RESUMO
Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.
Assuntos
Linfócitos B Reguladores/imunologia , Linfócitos B/imunologia , Interleucina-10/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Linfócitos B Reguladores/metabolismo , Linfócitos B Reguladores/patologia , Células Cultivadas , Imunofluorescência , Humanos , Terapia de Imunossupressão , Interleucina-10/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (PET) and gallium-67 citrate (gallium) response after chemotherapy are powerful prognostic factors in diffuse large B-cell lymphoma (DLBCL). However, clinical outcomes when consolidation radiation therapy (RT) is administered are less defined. PATIENTS AND METHODS: We reviewed 99 patients diagnosed with DLBCL from 1996 to 2007 at Duke University who had a post-chemotherapy response assessment with either PET or gallium and who subsequently received consolidation RT. Clinical outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Median follow-up was 4.4 years. Stage distribution was I-II in 70% and III-IV in 30%. Chemotherapy was R-CHOP or CHOP in 88%. Median RT dose was 30 Gy. Post-chemotherapy PET (n = 79) or gallium (n = 20) was positive in 21 of 99 patients and negative in 78 of 99 patients. Five-year in-field control was 95% with a negative PET/gallium scan versus 71% with a positive scan (P < 0.01). Five-year event-free survival (EFS; 83% versus 65%, P = 0.04) and overall survival (89% versus 73%, P = 0.04) were also significantly better when the post-chemotherapy PET/gallium was negative. CONCLUSIONS: A positive PET/gallium scan after chemotherapy is associated with an increased risk of local failure and death. Consolidation RT, however, still results in long-term EFS in 65% of patients.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/radioterapia , Terapia Combinada , Feminino , Fluordesoxiglucose F18 , Radioisótopos de Gálio , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.
Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Purinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Compostos de Boro/toxicidade , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Prognóstico , Purinas/toxicidade , Vidarabina/análogos & derivados , Vidarabina/farmacologiaRESUMO
Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.
Assuntos
Apolipoproteína E4/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Apolipoproteína E4/metabolismo , Apoptose/fisiologia , VLDL-Colesterol/sangue , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Masculino , Fatores de Risco , Distribuição por Sexo , Análise de SobrevidaRESUMO
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder. Less than 50 cases have been reported. We report the first case of CNL with an associated leukemia cutis. CNL was diagnosed in a 74-year-old white woman in 1998, based on neutrophilic infiltration of the bone marrow and absence of the Philadelphia chromosome. The patient presented to the dermatology service in August 1998 with a 2-week history of a pruritic eruption on the arms, hands, and legs. Physical examination revealed red to violaceous plaques on both thighs and knees, in addition to purpuric patches and plaques on the dorsal hands, arms, and legs. Leukemia cutis was demonstrated on biopsy specimens of several lesional sites. The eruption progressed, despite treatment with topical and systemic corticosteroids. Treatment with systemic chemotherapy did affect partial resolution of the eruption, with parallel decreases in bone pain and white blood cell count, but the disease progressed and the patient ultimately died 5 months after her initial skin findings. Only one other case of CNL with dermatologic manifestations has been reported, CNL associated with a reactional neutrophilic dermatosis. Comparison to and differentiation from this case is discussed. The importance of distinguishing the specific infiltrates of leukemia from the nonspecific infiltrates of reactional dermatoses, such as Sweet's syndrome, is illustrated.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia/diagnóstico , Pele/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biópsia por Agulha , Células da Medula Óssea/patologia , Progressão da Doença , Evolução Fatal , Feminino , Dermatoses da Mão/diagnóstico , Humanos , Dermatoses da Perna/diagnóstico , Leucemia/tratamento farmacológico , Leucemia/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaRESUMO
To evaluate the response rate and potential toxicities, a phase II trial was conducted of fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated low-grade and select intermediate-grade lymphoid malignancies. Symptomatic patients with preserved end organ function received cyclophosphamide 600 mg/m(2) intravenous (iv) day 1 and fludarabine 20 mg/m(2) iv days1 through 5, followed by filgrastim 5 microg/kg subcutaneous starting approximately day 8. Treatment was repeated every 28 days until maximum response or a maximum of 6 cycles. Sixty patients, median age 53.5 years, were enrolled. Thirty-seven patients with non-Hodgkin lymphoma (NHL) were stage IV and 6 were stage III. Eleven of 17 patients with chronic lymphocytic leukemia (CLL) were Rai intermediate risk and 6 were high risk. The overall complete response (CR) rate was 51% and the partial response (PR) rate was 41%. Of patients with CLL, 47% achieved a CR and the remaining 53% achieved a PR. Of patients with follicular lymphoma, 60% achieved CR and 32% achieved a PR. Although the toxicity of this regimen was mainly hematologic, significant nonhematologic