RESUMEN
BACKGROUND: Activated mutations in NOTCH1 are drivers of T-cell type acute lymphoblastic leukemia/lymphoma. The γ-secretase inhibitor (GSI), which suppresses the function of NOTCH1, is expected to be a molecular-targeted agent. NOTCH1 is also expressed in other malignant neoplasms. We aimed to determine the function of NOTCH1 expression and the effects of GSI on adult T-cell leukemia/lymphoma (ATL) caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. METHODS: We analyzed the expression of NOTCH1 in six ATL- and HTLV-1-infected cell lines and investigated the influence of activated NOTCH1 (i.e., the cleaved form of NOTCH1) together with GSI on cell proliferation. RESULTS: Activated NOTCH1 found in ATL- and HTLV-1-infected cell lines was undetectable after incubation with GSI, regardless of Tax expression (HTLV-1-coded protein). Whole-exome sequencing revealed that activated NOTCH1 mutations were undetectable in six ATL- and HTLV-1-infected cell lines, regardless of abundant NOTCH1 expression. Moreover, GSI did not suppress the growth of ATL cell lines. CONCLUSIONS: These findings suggested that NOTCH1 protein is constitutively activated but is likely a passenger during NOTCH1-mutation-negative ATL cell proliferation.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Línea Celular , Virus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by long-term human T-cell leukemia virus type I (HTLV-1) infection. Survivin-responsive, conditionally replicating adenoviruses regulated by multiple tumor-specific factors (Surv.m-CRAs), in which the expression of the adenoviral early region 1A gene is regulated by the survivin (BIRC5) promoter, can be used to treat several cancers. As survivin is overexpressed in ATL, we examined the effects of Surv.m-CRAs on ATL-selective replication and survival. METHODS: We tested two ATL cell lines and four HTLV-1-infected T-cell lines. The cells were subjected to infection with either E1-deleted, replication-defective adenoviruses or Surv.m-CRAs at various multiplicities of infection. RESULTS: Strong activation of survivin promoter was observed in all six cell lines. Moreover, the expression of the coxsackie and adenovirus receptor (CAR), which is important for adenoviral infection, was high in the cell lines. In contrast, we observed the absence of survivin promoter activity and a low expression of CAR in activated peripheral blood lymphocytes (PBLs) from healthy subjects. Surv.m-CRAs actively replicated and induced cytocidal effects in five out of six cell lines; conversely, we observed minimal viral replication and no marked cytotoxicity in normal activated PBLs. CONCLUSIONS: This is the first report demonstrating that Surv.m-CRAs constitute attractive potential anti-ATL agents.
Asunto(s)
Adenoviridae/fisiología , Leucemia-Linfoma de Células T del Adulto/genética , Survivin/genética , Adenoviridae/genética , Adenoviridae/metabolismo , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Línea Celular Tumoral , Humanos , Leucemia-Linfoma de Células T del Adulto/terapia , Regiones Promotoras Genéticas , Replicación ViralRESUMEN
This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Etopósido/efectos adversos , Etopósido/uso terapéutico , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Persona de Mediana Edad , Compuestos de Nitrosourea/efectos adversos , Compuestos de Nitrosourea/uso terapéutico , Prednisolona/efectos adversos , Prednisolona/uso terapéutico , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéutico , Vindesina/efectos adversos , Vindesina/uso terapéuticoRESUMEN
This study evaluated the clinical features of 276 patients with aggressive adult T-cell leukaemia-lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long-term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG-PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease-related deaths in 10 patients with lymphoma-type were observed in contrast to the 10 ATL-related deaths in other types. In multivariate analysis of 193 patients, the JCOG-PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG-PI was reproducible in an external validation. Patients with lymphoma-type who survived >5 years might have been cured. The JCOG-PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Japón/epidemiología , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Persona de Mediana Edad , Pronóstico , Sobrevivientes , Adulto JovenRESUMEN
OBJECTIVE: The ability of the ImmuKnow (Cylex) assay to predict the risk of infection in rheumatoid arthritis (RA) patients receiving synthetic or biological disease-modifying antirheumatic drugs (DMARDs) was examined. METHODS: The amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin was measured in whole blood from 117 RA patients without infection versus 17 RA patients with infection, and compared with results in 75 healthy controls. RESULTS: The mean ATP level was significantly lower in patients with infection compared to both healthy controls (P < 0.0005) and patients without infection (P = 0.040). Also, the mean ATP level in patients without infection was significantly lower than that in healthy controls (P = 0.012). There was no correlation between the ATP level and the Disease Activity Score in 28 joints. CONCLUSION: ImmuKnow assay results may be effective in identifying RA patients at increased risk of infection, but the results showed no correlation with RA activity. Larger studies are required to establish the clinical advantages of this assay in RA treatment.
