RESUMO
BACKGROUND: High-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation. PATIENTS AND METHODS: Between 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15-48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%). RESULTS: Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm-), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1-219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm- following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3-219 months). CONCLUSIONS: Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Transplante de Medula Óssea , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante , Adulto JovemRESUMO
BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Rabdomiossarcoma/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/mortalidade , Estudos Retrospectivos , Rabdomiossarcoma/mortalidade , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls. PATIENTS: HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients. RESULTS: After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05). CONCLUSION: We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.
Assuntos
Doadores de Sangue , Transplante de Medula Óssea , Neoplasias Ósseas/genética , Neoplasias Ósseas/terapia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Transplante de Células-Tronco Hematopoéticas , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Doadores de Tecidos , Adolescente , Adulto , Neoplasias Ósseas/patologia , Criança , Progressão da Doença , Feminino , Frequência do Gene , Genética Populacional , Alemanha , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Adulto JovemRESUMO
PURPOSE: The purpose of our study was to retrospectively evaluate the feasibility, toxicity and impact on overall (OS) and disease-free (DFS) survival of intra-arterial liver perfusion with mitomycin-C (MMC) [hypoxic liver perfusion with MMC (HLPM)] in patients with multifocal liver metastases or with unresectable primary liver tumours. MATERIALS AND METHODS: Forty-two patients underwent 56 intra-arterial liver infusions with MMC between June 2001 and May 2009. The patients presented specific characteristics, i.e. they were all refractory to locoregional (LR) and/or systemic treatments. HLPM consists of selective catheterisation of the common hepatic artery, permanent occlusion of the gastroduodenal artery at its origin using metal coils, an inflated balloon catheter placement at the origin of the proper hepatic artery to block blood flow and induce hypoxia for around 10 min, MMC infusion and vascular-bed occlusion through injection of an absorbable haemostatic agent. During the procedure, the patients received anaesthesiological monitoring. Biochemical and morphological responses were evaluated, as were haematological, hepatic and systemic toxicity. RESULTS: Patients were hospitalised for 10 days on average (range 7-15). Side effects were liver toxicity in all cases, acute pancreatitis in one case and liver failure in one case. Computed tomography performed at 30 days documented a partial response (PR) in 29%, stable disease (SD) in 45% and progressive disease (PD) in 26% of patients. The response lasted 4 months on average (range 3-6). Mean overall survival (OS) was 20 months for all patients, reaching 30 months in those with colorectal carcinoma. CONCLUSIONS: The procedure is feasible, and treatmentrelated toxicity and mortality rates are acceptable. It may be considered a palliative treatment option in patients with advanced liver disease in centres with adequately experienced medical teams.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Artéria Hepática , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Mitomicina/uso terapêutico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Hipóxia Celular , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Infusões Intra-Arteriais/métodos , Pacientes Internados , Tempo de Internação , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Metástase Neoplásica , Qualidade de Vida , Radiografia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The role of 18FDG-PET/CT during follow-up of patients affected by Hodgkin's lymphoma (HL) in complete remission after treatment is not fully elucidated, since a wide use of 18F fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) in this setting could be limited by a relative high rate of false-positive results. Herein, we summarize a retrospective analysis of 27 patients with Hodgkin's lymphoma in complete remission after the first-line (n = 20) or salvage (n = 7) therapy receiving serial 18FDG-PET/CT scans during follow-up. Out of 165 scans, 13 were suspected for relapse, which was confirmed in seven patients. All relapses were correctly identified by 18FDG-PET/CT positivity, with a 100% sensitivity; false-positive rate was 46% and negative predictive value was 100%. True-positive findings were mostly associated with multiple sites, subdiaphragmatic involvement, and/or previous sites of disease. According to our results, we conclude that performing routine PET/CT scan during follow-up of those patients who are at high risk of relapse would be advisable, although caution must be adopted when interpreting PET/CT results due to the relatively high rate of false-positive findings. If FDG abnormal uptake is present at multiple nodal sites, subdiaphragmatic lymph nodes, or previous sites of disease, histological verification of PET abnormal findings is warranted.
Assuntos
Fluordesoxiglucose F18 , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/prevenção & controle , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Hodgkin/patologia , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.
Assuntos
Antineoplásicos/uso terapêutico , Radioisótopos do Iodo/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Tolerância a Radiação , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Diferenciação Celular , Ensaios de Uso Compassivo , Progressão da Doença , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Fatores de Tempo , Adulto JovemRESUMO
We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.