toxicities, including infections, were seen. Twenty-four patients subsequently received an autologous or allogeneic stem cell transplant. Engraftment was rapid, and there were no noticeable procedure toxicities in the immediate posttransplant period attributable to the fludarabine and cyclophosphamide regimen. Fludarabine, cyclophosphamide, and filgrastim make up a highly active and well-tolerated regimen in CLL and NHL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma não Hodgkin/terapia , Transtornos Linfoproliferativos/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Filgrastim , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/patologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Recombinantes , Transplante Autólogo , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Health maintenance includes secondary prevention through cancer screening. There are no established guidelines for cancer screening patients with end-stage renal disease (ESRD). Using an established method of estimating life expectancy, published literature on cancer screening, and information from databases on mortality and malignancy (US Renal Data System 1997 Annual Data Report and the SEER Cancer and Statistical Review, 1973-1994), a "real-time life expectancy calculator" was developed to guide the primary help provider in making informed decisions on the benefits of cancer screening in individual patients. Potential days of life saved by each screening method can be calculated using the difference in life expectancy per the DEALE (declining exponential approximation of life expectancy) method with and without cancer screening. Using two sets of assumptions (one to enhance any bias toward support for screening and one to limit this bias), a range of potential days of life saved with screening for breast and colon cancer can be calculated in individual patients with ESRD. In breast cancer, for example, a 50-year-old black woman with ESRD and multiple risk factors would have 41 to 291 potential days of life saved with screening. A 60-year-old white woman with ESRD and diabetes mellitus (DM) would have only 1 to 16 days of life saved. This life expectancy calculator can guide the primary health care provider in making clinical decisions concerning screening in the ESRD population. In addition to assisting in patient education, the calculator can be updated as new information becomes available regarding relative risk, treatment, and mortality.
Assuntos
Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Expectativa de Vida , Programas de Rastreamento/métodos , Neoplasias/diagnóstico , Neoplasias/mortalidade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Neoplasias/etiologiaRESUMO
BACKGROUND: The natural history of chronic lymphocytic leukemia (CLL) is changing, although the reasons (potential changes in the disease's biology or in patterns in patient characteristics, treatment, or referral) are unclear. METHODS: This report uses National Cancer Data Base (NCDB) data, which reflect a hospital-based patient population from a broad spectrum of hospitals in the United States. Age, gender, race/ethnicity, income, treatment, overall survival, and relative survival were evaluated according to time period (1985-1990 and 1991-1995). Comparisons were made with U. S. population figures for 1990 and with series published over the last 70 years. RESULTS: CLL comprised 22.6% of the 108,396 cases of leukemia in the data base. The risk of developing CLL increased progressively with age and did not plateau; the average age was 69.6 years. At the time of initial diagnosis, 60.5% of patients received no treatment (this proportion increased from 58.1% to 62.7% between the 2 time periods). Overall survival was 48.2% at 5 years and 22.5% at 10 years. The 5-year relative survival was 69.5%, 72.2%, 63.1%, and 41.7% for age groups <40, 40-59, 60-79, and 80+ years, respectively; these rates indicated that CLL, and not comorbid disease, caused the greatest percentage of deaths. CONCLUSIONS: The risk of developing CLL increases progressively with age without plateauing and is 2.8 times higher for older men than for older women. There is an increasing trend toward no treatment at the time of initial diagnosis. Long term overall survival of CLL patients is poor. CLL is a more fatal disease among older individuals because of the disease itself, not because of comorbid conditions.
Assuntos
Leucemia Linfocítica Crônica de Células B/epidemiologia , Adulto , Distribuição por Idade , Idoso , Bases de Dados Factuais , Grupos Diagnósticos Relacionados , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Distribuição por Sexo , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
We performed a prospective infectious natural history study of 21 patients with low-grade lymphoproliferative disorders receiving fludarabine as initial (n = 5) or salvage (n = 16) therapy. 12 (57%) of these patients developed herpes zoster (n = 9), herpes simplex I (n = 1) or herpes simplex II (n = 2) infections at a median of 8 (range 1-17) months following initiation of fludarabine, with 75% of these having completed therapy. All patients with herpes zoster developed severe post-herpetic neuralgia. Factors differentiating patients developing these infections included older age and low serum IgG or IgA. Based upon these prospective data, we conclude that herpes virus infections frequently occur following fludarabine treatment, necessitating aggressive patient education and new prophylactic strategies.