Asunto(s)
Adenosina Trifosfato/sangre , Artritis Reumatoide/complicaciones , Linfocitos T CD4-Positivos/metabolismo , Infecciones/complicaciones , Adulto , Antirreumáticos/efectos adversos , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Femenino , Humanos , Inmunoensayo/métodos , Inmunosupresores/efectos adversos , Infecciones/etiología , Articulaciones/fisiopatología , Masculino , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Valor Predictivo de las Pruebas , Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type-I (HTLV-1). This study investigated whether the number of newly diagnosed patients with ATL is decreasing in the background of a declining number of individuals infected by HTLV-1 in Kagoshima, Japan, one of the most endemic areas of HTLV-1 in the world. We retrospectively analyzed the number of newly diagnosed patients with ATL between January 2001 and December 2021 in three major hospitals. The number of newly diagnosed patients with B-cell non-Hodgkin lymphoma (B-NHL) in the same period was examined as an internal control. One thousand eighteen and 2,029 patients with ATL and B-NHL were registered, respectively. The age-adjusted incidence of ATL steadily increased between 2001 and 2012, whereas that between 2013 and 2021 decreased. Despite the limitation of its retrospective nature, this is the first report indicating a decrease in ATL patients in Japan.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/epidemiología , Estudios Retrospectivos , Japón/epidemiología , Linfoma/complicacionesRESUMEN
Neurotoxicity is a common side effect of vincristine (VCR) treatment. Severe exacerbations of neuropathy have been reported in patients with Charcot-Marie-tooth disease (CMT) 1A with duplication of the peripheral myelin protein 22 (PMP22) gene. However, whether or not VCR exacerbates neuropathies through mutations in other CMT-associated genes besides PMP22 duplication has not been well studied. The purpose of this study was to identify mutations in any CMT-associated genes in a patient with hypersensitivity to VCR. We performed clinical, electrophysiological, and genetic examinations of a 23-year-old woman, who was hypersensitive to low-dose VCR, and her healthy mother. DNA analysis was performed using our specially designed resequencing array that simultaneously screens for 28 CMT-associated genes. Electrophysiological studies revealed that the patient and her healthy mother had demyelinating polyneuropathy. Furthermore, they showed the same novel mutation in the early growth response 2 (EGR2) gene. Recognizing pre-existing asymptomatic CMT by electrophysiological studies and genetic analysis before VCR treatment allowed us to prevent severe VCR-induced neuropathy.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Neuropatía Hereditaria Motora y Sensorial/inducido químicamente , Mutación , Vincristina/efectos adversos , Secuencia de Aminoácidos , Animales , Antineoplásicos Fitogénicos/efectos adversos , Análisis Mutacional de ADN , Femenino , Humanos , Datos de Secuencia Molecular , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Alineación de Secuencia , Adulto JovenRESUMEN
Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.
Asunto(s)
Infecciones por HTLV-I/virología , Virus Linfotrópico T Tipo 1 Humano/genética , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/virología , Provirus/genética , Carga Viral/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Southern Blotting , Portador Sano , Niño , ADN Viral/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Infecciones por HTLV-I/sangre , Infecciones por HTLV-I/epidemiología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Adulto JovenRESUMEN
Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sjögren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T-cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax-specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Epítopos , Virus Linfotrópico T Tipo 1 Humano/inmunología , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Paraparesia Espástica Tropical/inmunología , Linfocitos T Citotóxicos , Adulto , Anciano , Anciano de 80 o más Años , Epítopos/inmunología , Epítopos/metabolismo , Productos del Gen tax/inmunología , Productos del Gen tax/metabolismo , Variación Genética , Antígenos HLA-A/química , Antígenos HLA-A/inmunología , Antígenos HLA-A/metabolismo , Prueba de Histocompatibilidad , Humanos , Persona de Mediana Edad , Unión Proteica , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Adulto JovenRESUMEN
We describe a 44-yr-old Japanese woman with persistent polyclonal T-cell proliferation and recalcitrant clinical course of haemophagocytic syndrome (HPS). T cells bearing alphabeta T-cell receptors (TCR) expressed increased amounts of CD95 and of CD45RO, which are phenotypically memory T cells. The TCR repertoire was broad and diverse. Regardless of CD95 expression, these cells were resistant to CD95-mediated apoptosis. Aggressive natural killer cell leukaemia (ANKL) without an association with Epstein-Barr virus was detected 1 month after therapeutic splenectomy that followed 3 yr of immunosuppressive therapy against HPS. The immunophenotype of these leukaemia cells was CD56, CD16(dim), CD7, CD45RA and they expressed some CD2, CD8 and HLA-DR. Moreover, hyperdiploid clones with complex chromosomal abnormalities were also detected. Latent NK-cell malignancy seemed to cause the CD95-resistant memory T-cell proliferation and splenectomy resulted in overt ANKL progression. There should be careful consideration of the risks versus benefits of splenectomy in HPS, in light of the possibility of fatal leukaemia/lymphoma progression.