Assuntos
Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Antineoplásicos/uso terapêutico , Neoplasias da Mama/mortalidade , Terapia Combinada , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Efeito Enxerto vs Tumor , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Metástase Neoplásica , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Transplante HomólogoRESUMO
The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkin's lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkin's disease (HD, n=32). Median follow-up was 33 months (range, 12-82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL.
Assuntos
Linfoma/terapia , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Humanos , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Tempo , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
A prospective multicenter program was performed to evaluate the combination of rituximab and high-dose (hd) sequential chemotherapy delivered with multiple autologous peripheral blood progenitor cell (PBPC) support (R-HDS-maps regimen) in previously untreated patients with diffuse large B-cell lymphoma (DLB-CL) and age-adjusted International Prognostic Score (aaIPI) score 2-3. R-HDS-maps includes: (i) three APO courses; (ii) sequential administration of hd-cyclophosphamide (CY), hd-Ara-C, both supplemented with rituximab, hd-etoposide/cisplatin, PBPC harvests, following hd-CY and hd-Ara-C; (iii) hd-mitoxantrone (hd-Mito)/L-Pam + 2 further rituximab doses; (iv) involved-field radiotherapy. PBPC rescue was scheduled following Ara-C, etoposide/cisplatin and Mito/L-Pam. Between 1999 and 2004, 112 consecutive patients aged <65 years (74 score 2, 38 score 3) entered the study protocol. There were five early and two late toxic deaths. Overall 90 patients (80%) reached clinical remission (CR); at a median 48 months follow-up, 87 (78%) patients are alive, 82 (73%) in continuous CR, with 4 year overall survival (OS) and event-free survival (EFS) projections of 76% (CI 68-85%) and 73% (CI 64-81%), respectively. There were no significant differences in OS and EFS between subgroups with Germinal-Center and Activated B-cell phenotype. Thus, life expectancy of younger patients with aaIPI 2-3 DLB-CL is improved with the early administration of rituximab-supplemented intensive chemotherapy compared with the poor outcome following conventional chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/terapia , Linfoma Difuso de Grandes Células B/terapia , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Estudos Prospectivos , Rituximab , Transplante Autólogo , Resultado do TratamentoRESUMO
Renal cell carcinoma (RCC) is particularly sensitive to immune intervention. HLA-G, a non-classical HLA class I molecule with immunomodulatory properties, has been studied with regard to outcome after hematopoietic stem cell transplantation (HSCT), in particular the 14 bp insertion/deletion polymorphism in the 3' untranslated region. Here we analyzed n=56 patients affected by metastatic RCC who received an allogeneic HSCT between 1998 and 2006 in Milano, Marseille, Clermont-Ferrand and Stockholm. The 14 bp polymorphism was analyzed in correlation with overall survival (OS), PFS, acute and chronic GvHD. With a median follow-up of 13 years, a trend towards better outcome was observed when homozygosity for the 14bp-del allele was present: multivariate hazard ratio was 0.50 (95% confidence interval (CI): 0.23-1.13; P=0.10) and 0.57 (95% CI: 0.26-1.26; P=0.17) for OS and PFS, respectively, when 14bp-del/del was compared with 14bp-ins/X. Further exploratory analysis revealed a significant association between T/C at p3003 and improved OS (P=0.05) and PFS (P=0.006) compared with T/T. To our knowledge this is the first study on HLA-G and outcome after HSCT for a solid malignancy. After a coordinated multicenter study, we found that the more tolerogenic polymorphisms (14bp-del/del) is associated with better PFS and OS. The finding on p3003 deserves further investigation.
Assuntos
Carcinoma de Células Renais/genética , Antígenos HLA-G/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Polimorfismo Genético/genética , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Older age and a previously failed autologous stem-cell transplantation (SCT) are poor prognostic factors for patients receiving myeloablative conditioning and allogeneic SCT. Reduced-intensity conditioning (RIC) regimens achieved a significant reduction of treatment-related mortality, but the influence of previously described risk factors on the outcome of this novel transplantation strategy have not been fully analyzed yet. PATIENTS AND METHODS: One hundred fifty patients with advanced hematologic malignancies received a RIC regimen containing thiotepa (10 mg/kg), fludarabine (60 mg/m2), and cyclophosphamide (60 mg/kg), followed by an allogeneic transplantation from an HLA-identical sibling donor. Patients were divided into two cohorts according to age; 90 patients were younger than 55 years, and 60 patients were 55 years old or older. The other pretransplantation characteristics were fairly balanced. RESULTS: Actuarial 5-year nonrelapse mortality (NRM) rate was not statistically different between the groups (13% in the younger group and 19% in the older group). By univariate and multivariate analysis, NRM was significantly higher in older patients who previously experienced failure with an autograft. The occurrence of grade 3 to 4 acute graft-versus-host disease (GVHD) or extensive chronic GVHD was associated with a higher NRM in both age cohorts. Overall survival (OS) was not statistically different between the younger (66%) and older groups (61%). By multivariate analysis, refractory disease was associated with a worse OS irrespective of age group. CONCLUSION: RIC transplantations show a rather low NRM, and age > or = 55 years per se cannot be considered a risk factor anymore. The timing of transplantation and novel strategies for the prevention of severe GVHD could further improve patient outcome.
