RESUMO
Allogeneic hematopoietic cell transplantation (alloHCT) is a life-saving technology that can cure otherwise incurable diseases, but imposes significant physiologic stress upon recipients. This stress leads to short-term toxicity and mid- to long-term physical function impairment in some recipients. Exercise interventions have demonstrated preliminary efficacy in preserving physical function in HCT recipients, but the role of these interventions prior to HCT (prehabilitative) is less known. We tested a 5- to 12-week, prehabilitative higher intensity home-based aerobic exercise intervention in a randomized study of alloHCT candidates. Of 113 patients screened, 34 were randomized to control or intervention groups, 16 underwent pre- and post-intervention peak oxygen consumption (VO2peak) testing, and 12 underwent pre- and post-intervention 6-min walk distance (6MWD) testing. No significant differences in VO2peak or 6MWD were seen pre- to post-intervention between intervention and control groups, but final numbers of evaluable participants in each group were too small to draw inferences regarding the efficacy of the intervention. We conclude that the design of our prehabilitative intervention was not feasible in this pilot randomized study, and make recommendations regarding the design of future exercise intervention studies in alloHCT.
Assuntos
Terapia por Exercício/métodos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Serviços de Assistência Domiciliar , Cuidados Pré-Operatórios/métodos , Adulto , Idoso , Exercício Físico/fisiologia , Terapia por Exercício/organização & administração , Estudos de Viabilidade , Feminino , Serviços de Assistência Domiciliar/organização & administração , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Projetos Piloto , Padrões de Prática Médica , Transplante Homólogo , Resultado do TratamentoRESUMO
Impaired cardiorespiratory fitness is associated with inferior survival in patients preparing to undergo hematopoietic cell transplantation (HCT). Exercise training based on short, higher intensity intervals has the potential to efficiently improve cardiorespiratory fitness. We studied home-based interval exercise training (IET) in 40 patients before autologous (N=20) or allogeneic (N=20) HCT. Each session consisted of five, 3 min intervals of walking, jogging or cycling at 65-95% maximal heart rate (MHR) with 3 min of low-intensity exercise (<65% MHR) between intervals. Participants were asked to perform sessions at least three times weekly. The duration of the intervention was at least 6 weeks, depending on each patient's scheduled transplantation date. Cardiorespiratory fitness was assessed from a peak oxygen consumption test (VO2peak) and a 6 min walk (6MWD) before and after the intervention period. For the autologous HCT cohort, improvements in VO2peak (P=0.12) and 6MWD (P=0.19) were not statistically significant. For the allogeneic cohort, the median VO2peak improvement was 3.7 ml/kg min (P=0.005) and the median 6MWD improvement was 34 m (P=0.006). Home-based IET can be performed before HCT and has the potential to improve cardiorespiratory fitness.
Assuntos
Aptidão Cardiorrespiratória/fisiologia , Exercício Físico/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Serviços de Assistência Domiciliar , Idoso , Feminino , Frequência Cardíaca , Transplante de Células-Tronco Hematopoéticas/mortalidade , Treinamento Intervalado de Alta Intensidade/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , CaminhadaRESUMO
The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Neoplasias Meníngeas , Segunda Neoplasia Primária , Sarcoma Mieloide , Neoplasias Cutâneas , Adolescente , Adulto , Idoso , Aloenxertos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/terapia , Sarcoma Mieloide/mortalidade , Sarcoma Mieloide/terapia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapiaRESUMO
PURPOSE: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. PATIENTS AND METHODS: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. RESULTS: Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. CONCLUSION: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.
