RESUMO
This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760-1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.
Assuntos
Corticosteroides/administração & dosagem , Ciclofosfamida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Terapia de Salvação/métodos , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Neutropenia/induzido quimicamente , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Recidiva , Terapia de Salvação/efeitos adversos , Terapia de Salvação/mortalidade , Taxa de Sobrevida , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: According to current medical research, mammaglobin (hMAM) is expressed exclusively in the mammary glands of adult women and in mammary tumor cell lines. Therefore, we examined hMAM expression as a marker for the detection of carcinoma cells in the peripheral blood of patients with breast cancer (BC). PATIENTS AND METHODS: Blood samples obtained from 114 BC patients at the various stages of their disease and from 68 individuals without BC were screened for hMAM mRNA by a nested reverse transcriptase polymerase chain reaction (RT-PCR) assay. RESULTS: The assay exhibited a calculated analytical limit of one tumor cell per 10(6) to 10(7) WBCs. None of the samples from peripheral blood of 27 healthy individuals were positive, whereas 29 (25%) of 114 samples from BC patients were positive for hMAM mRNA. hMAM mRNA expression was detected in five (28%) of 18 BC patients at diagnosis, in three (6%) of 53 with no evidence of disease, and in 21 (49%) of 43 with metastatic disease. These results correlate with patients' carcinoembryonic antigen (CEA) plasma level and, to some extent, with estrogen receptor status. Two of 41 samples from patients with malignancies other than BC were also positive. CONCLUSION: In contrast to healthy volunteers, hMAM transcripts were detected in the peripheral blood of BC patients. The percentage of positivity relates to the clinical stages of disease, CEA plasma level, and estrogen receptor status. Aberrant hMAM expression might occur occasionally in malignancies other than BC. The clinical relevance of hMAM RT-PCR-based tumor cell detection in the peripheral blood of BC patients should be further evaluated in prospective studies.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/sangue , Carcinoma/sangue , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Uteroglobina/metabolismo , Adulto , Idoso , Neoplasias da Mama/patologia , Carcinoma/patologia , Estudos de Casos e Controles , Feminino , Humanos , Mamoglobina A , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Neoplásico/análise , Sensibilidade e EspecificidadeRESUMO
Trisomy 4 as single karyotype anomaly has recently been proposed as an acute myeloid leukemia (AML) specific aberration. Up to now, 20 cases have been reported in which the single abnormality occurred without additional chromosomal aberrations. Trisomy 4 has been found in both primary and secondary AML, the majority of cases being diagnosed as FAB M4 or M2 subtypes. In the cytogenetic analysis of 305 patients with AML, we found 209 cases with aberrant karyotypes, among them two patients (22a, male, M2; and 69a, male, M4) with trisomy 4 as single aberration. The younger patient achieved complete remission lasting 13 months and survived 22 months whereas the older patient died in aplastic phase due to septicaemia 5 weeks after admission. Trisomy 4 is proposed to be the primary aberration in both these cases of de novo AML. Although in one case, as in two cases reported earlier, cytogenetic results were only available in first relapse, we have no indication that trisomy 4 appeared in a secondary induced leukemia, because the leukemic blasts of the relapse were morphologically identical to first acute phase. In contrast to other specific chromosomal aberrations, results indicate that trisomy 4 has as yet no prognostic relevance concerning the clinical outcome.
Assuntos
Cromossomos Humanos Par 4 , Leucemia Mieloide Aguda/genética , Trissomia , Adulto , Idoso , Humanos , MasculinoRESUMO
A stochastic model was developed to validate the results obtained with the mammaglobin-nested RT-PCR assay for tumor cell detection in peripheral blood of breast cancer patients. Since the assay consists of four PCR setups per peripheral blood sample, the probabilities for receiving 0, 1, 2, 3, or 4 positive setups were calculated. In this model, samples with just 500 mammaglobin mRNA molecules are highly probable to result in at least three positive setups, whereas lower quantities shift the probabilities towards one or two positive setups. In the clinical trial, samples with one or two mammaglobin positive setups were detected in 6/143 (4%) patients with benign lesions of the breast, in 41/310 (13%) breast cancer patients with no evidence of disease and in 39/157 (25%) breast cancer patients with metastatic disease. On the contrary, no sample from patients with benign lesions of the breast resulted in three or four positive setups, but 5/310 (2%) breast cancer patients with no evidence of disease and 46/157 (29%) with metastatic disease. These results correspond with the model: an increased number of tumor cells in peripheral blood lead to a higher amount of mammaglobin mRNA molecules, and these samples may result in at least three positive setups. Samples with three orfour positive setups were mainly derived from breast cancer patients with metastatic disease and only occasionally from patients with no evidence of disease. On account of these results, samples with at least three positive setups are of prognostic value and regarded as tumor cell positive.