Asunto(s)
Células Asesinas Naturales/inmunología , Leucemia/inmunología , Leucemia/terapia , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/terapia , Esplenectomía/efectos adversos , Receptor fas/fisiología , Adulto , Proliferación Celular , Aberraciones Cromosómicas , Progresión de la Enfermedad , Resultado Fatal , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Inmunosupresores/uso terapéutico , Cariotipificación , Leucemia/diagnóstico , Linfohistiocitosis Hemofagocítica/diagnóstico , Factores de RiesgoRESUMEN
We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide/inducido químicamente , Leucemia-Linfoma de Células T del Adulto/complicaciones , Neoplasias Primarias Secundarias/inducido químicamente , Enfermedad Aguda , Alquilantes/uso terapéutico , Antraciclinas/uso terapéutico , Aberraciones Cromosómicas , Femenino , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mielomonocítica Aguda/inducido químicamente , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Podofilotoxina/uso terapéuticoRESUMEN
We report the case of a patient with acute promyelocytic leukemia (APL) carrying a novel chromosomal abnormality, t(2;7)(q33;q36). The 54-year-old woman was morphologically diagnosed with APL through bone marrow aspiration. The proportion of blast cells in bone marrow was 78%, including cells displaying Auer rods and faggot cells. Chromosomal analysis revealed the karyotype 46,XX,t(2;7)(q33;q36)[17]/46,XX[3]. The t(15;17) was not detected with conventional cytogenetic analysis. However, reverse transcriptase-polymerase chain reaction revealed the presence of a PML/RARA fusion gene. Cells displaying t(2;7)(q33;q36) disappeared after complete remission was achieved, using induction chemotherapy. Although several additional chromosomal abnormalities have been reported, this t(2;7)(q33;q36) without the classic t(15;17) represents a novel chromosomal abnormality associated with APL.
Asunto(s)
Cromosomas Humanos Par 2 , Cromosomas Humanos Par 7 , Leucemia Promielocítica Aguda/genética , Translocación Genética/genética , Bandeo Cromosómico , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Cariotipificación , Leucemia Promielocítica Aguda/patología , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We report a series of FDG PET findings of a 69-year-old male patient with autoimmune pancreatitis (AIP) associated with extrapancreatic disease. The first FDG PET revealed diffuse uptake of FDG in AIP and retroperitoneal fibrosis (RF). The second FDG PET after cessation of steroid treatment indicated subsiding of disease activity in AIP, continuous disease activity in RF, and new extrapancreatic lesions, including enlargement of a right salivary gland, nephritis, and lymphadenopathy. The last FDG PET under steroid treatment revealed reduced FDG uptake in the above abnormal FDG uptake lesions. A series of these FDG PET findings suggest the usefulness of FDG PET for the diagnosis and monitoring of AIP associated with extrapancreatic autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Fluorodesoxiglucosa F18 , Pancreatitis/diagnóstico , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Humanos , Masculino , Radiofármacos , Técnica de SustracciónRESUMEN
A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T-cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.
