RESUMO
Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly streptococcal and staphylococcal infections. This study evaluated the impact of prophylactic antibiotics on the incidence of serious bacterial infections (SBIs) during the first 2 months of treatment in patients with newly diagnosed MM. Patients with MM receiving initial chemotherapy were randomized on a 1:1:1 basis to daily ciprofloxacin (C; 500 mg twice daily), trimethoprim-sulfamethoxazole (T; DS twice daily) or observation (O) and evaluated for SBI (Eastern Cooperative Oncology Group ≥grade 3) for the first 2 months of treatment. From July 1998 to January 2008, 212 MM patients were randomized to C (n=69), T (n=76) or O (n=67). The incidence of SBI was comparable among groups: C=12.5%, T=6.8% and O=15.9%; P=0.218. Further, any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, P=0.954). We demonstrate that prophylactic antibiotics did not decrease the incidence of SBI (≥grade 3) within the first 2 months of treatment. We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy.
Assuntos
Anti-Infecciosos/administração & dosagem , Antibioticoprofilaxia , Infecções Bacterianas/prevenção & controle , Ciprofloxacina/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bactérias/patogenicidade , Infecções Bacterianas/induzido quimicamente , Infecções Bacterianas/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/microbiologia , PrognósticoRESUMO
Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 17/genética , Cadeias Pesadas de Imunoglobulinas/genética , Mieloma Múltiplo/genética , Poliploidia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Feminino , Seguimentos , Genes p53/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Taxa de Sobrevida , Translocação Genética , Resultado do TratamentoRESUMO
Hyperdiploid and non-hyperdiploid multiple myeloma represents distinct biological entities characterized by different patterns of genetic changes. We sought to determine whether ploidy category (non-hyperdiploid versus hyperdiploid) remains stable over time from diagnosis to progression. Of the 43 patients studied (39 by flow cytometry DNA index and 4 by a FISH-based index), only five (12%) altered their ploidy status at progression. In three of these patients, the change may possibly be attributable to technical artifacts because of the low absolute change in DNA index. For those who retain their ploidy subtypes, the DNA index change minimally (3.75+/-4.87%). It would appear that the initiating genetic events underlying hyperdiploid and non-hyperdiploid MM that marks them out as distinct entities continue to dominate and persist during disease evolution and progression.
Assuntos
DNA de Neoplasias/genética , Mieloma Múltiplo/genética , Ploidias , DNA de Neoplasias/análise , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Masculino , Mieloma Múltiplo/patologiaAssuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 4 , Mieloma Múltiplo/genética , Paraproteinemias/genética , Proteínas Tirosina Quinases , Translocação Genética/genética , Progressão da Doença , Testes Genéticos , Humanos , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
The Eastern Cooperative Oncology Group (ECOG) performed a prospectively randomized study (E6484) evaluating the use of interferon alfa 2a (IFN-alpha2a) in patients with aggressive low-grade or with intermediate-grade non-Hodgkin's lymphoma (NHL) accruing close to 300 patients between 1985 and 1988. Patients were eligible for study if they had bulky or symptomatic low-grade lymphoma or defined intermediate-grade subtypes. Of 291 patients enrolled, 249 were eligible for analysis. All patients were randomized to receive a four-drug cytotoxic chemotherapy regimen including cyclophosphamide, doxorubicin, vincristine and prednisone in 4-week cycles with or without IFN-alpha2a in addition (COPA vs I-COPA). Treatment was given for up to 8-10 months. This report, at a time when the median follow-up among survivors has reached 12 years, updates the analysis of time to treatment failure (TTF), duration of disease-free survival (DFS), and overall survival. Patients randomized to receive IFN-alpha2a had a prolonged TTF (P= 0.008; median 2.4 vs 1.6 years). DFS for those patients who