Assuntos
Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Fatores Etários , Idoso , Análise de Variância , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/epidemiologia , Neoplasias Hematológicas/mortalidade , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Medição de Risco , Análise de Sobrevida , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
In October 2005, the second international meeting on allogeneic transplantation in solid tumors was convened in Stresa (Italy). The aim of this second meeting was to share clinical experiences of allografting in solid tumors, to discuss preclinical data on the mechanisms of graft-versus-tumor (GVT) effect, and to review methods for more efficacious transplant approaches. On the first day, the most recent results in cancer immunotherapy were reviewed; head-to head comparisons of clinical results achieved by standard therapy and by allografting in renal, breast, and ovarian cancer were presented. On the second day, GVT mechanisms and preclinical models were examined; anecdotal reports of a GVT effect in sarcoma, pancreatic cancer, prostate cancer, colorectal cancer and lung cancer were presented; new strategies for optimizing transplant outcome were discussed, including patient selection, tumor debulking, auto-allo approaches, selective T-cell depletion, targeting with monoclonal antibodies, use of killer cell immunoglobulin-like receptor-ligand mismatched natural killer cells. In conclusion, allografting in solid tumors is feasible with limited toxicities and transplant-related mortality; a GVT effect has been documented in many different solid tumors; targeting of the immune response to the tumor by new strategies and identification of the target antigen(s) of the GVT effect are promising areas of research.
Assuntos
Transplante de Medula Óssea/métodos , Neoplasias/terapia , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/imunologia , Humanos , Imunoterapia/métodos , Imunologia de Transplantes , Transplante Homólogo , Resultado do TratamentoRESUMO
We assessed mammaglobin (MMG) gene expression in bone marrow (BM) aspirates from patients with advanced breast cancer who had received a reduced-intensity conditioning and stem cell allografting, in order to detect a graft-versus-tumor effect on micrometastatic disease. Nine patients received a reduced-intensity conditioning with fludarabine, cyclophosphamide, and thiotepa, followed by peripheral blood allografting from HLA-identical sibling donors. Nested RT-PCR analysis with sequence-specific primers for MMG was carried out on a monthly basis on BM samples. Three patients had MMG-positive BM, four patients had MMG-negative BM before allografting, and two were undetermined. In two patients, a clinical response after allografting (partial remission) occurred concurrently with the clearance of MMG expression, at a median of 6 months after allografting, following immune manipulation. In two patients, a prolonged stable disease and negative MMG expression occurred after day +360 from allografting. In two patients, progression of the disease was associated with MMG RT-PCR changing from negative to positive. In one case, a disease response occurring after donor lymphocyte infusion and grade II acute GVHD was heralded by negativization of MMG expression. Although preliminary, these data suggest that a graft-versus-breast cancer effect is detectable on micrometastatic BM disease.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Medula Óssea/metabolismo , Medula Óssea/metabolismo , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Efeito Enxerto vs Tumor , Proteínas de Neoplasias/biossíntese , Uteroglobina/biossíntese , Adulto , Medula Óssea/patologia , Neoplasias da Medula Óssea/patologia , Neoplasias da Medula Óssea/secundário , Neoplasias da Medula Óssea/terapia , Transplante de Medula Óssea , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Ciclofosfamida/administração & dosagem , Feminino , Sobrevivência de Enxerto , Humanos , Mamoglobina A , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Valor Preditivo dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosAssuntos
Genes Virais , Marcadores Genéticos , Vetores Genéticos/efeitos adversos , Receptor de Fator de Crescimento Neural/análise , Retroviridae/genética , Animais , Transplante de Medula Óssea , Cães , Humanos , Leucemia/etiologia , Leucemia/prevenção & controle , Camundongos , Ratos , Transdução GenéticaRESUMO