Assuntos
Neoplasias da Mama/diagnóstico , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase/normas , Uteroglobina/genética , Neoplasias da Mama/genética , DNA Complementar/análise , Feminino , Humanos , Mamoglobina A , Modelos Estatísticos , Células Neoplásicas Circulantes , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Processos EstocásticosAssuntos
Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Antígenos de Neoplasias/análise , Antígenos de Superfície/análise , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Relação Dose-Resposta a Droga , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , PrognósticoAssuntos
Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Aclarubicina/administração & dosagem , Adulto , Idoso , Citarabina/administração & dosagem , Avaliação de Medicamentos , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/classificação , Idoso , Idoso de 80 Anos ou mais , Citogenética , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoAssuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/sangue , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , RNA Mensageiro/metabolismo , Uteroglobina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mamoglobina A , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Essential thrombocythemia, a myeloproliferative disorder of clonal origin, is often associated with various clinical manifestations resulting from thromboembolic or hemorrhagic complications. The long-established successful method of treatment with cytotoxic agents or radioactive phosphorus has recently been superseded by interferon alpha. We treated 14 symptomatic patients with 5 x 10(6) IU recombinant interferon alpha-2b s.c. daily. 12/14 pts responded within 14-75 days. When platelet counts decreased to below 450 g/l the frequency of administration was reduced stepwise. 7 patients remained in CR during this reduction phase and treatment was stopped in 5 pts after 12-32 months. Until now, 3 of them are still in continuous good PR without any drug therapy and free of symptoms for 3+, 19+ and 36+ months. Continuous response during maintenance was associated with age, initial platelet count and time required to reduce platelet counts to less than 450 g/l.
Assuntos
Interferon-alfa/uso terapêutico , Trombocitemia Essencial/terapia , Adulto , Biópsia por Agulha , Contagem de Células Sanguíneas , Medula Óssea/patologia , Feminino , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Trombocitemia Essencial/sangue , Trombocitemia Essencial/patologiaRESUMO
Mammaglobin (hMAM) has been shown to be a marker for the detection of circulating tumor cells in the peripheral blood (pB) of breast cancer (BC) patients via a nested RT-PCR assay. 286 samples from BC patients were classified into four defined clinical subgroups: prior to and after surgery (pre, post), no evidence of disease (NED) and metastatic disease (MD). hMAM mRNA expression was detected in 2/46 pre (4%), 2/24 post (8%), 4/135 NED (3%) and 35/81 MD (43%) patients. 68 BC patients with NED and negative for hMAM mRNA in their pB were repeatedly tested for at least 6 months. Fifteen of these patients relapsed. Eight of them were hMAM-positive, 5 at time of relapse, one patient 13 months before and two patients 10 and 17 months after relapse was diagnosed. 7/15 BC patients relapsed within 24 months, 5 of them were hMAM-positive versus 3 of 8 patients with later relapses. On the basis of these preliminary results we conclude that tumor cells can be detected via hMAM nested RT-PCR in the pB of BC patients and that hMAM could be a marker for early relapse.
Assuntos
Neoplasias da Mama/diagnóstico , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes , RNA Mensageiro/sangue , Uteroglobina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Humanos , Mamoglobina A , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
To investigate the prognostic value of tumour cells in peripheral blood (pB) of breast cancer (BC) patients, pB samples from 143 patients with benign lesions of the breast and from 467 BC patients were tested via a nested RT-PCR assay for mammaglobin mRNA. No sample from patients with benign lesions of the breast was found to be mammaglobin positive in contrast to 5/310 (2%) BC patients with no evidence of disease (NED) and 46/157 (29%) patients with metastatic disease (MD). Two hundred and eighteen BC patients with NED were followed for at least 12 months. All five mammaglobin-positive BC patients relapsed 1-13 months after first examination of positive pB samples in contrast to 27/213 (13%) patients without detectable tumour cells in pB. Fifty-nine BC patients with MD were tested for mammaglobin expression in pB at the time of first diagnosis of MD; 20 of them (34%) were mammaglobin positive. Patients were followed for a median of 19 months (2-51 months). During this time, 19/59 (32%) died due to tumour progression. In Kaplan-Meier survival analysis, BC patients with mammaglobin-negative pB samples at time of diagnosis of MD lived significantly longer than mammaglobin-positive patients (log-rank test: P = 0.0013). In addition, mammaglobin was an independent prognostic parameter and the difference reached significance in univariate as well as in multivariate analysis (P < 0.01). We conclude that the presence of tumour cells in pB of BC patients is of prognostic value.
Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Taxa de SobrevidaRESUMO
High-dose conditioning regimens followed by autologous peripheral blood stem cell rescue are frequently used for the treatment of solid tumors and hematological malignancies. In 24 patients up to four peripheral stem cell collections (PBSC) were performed after priming with various chemotherapies and G-CSF (300 micrograms s.c. per day). In 16 patients (group A) more than 2 x 10(6) CD 34 positive cells per kg bodyweight could be collected; fewer were harvested in the remaining eight patients (group B). The amount of collected CD 34 positive cells correlated with the median number of these cells in the peripheral blood at the start of PBSC. The two groups differed both in recovery time after priming-induced cytopenia (4 vs 6 days from nadir) and in the number of WBC (21 x 10(6) mL-1 vs 6.1 x 10(6) mL-1) and platelets (133 x 10(6) mL-1 vs 58 x 10(6) mL-1) reached at first day of PBSC. No difference between the two groups was seen according to age, duration of disease or disease status. However, the intensity of prior treatment was significantly greater in group B than in group A. These observations indicate that the toxicity of previous chemotherapy is the most important factor for the mobilization of sufficient CD 34 positive cells into the peripheral blood.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucaférese/métodos , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Transplante AutólogoRESUMO
5 patients with metastatic tumors and 4 patients with hematological malignancies were treated either with G- or GM-CSF alone (5 micrograms/kg s.c.) or in combination with cyclophosphamide (7 g/m2) or epirubicin (120 mg/m2) to reduce either tumor mass or to maintain remission and to prime for peripheral stem cell collection.