had complete responses was also longer if IFN-alpha2a had been given (P = 0.035; median 2.7 vs 1.8 years). There was a clinically but not a statistically significant prolongation of overall survival by IFN-alpha2a (P= 0.107; median 7.8 vs 5.7 years). There were fewer deaths over time due to lymphoma in patients receiving IFN-alpha2a (67 vs 80 deaths). A subset analysis, based on disease histology (low-grade, follicular, intermediate-grade), revealed a significant prolongation of TTF in patients receiving IFN-alpha2a with either low-grade (P = 0.002; median 2.4 vs 1.6 years) or follicular (P= 0.01; median 2.5 vs 1.7 years) NHL but not intermediate grade (P = 0.622; median 2.3 vs 1.6 years) NHL. This analysis, performed approximately 12 years after closure of the study to accrual, supports the addition of interferon alfa to an induction cytotoxic chemotherapy regimen including cyclophosphamide and doxorubicin in the treatment of follicular NHL.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Humanos , Interferon alfa-2 , Linfoma não Hodgkin/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes , Taxa de SobrevidaRESUMO
Deletions of the long arm of chromosome 13 (13q-) are observed in patients with multiple myeloma (MM), are rarely observed in the monoclonal gammopathy of undetermined significance (MGUS) and have been associated with a worsened prognosis in MM. However, no minimally deleted region in the 13q arm has been defined at 13q, and consequently no tumor suppressor genes have yet been identified that are important for disease pathogenesis. We attempted to characterize these chromosome 13q deletions at the molecular cytogenetic level. We studied 351 newly diagnosed patients, entered into the E9486/E9487 clinical study of the Eastern Cooperative Oncology Group. Fluorescent in situ hybridization (FISH) combined with immune fluorescent detection (cIg-FISH) of clonal plasma cells (PC) and cytomorphology were used to analyze interphase, bone marrow (BM) cell, cytospin slides. We simultaneously used DNA probes for the following locus specific probes (LSI); LSI 13 (Rb) and D13S319, which hybridize to 13q14. We subsequently studied distal deletions using the D13S25 probe (13q14.3) and a subtelomeric probe (13qSTP) for the 13q-arm (D13S327) in 40 cases with documented LSI 13 (Rb)/D13S319 deletion and 40 without deletion of these loci. Of 325 evaluable patients, we found 13q deletions in 176 (54%) using LSI 13 (Rb) and D13S319 probes. Of 40 patients with LSI 13 (Rb)/D13S319 deletions, 34 (85%) had coexistent deletion of both D13S25/13qSTP. These results indicate that chromosome 13 deletions in MM involve loss of most if not all of the 13q arm perhaps even indicating monosomy. In six cases the 13qSTP signal was conserved, but D13S25 was lost indicating large interstitial deletions involving 13q14. In 39 of the 40 cases without LSI 13 (Rb)/D13S319 deletions, the normal pattern of two pairs of signals was observed for D13S25/13qSTP. Deletions involving 13q14 are very common in MM as detected by cIg-FISH. These deletions appear to predominantly involve loss of large segments of the 13q arm or monosomy 13, and only occasionally represent an interstitial deletion.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13 , Hibridização in Situ Fluorescente , Monossomia , Mieloma Múltiplo/genética , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Cromossomos Humanos Par 13/ultraestrutura , Sondas de DNA , Feminino , Marcadores Genéticos , Humanos , Interfase , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Previously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4(+) or CD19(+) cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3(+), CD4(+), CD8(+), CD19(+), and CD4(+) subset cell levels were all positively associated with survival (P =.0087 to P <.0001). A multivariate analysis incorporating CD4(+) and CD19(+) cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19(+) blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P <.0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8(+), which was greater than CD4(+), which was greater than CD19(+). This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19(+) blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.