Assuntos
Antineoplásicos/farmacocinética , Proteína Quinase CDC2/antagonistas & inibidores , Leucemia/tratamento farmacológico , Masoprocol/análogos & derivados , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Química Farmacêutica , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Testes de Função Hepática , Masculino , Masoprocol/administração & dosagem , Masoprocol/efeitos adversos , Masoprocol/farmacocinética , Dose Máxima Tolerável , Pessoa de Meia-Idade , Polietilenoglicóis/química , Indução de RemissãoRESUMO
Despite overall improvements in outcomes of patients with diffuse large B cell lymphoma (DLBCL), â¼30-40% of patients develop relapsed or refractory disease. For patients with chemo refractory disease, or recurrent disease following autologous hematopoietic SCT (auto-HCT), the prognosis is poor, with no consensus on the optimal therapy. Currently, owing to the graft vs lymphoma effect, hematopoietic allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative option for such patients. In addition, many patients who are considered today for auto-HCT actually have a low likelihood of benefit. For example, a patient with prior rituximab exposure who relapses within 1 year of diagnosis and has a second-line age-adjusted International Prognosis Index of 2 or 3 at relapse has a <25% chance of being cured by auto-HCT. It is possible that such patients may be better served with an allo-HCT. Unfortunately, in many cases, allo-HCT applicability is limited by patient age, comorbidities, performance status and treatment-related toxicities. Recent attempts to improve the efficacy of auto-HCT, such as incorporating radio-immunotherapy into the conditioning regimen, have not resulted in improved outcomes. However, incorporation of novel agents such as anti-programmed death-1 antibodies as maintenance therapy after auto-HCT show promise. Allo-HCT in relapsed/refractory DLBCL patients can result in a 30-40% PFS rate at 3 years, in part due to a graft vs DLBCL effect. While reduced-intensity/non-myeloablative conditioning is increasingly being used, certain patients may benefit from myeloablative conditioning. We present an algorithm intended to discriminate which relapsed and refractory DLBCL patients are most likely to benefit from auto-HCT vs allo-HCT. New approaches, using novel agents that target the molecular heterogeneity in DLBCL, will be an essential component of moving the field forward. Lastly, we propose a prospective registry-based study as the only feasible mechanism to define the optimal position of allo-HCT in the overall treatment strategy for DLBCL. It is hoped that this review will promote the development of prospective multicenter efforts to determine whether such patients do, in fact, benefit from earlier and/or more effective implementation of allo-HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/terapia , Algoritmos , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Efeito Enxerto vs Tumor , Humanos , Imunoterapia/métodos , Prognóstico , Recidiva , Sistema de Registros , Rituximab , Terapia de Salvação , Fatores de Tempo , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
The effectiveness of stem cell mobilization with G-CSF in lymphoma patients is suboptimal. We reviewed our institutional experience using chemomobilization with etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and G-CSF (5 µg/kg twice daily from day +3 through the final day of collection) in 159 patients with lymphoma. This approach resulted in successful mobilization (>2 × 10(6) CD34+ cells collected) in 94% of patients (83% within 4 apheresis sessions). Fifty-seven percent of patients yielded at least 5 × 10(6) cells in îº2 days and were defined as good mobilizers. The regimen was safe with a low rate of rehospitalization. Average costs were $14 923 for good mobilizers and $27 044 for poor mobilizers (P<0.05). Using our data, we performed a 'break-even' analysis that demonstrated that adding two doses of Plerixafor to predicted poor mobilizers at the time of first CD34+ cell count would achieve cost neutrality if the frequency of good mobilizers were to increase by 21%, while the frequency of good mobilizers would need to increase by 25% if three doses of Plerixafor were used. We conclude that chemomobilization with etoposide and G-CSF in patients with lymphoma is effective, with future opportunities for cost-neutral improvement using novel agents.
Assuntos
Antineoplásicos Fitogênicos , Etoposídeo , Mobilização de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/economia , Doença de Hodgkin , Linfoma não Hodgkin , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/economia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/economia , Autoenxertos , Benzilaminas , Custos e Análise de Custo , Ciclamos , Etoposídeo/administração & dosagem , Etoposídeo/economia , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/economia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/economia , Doença de Hodgkin/economia , Doença de Hodgkin/terapia , Humanos , Linfoma não Hodgkin/economia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
Infection remains an important cause of morbidity and mortality after bone marrow or stem cell transplantation. To evaluate the role of obtaining blood cultures for intermittent or persistent fever in neutropenic patients on antibiotic therapy, we performed a retrospective chart review of 196 consecutive patients admitted to the Bone Marrow Transplant Unit at the University of North Carolina Hospitals from 1995 to 1998. From the cohort of 196 patients, 154 patients developed neutropenic fever. The initial blood culture was positive in 16 of 145 patients during the first fever episode giving a prevalence of 11%. From the total of 109 patients that had blood cultures drawn after day 1 of fever, five patients had blood cultures positive for a pathogen, a prevalence of 4.6%. In only one patient, did blood cultures drawn after day 1 identify an organism not present on day 1 (prevalence 0.9%). After reviewing the results in the first 105 patients, we changed our timing of collection of blood cultures. Forty-nine patients were treated in this manner and we found that the mean number of blood cultures decreased from 9.2 to 4.7 per patient without a change in the frequency of infectious complications or length of hospitalization.
