RESUMO
Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.
Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Tacrolimo/uso terapêutico , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Humanos , Recidiva , Retratamento , Tiotepa/administração & dosagem , Topotecan/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaAssuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/cirurgia , Infecções Relacionadas à Prótese , Dispositivos de Acesso Vascular/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Cardiac complications of high-dose cytosine arabinoside (HiDAC), although rare, predominantly include pericarditis, pericardial effusion and cardiomyopathy (with concurrent use of cyclophosphamide). Clinically significant arrhythmias associated with HiDAC, although reported in the literature, are rare. The following case report has for the first time used the Naranjo Scale to document a high-probability association (definite adverse drug reaction) of cytarabine with symptomatic sinus bradycardia.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Bradicardia/induzido quimicamente , Bradicardia/diagnóstico , Citarabina/efeitos adversos , Eletrocardiografia , Bradicardia/fisiopatologia , Citarabina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 10(7) /kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51-76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.
Assuntos
Sangue Fetal/transplante , Leucemia/terapia , Síndromes Mielodisplásicas/terapia , Doença Aguda , Adolescente , Adulto , Plaquetas/patologia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Estimativa de Kaplan-Meier , Leucemia/imunologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Neutrófilos/patologia , Estudos Prospectivos , Recidiva , Condicionamento Pré-Transplante/métodos , Adulto JovemAssuntos
Antineoplásicos/administração & dosagem , Obstrução do Cateter/etiologia , Infecções Relacionadas a Cateter/microbiologia , Cateterismo Venoso Central/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Trombose Venosa/etiologia , Administração Intravenosa , Infecções Relacionadas a Cateter/diagnóstico , Cateterismo Venoso Central/instrumentação , Cateteres de Demora , Cateteres Venosos Centrais , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oklahoma , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Resultado do Tratamento , Trombose Venosa/diagnósticoAssuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Sarcoma Mieloide/patologia , Obstrução do Colo da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/patologia , Injúria Renal Aguda/genética , Feminino , Humanos , Sarcoma Mieloide/genética , Obstrução do Colo da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
The Ewing's family of tumors (EFT) comprises a molecularly defined group of "small round blue cell tumors", consisting of Ewing's sarcoma of bone (ESB), extraosseous Ewing's sarcoma (EES), peripheral primitive neuroectodermal tumor (pPNET), and Askin's tumor. Characteristic translocations that disrupt the EWSR1 gene located at 22q12 create novel fusion genes that are central to the pathogenesis. The EFT also shares certain clinical characteristics, such as a peak incidence during the teenage years, a tendency to spread rapidly, and responsiveness to the same chemotherapeutic regimens and radiation therapy. Nearly all patients have occult disseminated disease at diagnosis; hence, chemotherapy is routinely used. Improvements in multimodality treatment have had a dramatic impact on outcomes. EES/pPNET has been reported in a variety of sites, including the pancreas, though this is extremely rare. We describe a case of pancreatic EES/pPNET in a 35-year-old woman and provide a brief review of the relevant literature.
Assuntos
Terapia Combinada , Tumores Neuroectodérmicos Primitivos , Neoplasias Pancreáticas , Sarcoma de Ewing , Adulto , Proteínas de Ligação a Calmodulina/genética , Cromossomos Humanos Par 22 , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Estadiamento de Neoplasias , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/patologia , Tumores Neuroectodérmicos Primitivos/cirurgia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia , Translocação GenéticaRESUMO
The diagnosis of leptomeningeal carcinomatosis remains difficult despite improvement in central nervous system (CNS) imaging and cytologic examination of the cerebral spinal fluid. False-negative results are common, providing obstacles in assessing both prophylactic and therapeutic efforts. As a result of increased survival of patients with a variety of systemic neoplasms it is likely that central nervous involvement will need to be addressed more often. This article presents a patient with a diffuse large B-cell lymphoma with polymorphic features. Imaging using 18F-labeled fluorodeoxythymidine (FLT) proved useful in demonstrating both parenchymal and leptomeningeal CNS involvement. The potential for FLT to identify proliferative tissue may make it uniquely suitable for detection of CNS malignant disease.
Assuntos
Didesoxinucleosídeos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Neoplasias Meníngeas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Cyclosporine is commonly used as an immunosuppressive agent in both solid organ and bone marrow transplant. While used for graft rejection in organ transplantation, cyclosporine has been used to enable tolerance and for prevention of acute graft-versus-host disease in bone marrow transplant [Ratanatharathorn et al., Blood 1998;92:2303-2314]. Cyclosporine has a narrow therapeutic window, and many patients develop some level of toxicity even within the therapeutic range. Common toxicities include hypertension, nephrotoxicity, electrolyte abnormalities, hyperglycemia, and neurotoxicity [Woo et al., Bone Marrow Transplant 1997;20:1095-1098]. Management of cyclosporine toxicity is not clearly defined and is primarily supportive in nature. In cases of significant elevations of cyclosporine levels, limited data are available but suggest that whole blood exchange may be effective [Kwon et al., J Heart Lung Transplant 2006;25:483-485; Leitner et al., Transplantation 2003;75:1764-1765]. We present a case of successful rapid clearance of cyclosporine utilizing a combined approach of red cell exchange and plasma exchange.