Assuntos
Infecções por Herpesviridae/induzido quimicamente , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/tratamento farmacológico , Infecções Oportunistas/complicações , Vidarabina/análogos & derivados , Idoso , Feminino , Infecções por Herpesviridae/complicações , Humanos , Transtornos Linfoproliferativos/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vidarabina/efeitos adversosRESUMO
OBJECTIVE: To determine if D-dimer predicts outcomes in critically ill patients. DESIGN: Observational, cohort study. SETTING: Medical intensive care unit (MICU) of a tertiary care hospital. PATIENTS AND PARTICIPANTS: Seventy-four patients consecutively admitted to the MICU. INTERVENTIONS: D-dimer was measured by latex agglutination within 12 h of admission to the MICU. MEASUREMENTS AND RESULTS: Of the study population, 43.2% had positive D-dimers. The in-hospital mortality rate in D-dimer positive patients was 28.1% as compared to 7.1% in D-dimer negative subjects (p = 0.024). D-dimer positive patients had significantly greater frequencies of venous thromboses (21.9% vs 4.8%, p = 0.035). CONCLUSIONS: The D-dimer assay identifies patients at increased risk for mortality and may be a more sensitive test to determine the presence of underlying microvascular pathology in critically ill patients. A positive D-dimer at admission to the MICU is associated with an increased risk for the later development of a venous thromboembolic event (VTE).
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , APACHE , Idoso , Biomarcadores , Estudos de Coortes , Coagulação Intravascular Disseminada , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Testes de Fixação do Látex , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Trombose VenosaRESUMO
Flavopiridol has been reported to induce apoptosis in lymphoid cell lines via downregulation of bcl-2. The in vitro activity of flavopiridol against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing cytotoxicity were studied. The in vitro viability of mononuclear cells from CLL patients (n = 11) was reduced by 50% at 4 hours, 24 hours, and 4 days at a flavopiridol concentration of 1.15 micromol/L (95% confidence interval [CI] +/-0.31), 0.18 micromol/L (95% CI +/-0.04), and 0.16 micromol/L (95% CI +/-0.04), respectively. Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.18 micromol/L of flavopiridol resulted in both decreased expression of p53 protein and cleavage of the caspase-3 zymogen 32-kD protein with the appearance of its 20-kD subunit. Contrasting observations of others in tumor cell lines, flavopiridol cytotoxicity in CLL cells did not correlate with changes in bcl-2 protein expression alterations. We evaluated flavopiridol's dependence on intact p53 by exposing splenocytes from wild-type (p53(+/+)) and p53 null (p53(-/-)) mice that demonstrated no preferential cytotoxicity as compared with a marked differential with F-ara-a and radiation. Incubation of CLL cells with antiapoptotic cytokine interleukin-4 (IL-4) did not alter the LC50 of flavopiridol, as compared with a marked elevation noted with F-ara-a in the majority of patients tested. These data demonstrate that flavopiridol has significant in vitro activity against human CLL cells through activation of caspase-3, which appears to occur independently of bcl-2 modulation, the presence of IL-4, or p53 status. Such findings strongly support the early introduction of flavopiridol into clinical trials for patients with B-CLL.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases/fisiologia , Proteínas de Ciclo Celular , Precursores Enzimáticos/metabolismo , Flavonoides/farmacologia , Inibidores do Crescimento/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas de Neoplasias/fisiologia , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Proteínas Supressoras de Tumor , Animais , Antineoplásicos/administração & dosagem , Caspase 3 , Cromossomos Humanos Par 17/genética , Inibidor de Quinase Dependente de Ciclina p27 , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Flavonoides/administração & dosagem , Deleção de Genes , Genes p53 , Inibidores do Crescimento/administração & dosagem , Humanos , Hibridização in Situ Fluorescente , Interleucina-4/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Piperidinas/administração & dosagem , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Células Tumorais Cultivadas , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Proteína X Associada a bcl-2RESUMO
BACKGROUND: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. PATIENTS AND METHODS: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). RESULTS: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. CONCLUSIONS: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.