A monoclonal antibody reactive with the immunoglobulin heavy chain (TEC IgM) has been conjugated to saporin-6 (SAP), which is the major ribosome-inactivating protein from the seeds of the plant Saponaria officinalis. Studies with Burkitt's lymphoma cell line Bjab 113 demonstrate that this immunotoxin is capable of killing 3 logs (99.9%) of clonogenic lymphoma cells after a 2-hour incubation. The presence of human bone marrow inhibits the activity of the conjugate. However, full potency of TEC IgM-SAP immunotoxin is restored by adding 1 mM amantadine to the incubation medium. The reaction is highly specific and is inhibited by the presence of excess anti-mu-antibody or human serum. Clonal growth of other Burkitt's lymphoma cell lines is inhibited to a lesser extent by the immunotoxin. The presence of surface IgM on the different cell lines is directly correlated to target cell killing by TEC IgM-SAP. Isolation of Bjab 113 clones surviving treatment demonstrates that only a minority are truly resistant and that the others randomly escape the treatment. The highly potent and specific activity of this conjugate in the presence of bone marrow buffy coat and its exceptionally rapid onset of action make this conjugate a good candidate for the ex vivo elimination of neoplastic cells from the bone marrow of non-Hodgkin's lymphoma patients.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Linfoma de Burkitt/patologia , Imunotoxinas/uso terapêutico , N-Glicosil Hidrolases , Proteínas de Plantas/administração & dosagem , Linfócitos B , Humanos , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Células Tumorais CultivadasRESUMO
Long-term bone marrow cultures were established from single-cell suspensions of human bone marrow that had been treated with monoclonal antibodies and complement. Each treated cell suspension was evaluated for production of hematopoietic stem cells over 20 weeks. Treatment with antibody to HLA-DR (Ia), B1, J2, or J5 did not remove adherent cells including those differentiating to adipocytes in 17-hydroxycorticosteroid. In contrast, treatment with monoclonal antibody directed against human beta 2-microglobulin reduced adipocyte numbers by 100-fold and reduced the total adherent cell density over 70%. Cumulative total nonadherent cell and granulocyte-macrophage colony-forming units (GM-CFUc) production over 20 weeks was not significantly altered by one cycle of anti-Ia plus complement or up to three cycles of treatment with complement and anti-J2, -J5, or -B1. However, one cycle of treatment with anti-beta 2-micro-globulin depressed production of both GM-CFUc and nonadherent cells by over 100-fold compared to other treatment groups. While one cycle of treatment of anti-Ia and complement killed all detectable cells forming CFU-erythroid-granulocyte-megakaryocyte-macrophage, blast-forming units (erythroid), and GM-CFUc, GM cluster-forming cells survived. Treatment of marrow with three cycles of anti-Ia and complement removed all detectable GM colony- and GM cluster-forming cells; however, this marrow produced fewer cumulative Ia-positive GM-CFUc. Long-term bone marrow cultures may prove to be an interesting system for in vitro analysis of the effects of new immunotherapeutic agents including other monoclonal antibodies prior to clinical use.
Assuntos
Anticorpos Monoclonais , Medula Óssea/imunologia , Proteínas do Sistema Complemento , Hematopoese , Tecido Adiposo/citologia , Animais , Células da Medula Óssea , Células Cultivadas , Camundongos , Fatores de TempoRESUMO
Effective autologous bone marrow transplantation for leukemia and lymphoma is likely to depend upon the selective removal in vitro of malignant cells from normal human bone marrow precursors. Highly specific cytotoxic conjugates formed by coupling ricin A chain to monoclonal antibodies might prove useful for the selective elimination of malignant cells. Consequently, ricin A chain conjugates have been prepared with several different murine monoclonal antibodies and tested for their ability to eliminate clonogenic Burkitt's lymphoma cells from an excess of human bone marrow. The most active reagents included an antibody:A chain conjugate which bound to the nonpolymorphic chain of the la molecule and another which reacted with the mu heavy chain of cell surface immunoglobulin. Conjugates formed with anti-common acute lymphoblastic leukemia antigen, anti-Mr 26,000 glycoprotein, and anti-B1 were much less active on these Burkitt's cells, contrasting with results of complement-dependent tumor cell lysis. Tumor cell kill was partially inhibited by the addition of greater than 2 X 10(6) human bone marrow cells/ml but could be potentiated by increasing the concentration of conjugate or by the addition of 10 mM ammonium chloride. In the presence of ammonium chloride, at least 4 logs of clonogenic tumor cells could be eliminated within 24 h from a 20-fold excess of bone marrow using 10(-7) M ricin A chain linked to one or two different antibodies. Similar treatment of normal human bone marrow temporarily inhibited granulocyte-macrophage colony-forming units (cell) formation but did not compromise establishment of continuous bone marrow cultures. The degree of selective elimination of tumor cells with A chain antibody conjugates was comparable to that achieved with 4-hydroperoxycyclophosphamide or with multiple monoclonal antibodies and complement.