Assuntos
Sistema Imunitário/citologia , Mieloma Múltiplo/mortalidade , Análise Atuarial , Antígenos CD19/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Contagem de Células Sanguíneas , Complexo CD3/sangue , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Seguimentos , Humanos , Imunofenotipagem , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Análise Multivariada , Prognóstico , Receptores de IgG/sangue , Recidiva , Taxa de SobrevidaRESUMO
UNLABELLED: Recent data from GELF (Groupe d'Etude des Lymphomes Folliculaires) have shown that the addition of interferon alfa-2b (IFN) to a doxorubicin-containing regimen (CHVP: cyclophosphamide, doxorubicin, teniposide and prednisone) prolongs both progression-free survival and overall survival in high-tumor-burden follicular non-Hodgkin's lymphoma. This gain must be weighed against the incremental toxicity and cost of IFN over CHVP alone and the objective here was, to determine the marginal cost-effectiveness of additive IFN in the specific setting of high-tumor-burden follicular non-Hodgkin's lymphoma. Meta-analysis of GELF trial results employing a Markov model was used with three health states: No Progression, Progressive Disease, and Death. Treatment response, survival and toxicity data are drawn from the GELF study. The current study is based on the final analysis of 242 patients (J Clin Oncol 1998;16:2332-2338), with a six year median follow-up for overall survival (median overall survival: not reached for CHVP + IFN vs 5.6 years for CHVP Only, p = 0.008). MEASUREMENTS: Quality of life data (utilities) are taken from studies with similar dosing of IFN, from Q-TwiST (quality adjusted time without symptoms or toxicity) analysis of the GELF data and from a panel of experts gathered to develop treatment models for high-tumor-burden follicular non-Hodgkin's lymphoma. Costs and quality-adjusted years of life saved were discounted at 3% per annum. SETTING: Costs determined for university medical centers in the United States. Results showed that, at the median cohort age of 52, IFN add 9.9 quality-adjusted months at an added cost of $13,900 (marginal cost-effectiveness of $16,900 per quality-adjusted life year, or QALY). A more complex, two-stage model approximates the actual cohort survival curves much better than a simple, one-stage model, but both models yield essentially the same marginal cost-effectiveness. Sensitivity analysis to quality of life on IFN shows marginal cost-effectiveness ranging from $15,200/QALY (no penalty for IFN) to $21,300/QALY (20% quality adjustment, greater than that reported). The model is quite insensitive to the probability of IFN toxicity. The model is moderately sensitive to the efficacy of IFN in delaying progression, particularly in the first 18 months (pProgI), but the marginal cost-effectiveness does not rise to $50,000/QALY until pProgI increases 220% from the baseline. Although the model is moderately sensitive to the cost of IFN (cIFN), marginal cost-effectiveness is below $50,000/QALY for values of cIFN below $2580/month (baseline cIFN = $850/month, corresponding to a marginal cost-effectiveness of $16,900/QALY in the baseline case). If the model is modified to reflect the 14% overall survival advantage at five years found in trials utilizing more intensive initial chemotherapy (including the GELF trial), then the marginal cost-effectiveness drops to $11,900/QALY in the baseline case. In condusion, based on data from the GELF study, low-dose interferon alfa-2b is cost-effective when added to CHVP therapy in the treatment of high-tumor-burden follicular non-Hodgkin's lymphoma. The analysis is robust: the model employs very conservative assumptions, and additive IFN remains cost-effective over wide ranges of variables in sensitivity analyses. The marginal cost-effectiveness is best expressed as being in the range of $12,000/QALY to $17,000/QALY in the baseline case. A simple Markov model can be used to describe treatment regimens with distinct periods of therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/economia , Interferon-alfa/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/economia , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Análise Custo-Benefício , Humanos , Interferon alfa-2 , Cadeias de Markov , Proteínas Recombinantes , Análise de SobrevidaRESUMO