Assuntos
Adaptação Psicológica , Doença de Hodgkin/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Qualidade de Vida , Sobreviventes/psicologia , Adolescente , Adulto , Fatores Etários , Idoso , Distribuição de Qui-Quadrado , Criança , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Inquéritos e QuestionáriosRESUMO
PURPOSE: A report of the clinical features, treatment, and outcome of patients who developed hemolytic anemia (HA) temporally associated with fludarabine (Fludara; Berlex Laboratories, Richmond, CA) therapy for chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Data on 24 patients who developed HA related to fludarabine therapy were collected from the Spontaneous Reporting System of the Food and Drug Administration (FDA) and the Walter Reed Army Medical Center (Washington, DC). RESULTS: Seventeen (71%) patients developed HA after either the first, second, or third cycle of this drug. The longest duration of fludarabine therapy before HA occurred was six cycles. The median decline in hematocrit from baseline during the hemolytic episode was 14.1 (range, 8.0 to 28.9) for the 18 patients for whom this information was available. For the 11 patients for whom transfusion requirements were known, the number of transfusions administered ranged between three and 36. Seven (29%) patients died of medical complications associated with the HA. Seven of eight patients who were re-challenged with fludarabine after an episode of HA developed recurrent HA, and three of these patients died. CONCLUSION: HA associated with fludarabine therapy appears to be uncommon, but it can be severe and fatal, especially if a patient is re-treated with this drug after a previous episode of HA. The mechanism of this toxicity is unknown, but it may be caused by the release of a suppressed auto-antibody to a native red cell antigen.
Assuntos
Anemia Hemolítica/induzido quimicamente , Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Anemia Hemolítica/terapia , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
BACKGROUND: The effect of transfusion of small amounts of packed red blood cells (PRBC) on serum chemistry values is not known. METHODS: We studied 73 adult patients without evidence of bleeding who received 2-unit PRBC transfusions. In study 1 (n=39), we examined multiple laboratory values pretransfusion and 15 minutes, 1 hour, 2 hours, and 24 hours posttransfusion. In study 2 (n=34), we examined changes in fractionated bilirubin, lactate dehydrogenase, and haptoglobin prior to and 1 hour following the transfusion. RESULTS: Total bilirubin increased from a median pretransfusion baseline of 0.7 mg/dL to 1.4 mg/dL shortly after transfusion (P <0.0005), and then returned to normal 24 hours later. Of the 36 patients with normal pretreatment total bilirubin levels, 17 (47%) became transiently abnormal. The lactate dehydrogenase level increased similarly 15 minutes after transfusion, but returned to baseline 24 hours later. The unconjugated bilirubin level increased from a median baseline pretransfusion value of 0.3 mg/dL to 1.1 mg/dL at 1 hour posttransfusion (P <0.0005). No significant changes were noted in conjugated bilirubin levels or haptoglobin concentration following transfusion. CONCLUSIONS: Transient increases in serum bilirubin and lactate dehydrogenase are seen following transfusion of PRBC. These data should be considered when interpreting laboratory values during the first few hours after a transfusion.
Assuntos
Bilirrubina/sangue , Transfusão de Eritrócitos/efeitos adversos , L-Lactato Desidrogenase/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de TempoRESUMO
Immune dysregulation, a hallmark of chronic lymphocytic leukemia (CLL), manifests itself in three autoimmune diseases: warm autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenia (ITP); and, pure red cell aplasia (PRCA). AIHA occurs in 11% of advanced stage CLL patients. Prednisone is the first treatment of choice, with 90% responses and 65% complete responses. More than 60% of patients relapse when treatment is stopped. Intravenous immunoglobulin, the next line of treatment, causes responses in 40% of patients. While the data are very limited, cyclosporine A is a reasonable choice for third-line therapy. Alkylating agents, danazol, plasma exchange, immunoabsorption, vincristine-loaded platelets, splenectomy, and splenic irradiation are also reported to cause responses. The data on mechanisms of AIHA are most consistent with immune dysregulation leading to loss of tolerance to a self antigen which in turn leads to the immune-based hemolytic anemia. PRCA is underrecognized in CLL with 6% of CLL patients having PRCA when tested for it. Unlike AIHA, PRCA often occurs in early stage disease. Anemia, reticulocytopenia, and a marrow virtually devoid of red blood cell precursors are hallmarks of PRCA. Corticosteroid therapy is the first line of treatment. If a response is not obtained in 4 weeks, cyclosporine A should be added. Although the data on pathophysiology are very limited, PRCA appears to be the result of an abnormal T cell that both fails in its normal function to support growth and inhibits the growth of erythroid progenitor cells. ITP occurs in 2-3% of CLL patients, occurs in early stage disease and may be a presenting manifestation. Initial therapy for ITP mirrors the guidelines for primary ITP. Initial therapy should consist of prednisone. Seventy percent of patients respond. Splenectomy is a reasonable second-line treatment. Autoimmune phenomena, largely related to blood cells, are based in the immune dysregulation of CLL. Longer survivals in CLL patients, more treatment regimens per patient, and more immunosuppression with modern treatments, allow us to predict an increasing incidence of autoimmune blood cell diseases in CLL.
