazo de Estrógeno , Estrógenos/farmacología , Femenino , Humanos , Inmunoterapia , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Neoplasias Renales/enzimología , Recuento de Leucocitos , Masculino , Menopausia/metabolismo , Sarcoma de Kaposi/enzimología , Sarcoma de Kaposi/terapia , Factores SexualesRESUMEN
Cephalosporins are commonly used drugs that interact with red blood cell membranes. They frequently cause a positive direct antiglobulin test but rarely cause hemolysis. A case of cefotetan-induced hemolytic anemia is described in which two types of antibodies were detected. One reacted with red blood cells by a hapten mechanism, the other reacted with drug to form immune complexes. This case is compared with the 13 cases of cephalosporin-induced hemolytic anemia reported to date. Understanding the interactions of red blood cells and cephalosporins is critical to the safe use of these commonly prescribed drugs.
Asunto(s)
Cefalosporinas/farmacología , Hemólisis/efectos de los fármacos , Anemia Hemolítica/inducido químicamente , Cefotetán/efectos adversos , Cefotetán/farmacología , Cefalosporinas/efectos adversos , Eritrocitos/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Three previous articles have reported a PLA1 antigen in the plasma of stored blood which is capable of binding to PLA1-negative platelets in the presence of divalent cations, rendering them PLA1 positive. Such a mechanism could explain the enigma of posttransfusion purpura (PTP), i.e., severe thrombocytopenia in a healthy subject with PLA1-negative platelets secondary to the infusion of blood containing PLA1-positive platelets. We find that the PLA1 antigen of stored blood is due to the presence of platelet fragments which can be removed by centrifugation and that divalent cation-chelating agents play no role in the apparent binding of these fragments to platelets. The apparent conversion of PLA1-negative platelets to the PLA1-positive phenotype by incubation with stored plasma from a PLA1-positive subject is due to the cosedimentation of platelet fragments with the platelets. No soluble PLA1 antigen was found in the plasma of five patients with acute posttransfusion purpura.
Asunto(s)
Antígenos de Plaqueta Humana , Plaquetas/inmunología , Isoantígenos/análisis , Púrpura Trombocitopénica/etiología , Reacción a la Transfusión , Epítopos , Humanos , Integrina beta3 , Fenotipo , Glicoproteínas de Membrana Plaquetaria/análisis , Púrpura Trombocitopénica/sangreRESUMEN
Splenectomy has been the traditional initial treatment for hairy cell leukemia, with medical treatment reserved for resistant disease. This report describes two patients treated with recombinant alpha-2 interferon without prior splenectomy. Both patients responded well to interferon therapy. Alpha-2 interferon may become the initial therapy of choice for hairy cell leukemia.