Assuntos
Ciclosporina/intoxicação , Overdose de Drogas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Ciclosporina/uso terapêutico , Transfusão de Eritrócitos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores , Troca PlasmáticaRESUMO
Posaconazole is widely used for prophylaxis against invasive fungal infections in patients undergoing myeloablative therapy. Disseminated fusariosis is a serious invasive mold infection in such patients. Preclinical and clinical studies indicate activity of posaconazole against Fusarium. We describe two cases of disseminated fusariosis that occurred despite posaconazole prophylaxis.
Assuntos
Quimioprevenção/métodos , Fusarium/isolamento & purificação , Micoses/diagnóstico , Micoses/microbiologia , Triazóis/uso terapêutico , Adulto , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Micoses/prevenção & controleRESUMO
BACKGROUND: Radiotherapy (RT) and chemotherapy are important treatment modalities for a variety of malignant tumor types. During therapy for malignant diseases, often the limitation for further therapy is determined by the capability of the bone marrow to withstand radiochemotherapeutic effects. Evaluation of hematologic toxicity is commonly performed with peripheral blood counts, and occasionally, sampling of marrow through a bone marrow biopsy. Neither method provides a comprehensive assessment, as bone marrow biopsy is invasive, and both are subject to sampling variability. Fluorine-18-3'-fluoro-3'-deoxy-L-thymidine-PET (18F-FLT-PET) is a noninvasive method and related to the rate of DNA synthesis and visualizes the high cycling activity of hematopoietic cells in the bone marrow compartment. To prove the clinical consistency of marrow function and imaging, we investigated populations of patients typically seen in clinical practice, after radiation and chemotherapy. In this feasibility study, patients were evaluated (i) to prove the ability of visualization and quantification of the activity of the bone marrow compartment with 18F-FLT-PET and (ii) to examine the effect of RT and chemotherapy on bone marrow activity and the correlation with clinical findings. METHODS: Bone marrow activity in the cervical region of 10 patients with laryngeal carcinoma who received a mean total dose of 68 Gy (range 30-41 fractions) was evaluated with 18F-FLT-PET, before and 1 month after RT. Whole body FLT images were assessed in nine patients with nonseminomatous testicular germ cell tumor, before and 6 months after the last chemotherapy, consisting of four courses of bleomycin, cisplatin, and etoposide. The maximum standardized uptake value (SUVmax) was used to quantify FLT uptake in bone marrow at the standard bone marrow regions. RESULTS: A significant decrease in 18F-FLT-PET uptake was observed in all the studied laryngeal carcinoma patients in the cervical region after RT of the adjacent bone marrow compartment. Tumor stage and additional field-of-view of RT were inversely related to the 18F-FLT uptake in bone marrow. The mean 18F-FLT SUVmax before RT was 3.0+/-1.34 and after RT was 1.94+/-0.60 (P=0.013). The mean 18F-FLT SUVmax of the spine (Th5-Th12) regions outside the field-of-view of RT were stable and reproducible and not significantly different (5.56+/-1.56 vs. 5.16+/-1.35, P=0.16). Chemotherapy did not result in a significant difference of whole body SUVmax value, with a mean SUVmax of 4.99+/-1.15 prechemotherapy, and a mean SUVmax of 5.28+/-1.0 postchemotherapy (P=0.21). Laboratory analysis of the hematologic parameters confirmed repopulation of the bone marrow. CONCLUSION: 18F-FLT uptake in the bone marrow decreases after RT, but not after chemotherapy. We conclude that 18F-FLT-PET is a potential noninvasive tool that can be used in the assessment of quantification of cellular division in the hematopoietic organ.
Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Didesoxinucleosídeos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Tomografia por Emissão de Pósitrons , Radioterapia/efeitos adversos , Adulto , Idoso , Estudos de Viabilidade , Humanos , Neoplasias Laríngeas/diagnóstico por imagem , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/radioterapia , Masculino , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/radioterapia , Estudos Retrospectivos , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/radioterapiaRESUMO
Serous atrophy or gelatinous transformation of the bone marrow (GMT), often seen with severe nutritional deprivation in Anorexia Nervosa (AN), is characterized by hypocellularity and patchy or diffuse replacement of the bone marrow with hyaluronic acid-like mucopolysaccharide material. Treatment with nutritional support alone is often temporary due to the relapsing nature of AN. We present the case of a patient with pancytopenia due to GMT who had multiple prior hospitalizations for infections and blood transfusions. Nutritional support was inadequate in restoring her bone marrow function. She was successfully treated with hematopoietic growth factors and achieved a sustained hematopoietic recovery. In addition, use of growth factors resulted in a 91% reduction in the cost of health care delivered to this patient.