Asunto(s)
Hepatitis/complicaciones , Leucemia-Linfoma de Células T del Adulto/etiología , Fallo Hepático Agudo/complicaciones , Trasplante de Hígado , Donadores Vivos , Resultado Fatal , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/virología , Hepatitis/patología , Hepatitis/terapia , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Fallo Hepático Agudo/patología , Fallo Hepático Agudo/terapia , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
The Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group conducted a phase II trial of LSG12 therapy for 45 elderly patients with aggressive lymphoma to clarify whether LSG12 reduces severe infection without lowering the complete response (CR) rate in comparison with LSG4. LSG12, which consisted of a regimen of vincristine, cyclophosphamide, prednisolone, doxorubicin, vindesine, etoposide, and procarbazine (VEPA/FEPP), excluded bleomycin and methotrexate of LSG4 therapy, reduced the dosages of doxorubicin and cyclophosphamide, and increased etoposide and procarbazine dosages instead. Inclusion criteria consisted of a patient age of 70 to 75 years, a World Health Organization performance status of 0 to 2, and acceptable organ function. The treatment was completed in 47% of the patients and terminated early for disease progression in 20% and for toxicity in 16%. The CR rate was 60% (95% confidence interval [CI], 44%-74%). The 5-year overall survival (OS) rate was 42% (95% CI, 27%-57%), and the median OS time was 4.3 years. Leukopenia of grade 3 to 4 occurred in 98% of the patients, and severe infection occurred in 9%. Eight patients with hepatitis C virus (HCV) antibody showed no severe hepatic toxicity and had a better CR or OS rate than the 37 HCV-negative patients. Although the outcomes of LSG12 met our expectations with a reduction in severe infection and equivalent CR and OS outcomes compared with LSG4 and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), the possibility of a regimen more beneficial than LSG12 for aggressive lymphoma in the elderly patient should be explored because of frequent hematologic toxicity and poor compliance in LSG12.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/mortalidad , Masculino , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Procarbazina/administración & dosificación , Procarbazina/efectos adversos , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Vindesina/administración & dosificación , Vindesina/efectos adversosRESUMEN
We previously reported that monotherapy with carbapenem or cefepime exhibited efficacy equivalent to cefepime plus an aminoglycoside as initial therapy for febrile neutropenia (FN), achieving an adequate response in two-thirds of the patients. However, only one-third of the remaining poor responders to monotherapy became afebrile after an aminoglycoside was added to the initial carbapenem or cefepime. The present study was designed to evaluate the benefit of intravenous ciprofloxacin for neutropenic patients with fever who were refractory to initial therapy given for the first 3 days. Patients with FN--as defined by an axillary temperature >or=37.5 degrees C and a neutrophil count <1,000/microL-who had no response to initial therapy with carbapenem or cefepime for 72 hours were to receive additional ciprofloxacin 600 mg/day. They were otherwise managed according to the Japanese guidelines for FN. An adequate response was defined as a decline of temperature to <37.5 degrees C within 7 days after initiation of ciprofloxacin treatment. Thirty-one patients with FN (seventeen male and fourteen female; mean age 53.1 +/- 14.8 years) were entered in the study. The initial antibiotics were cefepime (2 - 4 g/day) in twenty and carbapenem (1 - 2 g/day) in eleven. Three patients were excluded from analysis, leaving 28 patients for evaluation of efficacy. The response rate was 16/31 patients (51.6%),with four patients judged non-assessable due to adverse effects, protocol violation or early change to other agents. Adverse events occurred in seventeen patients, but all were mild and reversible. Only three patients had adverse events (skin rash, hepatic dysfunction and elevation of alkaline phosphatase in one patient, respectively) considered related to ciprofloxacin. These findings indicate that addition of intravenous ciprofloxacin is effective against FN refractory to initial antibiotic therapy and has acceptable toxicity.
Asunto(s)
Ciprofloxacina/administración & dosificación , Neutropenia/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Algoritmos , Carbapenémicos/uso terapéutico , Cefepima , Cefalosporinas/uso terapéutico , Ciprofloxacina/toxicidad , Femenino , Fiebre/tratamiento farmacológico , Enfermedades Hematológicas/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/complicaciones , Inducción de Remisión/métodos , Terapia Recuperativa/efectos adversos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
A 61-year-old man with progressive adult T-cell leukemia/lymphoma (ATLL) successfully received reduced-intensity conditioning stem cell transplantation (RIST) without T-cell depletion (TCD) from his HLA-incompatible son, who had negative results for human T-lymphotropic virus type 1 (HTLV-1) (1-locus, 1-allele mismatch in the graft-versus-host [GVH] direction; 2-loci, 1-allele mismatch in the host-versus-graft direction). The preparatory regimen consisted of fludarabine, busulfan, and rabbit antithymocyte globulin. GVH disease (GVHD) prophylaxis consisted of short-term administration of methotrexate, tacrolimus, and methylprednisolone. The patient achieved complete donor chimerism on day 30 after transplantation. On approximately day 50 the patient started to experience steroid-refractory skin GVHD (grade IV), which was successfully managed with basiliximab (anti-CD25 monoclonal antibody) and mycophenolate mofetil (MMF). Serial analysis of HTLV-1 proviral load by quantitative polymerase chain reaction analysis using whole peripheral blood demonstrated undetectable levels from day 90. At the time of this writing the patient had been in complete remission for more than 16 months. The results in this case suggest the potential of non-TCD RIST from an HLA-incompatible relative donor as an alternative source of hematopoietic stem cells even for an elderly patient with advanced ATLL. In addition, basiliximab combined with MMF may be effective for the treatment of steroid-refractory skin GVHD without deteriorating the graft-versus-ATL effect.