Thirty-three evaluable patients with Hodgkin's disease who failed radiotherapy were treated on this phase II study with bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone given every 28 days for a minimum of eight courses. Twenty-five patients (76%; 95% CI=55.6-87.1%) achieved a complete remission, the median duration of which cannot yet be determined, but the probability of remaining in continuous complete remission at 10 years is.64. The median survival from entry on this study for all evaluable patients is 10 years, and 12 patients were alive at the time of this analysis with a median follow-up for them of 15.5 years. Of the 22 patients who died, 11 died of progressive or recurrent Hodgkin's disease and 11 died of other causes including 7 second primary neoplasms and at least one myocardial infarction. Both are now well known late complications of Hodgkin's disease treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bleomicina/administração & dosagem , Bleomicina/toxicidade , Causas de Morte , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Feminino , Doença de Hodgkin/complicações , Doença de Hodgkin/mortalidade , Humanos , Lomustina/administração & dosagem , Lomustina/toxicidade , Irradiação Linfática , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/toxicidade , Procarbazina/administração & dosagem , Procarbazina/toxicidade , Recidiva , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/toxicidadeRESUMO
PURPOSE: Phase II studies were conducted to evaluate the safety and efficacy of the interferon inducer Poly ICLC at low doses in advanced renal cancer and relapsed or refractory lymphoma. PATIENTS AND METHODS: Twenty-nine patients with advanced renal carcinoma and eleven patients with lymphoma were treated with poly ICLC. Patients received 0.25 mg/m2 of poly ICLC intravenously twice weekly three days apart until progression or unacceptable toxicity. RESULTS: There were no objective responses. Six patients with renal carcinoma had stable disease as best response with one patient receiving 62 weeks of therapy. Toxicity included grade 3 anemia in 8 patients and grade 4 anemia in one patient. All patients were anemic prior to entry with a median grade 2 anemia at baseline. Grade 4 neutropenia, thrombocytopenia and injection site pain occurred in one patient each. Grade 3 fever, chills or fatigue occurred in four, three, and three patients respectively. Any grade fever occurred in 10 patients (25.6%) and any grade chills occurred in 9 patients (23.1%). CONCLUSION: Poly ICLC at this dose and schedule is well tolerated in both patient populations and is inactive in renal carcinoma.
Assuntos
Carboximetilcelulose Sódica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Indutores de Interferon/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Linfoma/tratamento farmacológico , Poli I-C/administração & dosagem , Polilisina/administração & dosagem , Adulto , Idoso , Carboximetilcelulose Sódica/efeitos adversos , Carboximetilcelulose Sódica/análogos & derivados , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indutores de Interferon/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia , Neutropenia/induzido quimicamente , Poli I-C/efeitos adversos , Polilisina/efeitos adversos , Polilisina/análogos & derivados , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: The importance of the bone marrow microenvironment in multiple myeloma is receiving increasing attention. Recent studies have suggested the importance of cytokine production and cell-cell contact by bone marrow stromal cells in the survival of myeloma cells. METHODS: In the current study, the authors examined bone marrow mesenchymal progenitor cell (MPC) cultures derived from eight multiple myeloma patients (mean age, 58 years) and nine normal donors (mean age, 61 years), with emphasis on cell surface antigens, cytokine, and growth factor expression. RESULTS: The authors have found, based on analysis of cellular receptors, growth factors, and cytokine expression, that myeloma MPCs are phenotypically and functionally distinguishable from normal donor MPCs. Immunofluorescence analysis of MPC monolayers shows that myeloma MPC cultures expressed reduced cell surface vascular cell adhesion molecule-1 and fibronectin, in contrast with the strong expression found on normal donor MPCs. Furthermore, a subset of myeloma MPCs strongly express intracellular receptor for hyaluronan-mediated motility, whereas normal MPCs do not. Cytokine expression in bone marrow MPC cultures was examined by reverse transcription-polymerase chain reaction and enzyme linked immunosorbent assay. Bone marrow MPCs constitutively express interleukin (IL)-1beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, stem cell factor (SCF), and tumor necrosis factor (TNF)-alpha. In comparison to normal MPCs, multiple myeloma MPCs express increased basal levels of IL-1beta and TNF-alpha. In vitro exposure of MPC cultures to dexamethasone resulted in the down-regulation of IL-6, G-CSF, and GM-CSF in both normal and myeloma MPC cultures. However, dexamethasone treatment significantly increased expression of SCF-1 in myeloma MPCs. CONCLUSIONS: In myeloma, bone marrow stromal cells provide paracrine factors, through cytokine production and cell-cell contact, which play a role in plasma cell growth and survival. The authors' data indicate differences in bone marrow MPCs, which may be biologically relevant to the growth and survival of myeloma plasma cells.