Assuntos
Bacteriemia/diagnóstico , Técnicas Bacteriológicas/estatística & dados numéricos , Transplante de Medula Óssea , Neutropenia/microbiologia , Neutropenia/terapia , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Técnicas Bacteriológicas/economia , Técnicas Bacteriológicas/métodos , Sangue/microbiologia , Criança , Pré-Escolar , Estudos de Coortes , Meios de Cultura , Feminino , Febre/tratamento farmacológico , Febre/microbiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Autologous transplantation is increasingly used to treat epithelial ovarian cancer. However, it is not clear which patients may benefit. OBJECTIVE: To determine overall and progression-free survival and factors associated with favorable outcome after autotransplantation for ovarian cancer. DESIGN: Observational cohort study. SETTING: 57 centers reporting to the Autologous Blood and Marrow Transplant Registry (ABMTR). PATIENTS: 421 women who received transplants between 1989 and 1996. INTERVENTIONS: High-dose chemotherapy using diverse regimens with hematopoietic stem-cell rescue. MEASUREMENTS: Primary outcomes were progression-free survival and overall survival. Multivariate analyses using Cox proportional hazards regression considered the following factors: age, Karnofsky performance score, initial stage, histologic characteristics, previous therapy, remission status, extent of disease, graft source, transplant regimen, and year of transplantation. RESULTS: Most patients had extensive previous chemotherapy. Forty-one percent had platinum-resistant tumors, and 38% had tumors at least 1 cm in diameter. Only 34 patients (8%) received transplants as part of initial therapy. The probability of death within 100 days was 11% (95% CI, 8% to 14%). Two-year progression-free survival was 12% (CI, 9% to 16%), and 2-year overall survival was 35% (CI, 30% to 41%). Younger age, Karnofsky performance score of at least 90%, non-clear-cell disease, remission at transplantation, and platinum sensitivity were associated with better outcomes. Progression-free and overall survival were 22% (CI, 12% to 33%) and 55% (CI, 42% to 66%), respectively, for women with a high Karnofsky performance score and non-clear-cell, platinum-sensitive tumors. CONCLUSIONS: Some subgroups of patients with ovarian cancer seem to have good outcomes after autotransplantation, although several biases may have affected these observations. Phase III trials are needed to compare such outcomes with outcomes of conventional chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/terapia , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma/mortalidade , Estudos de Coortes , Terapia Combinada , Interpretação Estatística de Dados , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estadiamento de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Indução de Remissão , Taxa de Sobrevida , Transplante AutólogoRESUMO
HLA-identical bone marrow or stem cell transplantation from a sibling is the preferred treatment for patients with chronic myelogenous leukemia, bone marrow failure syndromes, relapsed acute leukemia, and specific inborn errors of metabolism. Several groups have shown that granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells (PBPCs) obtained from HLA-matched siblings are effective in reconstitution of marrow function after marrow ablative conditioning therapy. To evaluate whether G-CSF treatment before bone marrow harvest leads to enhanced recovery of PBPC counts and recovery from limited graft-versus-host disease (GVHD), we assessed the outcome of a sequential cohort of patients treated identically and then given either G-CSF--mobilized PBPCs or G-CSF--stimulated bone marrow from HLA-identical siblings. We show that the time to neutrophil engraftment is identical in the 2 cohorts, whereas platelet engraftment is earlier with the use of PBPCs. The incidence of acute GVHD was decreased, and that of chronic GVHD significantly decreased, in the group receiving bone marrow. Overall survival was not different between the 2 groups. Thus, G-CSF--stimulated bone marrow offers a source of stem cells that allows for early neutrophil engraftment with a decreased risk of GVHD.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Células Sanguíneas , Células da Medula Óssea , Criança , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade , Neoplasias/terapia , Análise de Sobrevida , Transplante HomólogoRESUMO
The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.