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Células da Medula Óssea , Linfoma de Burkitt/imunologia , Células-Tronco Neoplásicas/imunologia , Ricina/administração & dosagem , Cloreto de Amônio/farmacologia , Anticorpos Monoclonais/administração & dosagem , Antígenos de Neoplasias/imunologia , Transplante de Medula Óssea , Linfoma de Burkitt/terapia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Proteínas do Sistema Complemento/imunologia , Relação Dose-Resposta a Droga , Células-Tronco Hematopoéticas/citologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoterapia , Técnicas In Vitro , Receptores de Antígenos de Linfócitos B/imunologiaRESUMO
We evaluated the cytotoxicity of the immunotoxin OKT1-SAP on fresh B-chronic lymphocytic leukemia (B-CLL) cells from 31 consecutive patients. OKT1-SAP comprised the OKT1 (CD5) monoclonal antibody disulfide linked to saporin-6 (SAP) ribosome-inactivating protein from the plant Saponaria officinalis. The effect of OKT1-SAP on target CD5-positive B-CLL cells was estimated using an in vitro proliferation inhibition assay in which control or OKT1-SAP-treated B-CLL cells were induced to proliferate by sequential stimulation with insolubilized anti-C3b receptor CB04 (CD35) antibody and low molecular weight B-cell growth factor. In 90% of patients, OKT1-SAP specifically suppressed B-CLL cell proliferation in a dose-related manner (50% inhibitory concentration, 4.0-6.8 nM). Taken together the findings reported in this article provide information relevant to the clinical development of immunotoxins because: (a) the in vitro conditions under which B-CLL cell proliferation is inhibited by OKT1-SAP are achievable in vivo without nonspecific toxicity according to our previous toxicology and pharmacokinetics studies in primates; and (b) the B-CLL cell proliferation inhibition assay described here provides a basis for future comparative studies.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Imunotoxinas/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , N-Glicosil Hidrolases , Proteínas de Plantas/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Idoso , Anticorpos Monoclonais , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Feminino , Humanos , Cinética , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Células Tumorais Cultivadas/citologiaRESUMO
Peptide presentation by autologous dendritic cells (DCs) is a new tool to activate tumor antigen-specific T cells in melanoma patients. However, it is not known whether autologous DCs, differentiated by two of the most efficient protocols (from CD34+ progenitors or from monocytes), are equally effective as professional antigen-presenting cells (APCs) when the patients have a low frequency of peptide-specific precursors. To this end, a limiting dilution assay was applied to evaluate the frequency of antigen-specific CTL precursors (CTLps) in peripheral blood of HLA-A*0201+ melanoma patients. Then, from two melanoma patients showing low frequency of CTLps to melanoma antigen-A/melanoma antigen recognized by T cell (Melan-A/Mart-1)(27-35) peptide, autologous DCs were differentiated from granulocyte colony-stimulating factor-mobilized CD34+ progenitors or from monocytes. CD34+- and monocyte-derived DCs were characterized by a similar proportion of CD1a+ cells expressing HLA class II antigens and CD54, CD80, and CD86 molecules. Both types of DC presented Melan-A/Mart-1(27-35) and tyrosinase(369-377) peptides to melanoma-specific CTL clones and were equally effective as peptide-pulsed APCs in the activation of influenza A matrix(58-66)-specific CTLs from high-frequency precursors (1294/10(6) and 1789/10(6) lymphocytes in the two patients). However, efficient activation of Melan-A/Mart-1(27-35)-specific CTLs from low-frequency precursors (158/10(6) and 77/10(6) lymphocytes) of the two patients was markedly dependent on the use of peptide-loaded CD34+-derived DCs. These results suggest that CD34+- and monocyte-derived DCs are not functionally equivalent APCs for the activation of low-frequency peptide-specific CTLps.
Assuntos
Células Apresentadoras de Antígenos/fisiologia , Antígenos CD34/fisiologia , Células Dendríticas/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Melanoma/imunologia , Linfócitos T Citotóxicos/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Melanoma/sangue , Monócitos/fisiologia , FenótipoRESUMO
Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.