Assuntos
Células da Medula Óssea/metabolismo , Mesoderma/metabolismo , Mieloma Múltiplo/metabolismo , Células-Tronco/metabolismo , Adulto , Idoso , Antígenos CD/análise , Antineoplásicos Hormonais/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Ciclo Celular , Divisão Celular , Células Cultivadas , Citocinas/metabolismo , Dexametasona/farmacologia , Ensaio de Imunoadsorção Enzimática , Técnica Indireta de Fluorescência para Anticorpo , Substâncias de Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Integrinas/análise , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.
Assuntos
Leucemia Megacarioblástica Aguda/terapia , Adolescente , Adulto , Idoso , Antraciclinas/administração & dosagem , Antígenos/análise , Antígenos CD7/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Plaquetas/imunologia , Medula Óssea/patologia , Antígenos CD2/análise , Aberrações Cromossômicas , Cromossomos Humanos Par 3 , Citarabina/administração & dosagem , Feminino , Humanos , Imunofenotipagem , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Peroxidase/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
The prognosis for patients with acute myeloid leukemia in first relapse is generally poor. The ability to induce a second complete remission (CR) with the same chemotherapy used in initial induction therapy is limited. Remission inversion rate, defined as achieving a longer second CR than the first CR in response to standard chemotherapy for relapse, is important in assessing studies of novel chemotherapy or immunologic treatment strategies for patients with relapsed disease. One hundred and twenty-four patients entered on two Eastern Cooperative Oncology Group (ECOG) studies for patients with relapsed AML were analyzed to determine the remission inversion rate. Twenty-two of the 124 patients (18%; 95% confidence interval 12-26%) experienced a longer second CR duration than the first CR duration by at least 2 months. Inversion of CR duration is thus not a rare event. The inversion frequency reported here establishes a baseline upon which future studies in relapsed disease need to be defined.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Indução de Remissão , Doença Aguda , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de SobrevidaRESUMO
The Eastern Cooperative Oncology Group (ECOG) conducted a prospective phase III study in patients with relapsed/refractory acute myeloid leukemia (AML) to evaluate whether administration of repeated courses of low-dose cytarabine (LDAC) maintenance therapy after induction of complete remission in advanced AML would improve disease-free and overall survival. Patients with AML in second/later relapse or refractory disease were first treated with a combination of high-dose cytarabine and amsacrine. Those who achieved complete remission were then randomized to observation or to receive LDAC, 10 mg/m2 subcutaneously twice a day x2 21 days every 2 months until relapse occurred. Of 86 patients eligible for randomization, 41 patients were assigned to receive LDAC and 45 patients to observation. The median disease-free survival was 7.4 months for patients assigned to LDAC compared to 3.3 months for patients receiving no additional therapy, P= 0.084. The median survival from randomization was 10.9 months and 7.0 months for patients receiving LDAC maintenance chemotherapy and observation, respectively (P= 0.615). The data from this study suggest that LDAC maintenance therapy given to patients with advanced AML who achieve complete remission can increase disease-free survival compared to observation, but does not improve overall survival. Nevertheless, because of the ineffectiveness and toxicity of intensive post-remission chemotherapy in this circumstance, LDAC maintenance therapy, a tolerable outpatient regimen, offers the potential for improved quality of life.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Indução de RemissãoRESUMO
Bone involvement is a central feature of multiple myeloma (MM). We investigated whether serum markers of osteoblastic and osteoclastic activity correlate with the presence of bone disease and survival in 313 MM patients enrolled in a phase III trial (E9486). Five markers were measured, including osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), bone alkaline phosphatase (BAP), carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). We analysed the relationship between serum levels of these markers and the presence of bone manifestations, and survival. Serum levels of ICTP and BAP correlated significantly with bone pain, lesions and fractures. Serum level of ICTP was also higher in stage II-III compared with stage I disease. The serum level of ICTP was significantly associated with shortened survival in the univariate analysis. The median survival times were 4.1 and 3.5 years for low and high ICTP respectively (P = 0.02). There was a strong relationship between ICTP and beta-2-micrgolobulin (B2M). ICTP stands out as a significant marker of bone disease. Incorporation of these markers into clinical trials assessing the use of bisphosphonates in MM is needed to determine whether they might serve as indicators of effectiveness of these agents.