Assuntos
Antígenos CD34/sangue , Preservação de Sangue , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucaférese/economia , Linfoma/terapia , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Plaquetas/imunologia , Contagem de Células , Criopreservação , Feminino , Sobrevivência de Enxerto , Mobilização de Células-Tronco Hematopoéticas , Humanos , Linfoma/economia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Contagem de Plaquetas , Transfusão de Plaquetas , Estudos Prospectivos , Transplante Autólogo/economiaRESUMO
In the 1980s it became clear that low numbers of primitive hematopoietic cells were present in the peripheral bloodstream. Early clinical trials by investigators in the USA, Australia, and Germany demonstrated that these cells could be collected and reinfused to support high-dose chemotherapy procedures in patients otherwise unable to undergo bone marrow collection, usually because of prior pelvic irradiation. It was, however, difficult to obtain adequate numbers of stem cells from patients in the steady state. It was not until the demonstration by Socinski in Boston and Gianni in Milan that these circulating cells were markedly increased following the administration of either cytokines, chemotherapy, or a combination of both that the use of peripheral blood stem cells over bone marrow began to be widely undertaken. Since that time, peripheral blood stem cell collection has become the preferred means of stem cell support for high-dose chemotherapy because of the reduction in time to neutrophil and platelet engraftment, reduction in the number of transfusions and hospital stay, and an apparent reduction in tumor cell contamination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hematológicas/terapia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Terapia Combinada , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Células-Tronco Hematopoéticas/patologia , HumanosRESUMO
This randomized study compared the number of leukaphereses required to collect an optimal target yield of 5 x 10(6) CD34(+) peripheral blood progenitor cells/kg, using either stem cell factor (SCF) at 20 micrograms/kg/d in combination with Filgrastim at 10 micrograms/kg/d or Filgrastim alone at 10 micrograms/kg/d, from 203 patients with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield of CD34(+) cells had been reached or a maximum of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the patients treated with SCF plus Filgrastim (n = 100) compared with 47% of those receiving Filgrastim alone (n = 103) reached the CD34(+) cell target yield. There was a clinically and statistically significant reduction (P <.05) in the number of leukaphereses required to reach the target yield for the patients receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with patients receiving Filgrastim alone (median, 6 or more leukapherses; ie, <50% of patients reached the target in 5 leukaphereses). All patients receiving SCF were premedicated with antihistamines, albuterol, and pseudoephedrine. Treatment was safe, generally well tolerated, and not associated with life-threatening or fatal toxicity. In conclusion, SCF plus Filgrastim is a more effective peripheral blood progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In addition to the potential for reduced leukapheresis-related morbidity and costs, SCF offers additional options for obtaining cells for further graft manipulation.