Assuntos
Anemia Hemolítica Autoimune/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Púrpura Trombocitopênica Idiopática/etiologia , Aplasia Pura de Série Vermelha/etiologia , Anemia Hemolítica Autoimune/terapia , Humanos , Púrpura Trombocitopênica Idiopática/terapia , Aplasia Pura de Série Vermelha/terapiaRESUMO
Fludarabine is a highly effective chemotherapeutic agent for chronic lymphocytic leukemia/small lymphocytic lymphoma and is also active in other B-cell lymphoproliferative disorders. Although highly efficacious in destroying the malignant B-cells, fludarabine also causes T-cell lymphopenia and immunosuppression. We present five patients given fludarabine for low-grade B-cell lymphoproliferative disorders who showed transformation of the primary neoplasm to a higher grade tumor. Immunohistologic antibody studies were performed on paraffin-embedded tissue sections of the initial tissue (when available) and on the follow-up biopsy specimens for CD20, CD3, CD45RO, CD43, CD30, CD15, and latent membrane protein (LMP-1) for Epstein-Barr virus (EBV). The initial diagnoses in these five patients included chronic lymphocytic leukemia/small lymphocytic lymphoma (three cases), follicle center lymphoma (one case), and Waldenstrom's macroglobulinemia (one case). All of the follow-up biopsy specimens showed scattered Hodgkin's-like cells, and two of the five also showed foci of large-cell transformation. The Hodgkin's-like cells showed CD30 immunoreactivity in four of the five cases and CD15 immunoreactivity in three of the five. Strong immunoreactivity of the large, atypical, Hodgkin's-like cells for LMP-1 of EBV was noted in four cases; in the remaining case, this finding was equivocal. In situ hybridization for EBV-encoded RNA was positive in four of the five cases. Molecular studies by polymerase chain reaction (PCR) showed the presence of EBV in three of the five cases. PCR for detection of immunoglobulin heavy chain demonstrated identical monoclonal rearrangements in the original lymphoma and transformation in one case with available material. The CD4 lymphocyte count in each patient was less than 550/microL, indicating cellular dysfunction. Transformation of low-grade non-Hodgkin's lymphomas after fludarabine therapy might be associated with EBV and severe immunosuppression.
Assuntos
Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Herpesvirus Humano 4/isolamento & purificação , Linfoma de Células B/virologia , Linfoma não Hodgkin/virologia , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos Virais/metabolismo , Contagem de Linfócito CD4 , Primers do DNA/química , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Humanos , Hibridização In Situ , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Viral/metabolismo , Vidarabina/uso terapêutico , Proteínas da Matriz Viral/metabolismoAssuntos
Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hipertensão/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/efeitos adversos , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Paclitaxel/uso terapêuticoRESUMO
The high incidence of opportunistic pulmonary infections in fludarabine-treated patients at Walter Reed Army Medical Center (WRAMC) and in the literature are described. A CancerLit search of fludarabine from June 1983-April 1994 with subsequent cross referencing and a retrospective review of all patients receiving fludarabine at WRAMC was performed. A total of 2,269 patients with low-grade lymphoid malignancies who received 7,547 + cycles of fludarabine were identified from the literature. Seventy-three (3.2%) of these patients developed opportunistic infections. Seventy-one (97%) of these infections occurred in patients who were pretreated with alkylator regimens or corticosteroids. Forty-five (2%) of these were of respiratory origin and associated with a 56% mortality rate. In contrast, 6 of the 21 patients (29%) treated with fludarabine at WRAMC developed opportunistic pulmonary infections which included three Pneumocystis carinii (PCP), one PCP/disseminated Candidiasis, one Mycobacterium avium intracellulare, and one Aspergillus niger pneumonia. These infections developed during and after treatment with fludarabine in alkylator-resistant patients who had received corticosteroids before (n = 6), during (n = 1), or after (n = 4) fludarabine therapy. Lack of PCP prophylaxis was the only significant (P = .018) variable that differentiated patients who developed opportunistic pulmonary infections. Corticosteroid treatment before, during, or after fludarabine treatment in patients with alkylator-resistant, low-grade lymphoid malignancies who have not received PCP prophylaxis is associated with an increased risk of opportunistic pulmonary infections. Aggressive work-up of pulmonary syndromes and PCP prophylaxis in these patients should be considered during and after treatment with fludarabine.