Asunto(s)
Prueba de Histocompatibilidad , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/terapia , Trasplante de Células Madre , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Reacción Injerto-Huésped , Antígenos HLA/inmunología , Humanos , Masculino , Persona de Mediana Edad , Quimera por Trasplante , Resultado del TratamientoRESUMEN
Recent multidrug chemotherapy for adult T-cell leukemia (ATL) showed improved findings, however, these protocols often induced persistent myelosuppression. Among 67 patients with acute and lymphoma type ATL treated between January 1996 and December 1998, 42 patients died during this period and showed chemotherapy-induced myelosuppression. To characterize the relation between the severity of myelosuppression and the endogenous thrombopoietin (TPO) or granulocyte-colony stimulating factor (G-CSF) levels in ATL patients, we measured these hematopoietic factors using ELISA method. Nineteen patients with acute or lymphoma type ATL and 16 healthy individuals were examined. During thrombocytopenia, the serum TPO levels were significantly higher than that of controls (P < 0.0001) and were inversely correlated with the platelet counts (r = -0.687 P < 0.001). Later in the chemotherapy cycle, severe persistent thrombocytopenia occurred and TPO levels elevated and remained at a high level approximating the TPO levels of exogenous TPO administration (0.3 microg/kg body weight). On the other hand, the serum G-CSF levels with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L were significantly higher than controls (P = 0.009) and inversely correlated with ANC (r = -0.382 P = 0.0034). However, G-CSF levels in six samples obtained after 6 h of G-CSF (100-150 microg per body) administration was approximately 50-fold higher than that in the neutropenic states. These findings suggested that G-CSF can effectively reduce the severity and duration of intensified chemotherapy-induced neutropenia and higher dose exogenous TPO (higher than 0.6 microg/kg per day) therapy may be required to enhance platelet recovery after intensive chemotherapy in ATL patients.
Asunto(s)
Antineoplásicos/efectos adversos , Factor Estimulante de Colonias de Granulocitos/sangre , Leucemia-Linfoma de Células T del Adulto/sangre , Trombopoyetina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/complicaciones , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/inducido químicamente , Estadísticas no Paramétricas , Trombocitopenia/sangre , Trombocitopenia/inducido químicamenteRESUMEN
We established and characterized a c-kit positive cell line from the bone marrow of a patient with biphenotypic acute leukemia (BAL). The cell line, designated TMBL-1, carried a His-175 mutant p53. The immunophenotype of the primary leukemia cells at diagnosis was cytoplasmic CD3+, CD7+, CD13+, CD33-, interleukin-7 (IL-7) receptor+ and c-kit -. However, leukemia cells in relapse and TMBL-1 cells were CD33+ and c-kit +. Immunophenotypically, TMBL-1 is a BAL cell line that coexpresses T-lymphoid and myeloid markers which fulfill the criteria of the European Group for the Immunological Characterization of Leukemia. Stem cell factor (SCF), a key regulator of hematopoiesis signaling through c-kit, enhanced the proliferation of TMBL-1 cells. Direct sequencing revealed the conversion at codon 175 of the p53 gene in the TMBL-1 cells. Primary leukemia cells in relapse also carried the same point mutation but not at diagnosis. Moreover, TMBL-1 cells are sensitive to paclitaxel, which could induce p53-independent apoptosis. The biphenotypic features and p53 mutation may be associated with progression to a more malignant type. This cell line may provide new information on the role of SCF in the overlapping area between early T-lymphoid/myeloid cells, and help in the design of new therapies targeted towards p53 mutations.
Asunto(s)
Leucemia/patología , Mutación Puntual , Proteínas Proto-Oncogénicas c-kit , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Adulto , Células de la Médula Ósea , División Celular/efectos de los fármacos , Humanos , Inmunofenotipificación , Masculino , Células Mieloides/patología , Paclitaxel/farmacología , Factor de Células Madre/farmacología , Linfocitos T/patologíaRESUMEN
Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.