Assuntos
Neoplasias da Mama/terapia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Fator de Células-Tronco/uso terapêutico , Adulto , Antígenos CD/sangue , Antígenos CD34/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Filgrastim , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Leucaférese , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas RecombinantesRESUMO
Recent advances in hematopoietic support have extended the application of high-dose chemotherapy in the treatment of malignancy. The use of colony-stimulating factors and peripheral blood progenitor cells significantly have decreased the morbidity and mortality of such treatment compared with traditional autologous bone marrow transplantation. These innovations facilitate the use of multiple cycles of high-dose chemotherapy as consolidation after achieving best response to conventional chemotherapy or as initial treatment. Developing data suggest that this approach in both of these settings merit further evaluation for the treatment of epithelial ovarian carcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores Estimuladores de Colônias/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Esquema de Medicação , Feminino , HumanosRESUMO
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer deaths in the United States. The combination of more active agents like vinorelbine and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with cisplatin has led to improved survival for patients with advanced metastatic disease. The ability to escalate the dose of cisplatin-based regimens is limited by nonhematologic toxicities and is especially difficult in the population of patients with advanced NSCLC. However, the development of new agents with significant activity against NSCLC as well as new strategies for high-dose therapy have made it possible to examine the potential of dose-intense therapy in this population. A phase I trial performed at the University of North Carolina was designed to evaluate paclitaxel 250 mg/m2 given over 24 hours plus escalating doses of carboplatin starting at an area under the concentration-time curve (AUC) dose of 8 supported by peripheral blood stem cells and filgrastim in the treatment of advanced NSCLC. The AUC dose of carboplatin was escalated in increments of 2. The maximum tolerated dose of carboplatin combined with paclitaxel 250 mg/m2 administered over 24 hours was defined at an AUC of 18. In this study, six of seven patients with advanced NSCLC had major responses. This regimen is currently being tested in patients with locally advanced NSCLC by the Cancer and Leukemia Group B: patients receive two cycles of induction therapy with paclitaxel 250 mg/m2 over 3 hours followed by carboplatin at an AUC of 18 supported by peripheral blood stem cells and filgrastim. Depending on response to induction therapy, patients then receive surgical resection, thoracic radiation therapy, or both. This phase II trial will examine clinical and pathologic responses and the toxicity of this high-dose regimen in patients with locally advanced NSCLC. Ultimately, phase III trials will be needed to establish the role of this approach in NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Ensaios Clínicos como Assunto , Terapia Combinada , Esquema de Medicação , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Paclitaxel/farmacocinética , Proteínas RecombinantesRESUMO
Bone marrow transplantation (BMT) is increasingly used in the treatment of hematologic malignancies, solid tumors, and congenital diseases. The number of patients receiving a BMT increased from approximately 5000 in 1989 to 12,000 in 1995. Infectious complications are the most common cause of morbidity and mortality in the peritransplant period in patients undergoing autologous BMT. Additionally, infectious complications are a serious cause of complications in recipients of matched sibling allogeneic BMT, unrelated BMT, and related mismatched BMT.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Controle de Infecções/métodos , Antibacterianos/uso terapêutico , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/prevenção & controle , Ensaios Clínicos como Assunto , Infecção Hospitalar/prevenção & controle , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/prevenção & controle , Humanos , Hospedeiro Imunocomprometido , Micoses/diagnóstico , Micoses/prevenção & controle , Viroses/diagnóstico , Viroses/prevenção & controleRESUMO
The graft-versus-leukemia effect is critical to the maintenance of remission in patients transplanted for the treatment of chronic myelogenous leukemia (CML). A pivotal issue in transplantation for CML is whether donor lymphocytes are specific for host tumor or myeloid cells or a subset of the lymphocytes that cause graft-versus-host disease. We have enrolled seven patients in an experimental trial to evaluate the specificity of HLA-matched donor lymphocytes in vitro. We have produced 11 CD4+ cytotoxic and proliferative T-cell clones from five of the donors that only lyse or proliferate to leukemic myeloid cells. These T lymphocytes do not react with interleukin (IL)-2-stimulated blasts, natural killer-sensitive targets, donor neutrophils, or bcr-abl+ EBV-lymphoblastoid cell lines. We show that the addition of the cytokines IL-7 and IL-12 during the production of T-cell clones enhances the recovery of myeloid-specific clones in vitro. Five of the myeloid-specific clones that we produced maintained specificity over 12 weeks in culture. Adoption of this method should allow for the expansion and in vivo testing of CML-specific CD4+ T-cell clones in adoptive immunotherapy.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunoterapia Adotiva/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Imunologia de Transplantes , Adulto , Linfócitos T CD4-Positivos/citologia , Feminino , Citometria de Fluxo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