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Colágeno/sangue , Mieloma Múltiplo/sangue , Peptídeos/sangue , Fosfatase Ácida/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/mortalidade , Colágeno Tipo I , Intervalo Livre de Doença , Feminino , Glicoproteínas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/mortalidade , Análise Multivariada , Osteocalcina/sangue , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1, 000 mg/m(2). Fludarabine 20 mg/m(2) was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m(2)), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1, 000 mg/m(2) day 1 and fludarabine 20 mg/m(2) days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Vidarabina/toxicidadeRESUMO
PURPOSE: A randomized phase III clinical trial of adjuvant active specific immunotherapy (ASI) with an autologous tumor cell-bacillus Calmette-Guérin (BCG) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients. PATIENTS AND METHODS: Patients (n = 412) with colon cancer (297 with stage II disease, 115 with stage III disease) were randomly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 10(7) irradiated autologous tumor cells beginning approximately 4 weeks after surgery. The first two weekly injections also contained 10(7) BCG organisms. Patients were observed for determination of time to recurrence and disease-free and overall survival. RESULTS: This was a negative study in that after a 7.6-year median follow-up period, there were no statistically significant differences in clinical outcomes between the treatment arms. However, there were disease-free survival (P =.078) and overall survival (P =.12) trends in favor of ASI when treatment compliance was evaluated, ie, patients who received the intended treatment had a delayed cutaneous hypersensitivity (DCH) response to the third vaccination (induration >/=5 mm). Also, the magnitude of the DCH response correlated with improved prognosis. The 5-year survival proportion was 84.6% for those with indurations greater than 10 mm, compared with 45.0% for those with indurations less than 5 mm. CONCLUSIONS: When all randomized patients were evaluated, no significant clinical benefit was seen with ASI in surgically resected colon cancer patients with stage II or III colon cancer. However, there was an indication that treatment compliance with effective immunization results in disease-free and overall survival benefits.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Neoplasias do Colo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented.
Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Pulmonares/diagnóstico , Programas de Rastreamento , Neoplasias Ovarianas/diagnóstico , Neoplasias da Próstata/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Neoplasias Colorretais/prevenção & controle , Feminino , Humanos , Neoplasias Pulmonares/prevenção & controle , Masculino , Estudos Multicêntricos como Assunto , Neoplasias Ovarianas/prevenção & controle , Neoplasias da Próstata/prevenção & controleRESUMO
Hypodiploid multiple myeloma is uncommon when assessed by DNA content flow cytometry, having been reported in less than 6% of patients with newly diagnosed multiple myeloma. Previous studies have shown these patients to be unresponsive to therapy and to have short survival. To address this further, we studied 349 of 504 patients eligible for Eastern Cooperative Oncology Group (ECOG) treatment trial E9486 and laboratory correlative study E9487 who had marrow mononuclear cells available for ploidy analysis. Marrow samples were studied by dual channel flow cytometry, using propidium iodide to measure the DNA content and kappa and lambda light chain antisera to identify the clonal cells. A DNA index < 0.95 was considered hypodiploid. Five patients (1.4%) were found to have hypodiploid DNA content in their marrow plasma cells. Three of the 5 patients with hypodiploid myeloma had a partial objective response to chemotherapy, which is not different from the overall objective response rate for all patients enrolled on E9486. All five patients with hypodiploid multiple myeloma died within 4 years from diagnosis, but these patients had a similar overall median survival (2.6 years) compared to the patients with diploid DNA content. Our studies confirm the poorer survival of patients with diploid versus hyperdiploid myeloma; we cannot confirm, however, the previously reported very poor outcome associated with hypodiploid myeloma using DNA content flow cytometry. Hypodiploid DNA content of plasma cells by flow cytometry may not be as ominous a factor as previously reported.