Assuntos
Anorexia Nervosa/complicações , Doenças da Medula Óssea/tratamento farmacológico , Eritropoetina/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hematínicos/uso terapêutico , Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Pancitopenia/tratamento farmacológico , Adulto , Anorexia Nervosa/sangue , Anorexia Nervosa/patologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Doenças da Medula Óssea/etiologia , Doenças da Medula Óssea/patologia , Darbepoetina alfa , Eritropoetina/uso terapêutico , Feminino , Filgrastim , Humanos , Pancitopenia/etiologia , Pancitopenia/patologia , Polietilenoglicóis , Proteínas Recombinantes , Resultado do TratamentoAssuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 4 , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Aberrações Cromossômicas , Citogenética , Diagnóstico Diferencial , Humanos , Cariotipagem , Leucemia Linfocítica Crônica de Células B/terapia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Progress has been slow in defining molecular requirements for human B lymphopoiesis in part because of differences from experimental animals and also because of the lack of culture conditions that efficiently support the process. We recently found that human CD10+ lymphocytes were produced when CD34+ hematopoietic stem and progenitor cells were cultured in contact with human mesenchymal stem cells (hMSC). Further investigation revealed that it occurred even when progenitors were separated from hMSC by membrane filters. Experiments with neutralizing antibodies suggested that important heat labile factors produced by hMSC are unlikely to be IL-7, TSLP, CXCL12 or hemokinin-1. Further manipulation of culture conditions revealed that optimal lymphopoiesis required careful selection of fetal calf serum lots, maintenance of high cell densities, as well as recombinant cytokines (SCF, FL and G-CSF). G-CSF was particularly important when adult bone marrow rather than umbilical cord blood derived CD34+ cells were used to initiate the cultures. These improved methods should facilitate identification of molecules that can be used to speed regeneration of the humoral immune system following chemotherapy and might suggest ways to inhibit growth of B lineage malignancies.
Assuntos
Linfócitos B/citologia , Técnicas de Cocultura/métodos , Meios de Cultivo Condicionados/química , Linfopoese , Animais , Linfócitos B/imunologia , Separação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Camundongos , Camundongos SCID , Células Estromais , Transplante HeterólogoRESUMO
OBJECTIVE: The success of bone marrow transplantation in hematologic and oncologic diseases depends upon the ability to provide adequate hematologic and immunologic support in a timely manner. There is no current imaging tool for the evaluation of the bone marrow compartment in the peri-transplant period. In this study, we tested our hypothesis that whole-body positron emission tomography using fluorine-18 (F-18)-fluorothymidine has the ability to provide information about the functioning normal bone marrow and its physiologic distribution. METHODS: Wistar Furth rats were irradiated with 950 cGy followed 2 days later by syngeneic bone marrow transplantation. The animals were subjected to positron emission tomography using F-18-fluorothymidine imaging before and after ablation as well as after 4, 7, and 14 days after bone marrow transplantation. In a different set of syngeneic bone marrow transplant model, positron emission tomography using F-18-fluorodeoxyglucose was carried out for comparison. Imaging results were correlated with marrow histology upon necropsy. RESULTS: F-18-fluorothymidine images showed definitive recovery of marrow within 4 days after transplant. In contrast, F-18-fluorodeoxyglucose was unable to present a corresponding picture. Sternum and humerus marrow in the images were analyzed by drawing three-dimensional regions of interest to obtain quantitative uptake value of tracers, which corroborated the image data. CONCLUSION: We conclude that positron emission tomography using F-18-fluorothymidine offers a clinically useful noninvasive technique to evaluate bone marrow injury and recovery.
Assuntos
Transplante de Medula Óssea , Medula Óssea/diagnóstico por imagem , Didesoxinucleosídeos , Modelos Animais , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Didesoxinucleosídeos/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Endogâmicos WFAssuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ferro/uso terapêutico , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados , Bevacizumab , Quimioterapia Combinada , Ferritinas/sangue , Humanos , Infusões Intravenosas , Masculino , Telangiectasia Hemorrágica Hereditária/sangue , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
BACKGROUND: This study assesses the efficacy of epirubicin and docetaxel as neoadjuvant therapy for women with breast cancer. PATIENTS AND METHODS: This is a single institution, single arm, phase II study of epirubicin given at 75 mg/m(2) and docetaxel at 75 mg/m(2) every three weeks for four cycles prior to surgical excision in women with large breast cancers. Pegfilgrastim was routinely administered as primary prophylaxis against febrile neutropenia. RESULTS: Out of the 18 patients enrolled on the study, 12 (66.7%) had a clinical response and 13 (72.2%) had a pathologic response, with a pathologic complete response of 5.6%. Pre-menopausal women and patients with estrogen receptor positive tumors had a higher response rate. One patient died due to sepsis and febrile neutropenia. CONCLUSION: Combination chemotherapy with epirubicin and docetaxel is highly active against breast cancer. With close monitoring for toxicity, this combination can be safely administered with mild side-effects.