We infused peripheral blood stem cells (PBSC) into 51 patients with various malignant disorders, after myeloablative conditioning. Twenty-four patients also received autologous bone marrow (PBSC + BM). In a multivariate analysis, the only statistically significant predictors of neutrophil engraftment were log-dose CFU-GM (P < 0.001) and the number of prior chemotherapy regimens (P = 0.004). The factors predicting RBC and platelet engraftment were log-dose CFU-GM (P = 0.002), PBSC + BM infusion (P = 0.007) and the absence of neoplastic bone marrow involvement (P = 0.009). Seven patients remained platelet and/or red cell transfusion-dependent for 100 days or more post-transplant after good neutrophil recovery. Six of these seven long-term engraftment failures, as well as five additional patients, received < 10(5) CFU-GM/kg. Of the 11 patients who received < 10(5) CFU-GM/kg (low-dose patients), seven were PBSC recipients, of whom six were long-term engraftment failures. In contrast, there were no long-term engraftment failures among the four low-dose autologous marrow recipients. This difference in long-term engraftment failure rate was significant (P = 0.015). The low-dose PBSC patients all had a diagnosis of lymphoma with bone marrow involvement. The low-dose PBSC + BM group was more heterogeneous, but no patient had malignant involvement of the marrow. The low-dose PBSC patients had also received significantly more prior chemotherapy regimens than the low-dose PBSC + BM patients and a significantly higher proportion received total body irradiation (TBI) as part of their conditioning regimen. We conclude that marrow damage resulting from a combination of neoplastic infiltration, chemotherapy and TBI may result not only in low PBSC yields but also in an impaired capacity of the marrow microenvironment to support transplanted stem cells.
Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Condicionamento Pré-Transplante , Adulto , Idoso , Ensaio de Unidades Formadoras de Colônias , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Tempo , Transplante AutólogoRESUMO
An essential component of combination high-dose chemotherapy and irradiation for the treatment of a variety of solid and hematologic malignancies is the ability to collect and reinfuse large numbers of peripheral blood progenitor cells (PBPCs). The reinfused PBPCs are used to replace pluripotent hematopoietic stem cells after marrow ablative therapy and to potentiate earlier blood cell count recovery after myelosuppressive (but not truly ablative) treatment. The PBPCs are mobilized from the marrow compartment into the peripheral bloodstream after treatment with chemotherapy, granulocyte colony-stimulating factor, or both. A number of single and combination chemotherapeutic agents have been used to mobilize PBPCs. In administering these agents, a balance must be found in all cases between effective PBPC mobilization and possible damage to the hematopoietic stem cell pool and overall patient tolerance. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) causes no thrombocytopenia or cumulative hematopoietic toxicity and was found to effectively mobilize PBPCs without damaging the stem cell pool. Paclitaxel has the additional advantage of not causing the bladder toxicity seen with cyclophosphamide. Its antitumor effectiveness in breast and ovarian cancer makes it an especially useful component of therapy for both pretreatment cytoreduction as well as PBPC mobilization in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Paclitaxel/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Trombocitopenia , Condicionamento Pré-TransplanteRESUMO
The treatment of non-small-cell lung cancer (NSCLC) has recently undergone major changes due to the availability of new drugs that demonstrate substantial activity in NSCLC patients. Although cure for the majority of stage III NSCLC and effectively all stage IV disease patients remains rare, a number of compounds, including carboplatin, paclitaxel, docetaxel, irinotecan, and vinorelbine, have proved useful in the treatment of these patients. Together with a number of phase II trials, phase I trials utilizing escalating doses of carboplatin and paclitaxel with growth factor or growth factor and blood stem-cell support have shown that substantial increases in dose intensity can be achieved. These studies in small numbers of patients have demonstrated that these regimens have encouraging activity and have formed the basis of a Cancer and Leukemia Group B (CALGB) phase II pilot study. This study will utilize two cycles of high-dose carboplatin and Taxol given at an AUC dose of 18 and a 24-h infusion dose of 250 mg/m2, respectively, with growth factor and stem-cell support to treat stage III NSCLC patients. Patients will also receive multimodality therapy, including radiation with or without surgery. It is hoped that this effort to intensify treatment in patients with limited-stage disease will improve survival and benefit the large number of patients with stage III tumors. This paper outlines the phase I results that formed the basis of the CALGB trial and reviews several recent reports of phase II or phase III trials of single-agent and combination regimens for NSCLC.