Assuntos
Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto , Antígenos CD19/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Resultado do TratamentoRESUMO
Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.
Assuntos
Vírus BK/patogenicidade , Doença Enxerto-Hospedeiro/mortalidade , Doenças Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Nefropatias/mortalidade , Infecções por Polyomavirus/mortalidade , Infecções Tumorais por Vírus/mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Taxa de Filtração Glomerular , Doença Enxerto-Hospedeiro/etiologia , Doenças Hematológicas/complicações , Doenças Hematológicas/terapia , Humanos , Lactente , Recém-Nascido , Nefropatias/virologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Infecções Tumorais por Vírus/virologia , Adulto JovemRESUMO
BACKGROUND: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. PATIENTS AND METHODS: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. RESULTS: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. CONCLUSION: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed.
Assuntos
Antineoplásicos/uso terapêutico , Substituição de Medicamentos , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Terapia de Salvação , Adenina/análogos & derivados , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/sangue , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/sangue , Linfoma de Célula do Manto/enzimologia , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Piperidinas , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação/efeitos adversos , Texas , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) and its common variants mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are rare extranodal non-Hodgkin's lymphomas. Patients who present with advanced disease and large-cell transformation (LCT) are incurable with standard treatments. In this article, we report the largest single-center experience with allogeneic stem-cell transplantation (SCT) for advanced CTCL. PATIENTS AND METHODS: This is a prospective case series of 47 CTCL patients who underwent allogeneic SCT after failure of standard therapy between July 2001 and September 2013. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) curves. The method of Fine and Gray was used to fit regression models to the same covariates for these cumulative incidence data. RESULTS: The Kaplan-Meier estimates of OS and PFS at 4 years were 51% and 26%, respectively. There was no statistical difference in the OS in patients who had MF alone, SS, MF with LCT, or SS with LCT. PFS at 4 years was superior in patients who had SS versus those who did not (52.4% versus 9.9%; P = 0.02). The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 40% and 28%, respectively. The cumulative nonrelapse mortality rate was 16.7% at 2 years. CONCLUSION: Allogeneic SCT may result in long-term remissions in a subset of patients with advanced CTCL. Although post-SCT relapse rates are high, many patients respond to immunomodulation and achieve durable remissions. CLINICALTRIALSGOV: NCT00506129.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo/métodos , Transplante Homólogo/tendências , Adulto JovemRESUMO
BACKGROUND: High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. PATIENTS AND METHODS: Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. RESULTS: We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. CONCLUSIONS: Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. CLINICALTRIALSGOV: NCT00936936.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Neoplasias do Mediastino/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Retroperitoneais/terapia , Neoplasias Testiculares/terapia , Adolescente , Adulto , Idoso , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Criança , Cisplatino/administração & dosagem , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Masculino , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Neoplasias Retroperitoneais/mortalidade , Neoplasias Retroperitoneais/patologia , Terapia de Salvação , Taxa de Sobrevida , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/patologia , Transplante Autólogo , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Hematopoietic stem cell transplant (HCT) recipients are more susceptible to infections from vaccine-preventable diseases than the general population. Despite the development of international consensus guidelines addressing immunization after HCT, studies have shown that deviations from recommended immunization practices commonly occur. METHODS: An anonymous survey aimed at determining awareness of the guidelines and attitudes toward vaccination was distributed to our HCT clinicians. In parallel, we retrospectively evaluated patients' characteristics and post-HCT vaccine administration practices from 2010 to 2013. RESULTS: The majority of survey respondents (96%) were familiar with post-HCT vaccination protocols. Seventy-four percent of respondents reported that influenza vaccines were given to >70% of their patients, and 41% stated that they prescribed live vaccines to eligible patients. However, our pharmacy database review revealed that 38% of patients received the first series of vaccinations by the recommended 6 months post HCT, and 60% received them by 1 year after HCT. Most patients who had their vaccines withheld had relapsed disease or were undergoing treatment for graft-versus-host disease. Furthermore, we identified lower immunization rates in non-English speaking individuals, African-Americans, and Hispanic patients. CONCLUSIONS: Survey respondents reported being aware of current guidelines; however, adherence to the recommendations varied, likely connected to conflicting data on vaccine effectiveness and a lack of clear recommendations in complex clinical scenarios. Similar to the general population, patient barriers also could have contributed to lower vaccination rates in some cases. To decrease the large gap between the post-HCT vaccination guidelines and clinical practice, further studies on vaccine effectiveness and specific populations are warranted.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Transplante de Células-Tronco Hematopoéticas , Guias de Prática Clínica como Assunto , Vacinação , Vacinas/administração & dosagem , Vacinas/imunologia , Coleta de Dados , Humanos , Padrões de Prática Médica , Estudos RetrospectivosRESUMO
We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 µM/min for patients age <60 years and 4000 µM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Clofarabina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
Sleeping Beauty (SB3) transposon and transposase constitute a DNA plasmid system used for therapeutic human cell genetic engineering. Here we report a comparison of SB100X, a newly developed hyperactive SB transposase, to a previous generation SB11 transposase to achieve stable expression of a CD19-specific chimeric antigen receptor (CAR3) in primary human T cells. The electro-transfer of SB100X expressed from a DNA plasmid or as an introduced mRNA species had superior transposase activity in T cells based on the measurement of excision circles released after transposition and emergence of CAR expression on T cells selectively propagated upon CD19+ artificial antigen-presenting cells. Given that T cells modified with SB100X and SB11 integrate on average one copy of the CAR transposon in each T-cell genome, the improved transposition mediated by SB100X apparently leads to an augmented founder effect of electroporated T cells with durable integration of CAR. In aggregate, SB100X improves SB transposition in primary human T cells and can be titrated with an SB transposon plasmid to improve the generation of CD19-specific CAR+ T cells.
Assuntos
Antígenos CD19/metabolismo , Técnicas de Transferência de Genes , Receptores de Antígenos/metabolismo , Linfócitos T/metabolismo , Transposases/genética , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Eletroporação , Humanos , Neoplasias/imunologia , RNA Mensageiro , Receptores de Antígenos/genéticaRESUMO
BACKGROUND: T-cell lymphomas are a heterogeneous group of non-Hodgkin's lymphomas (NHLs). With the exception of anaplastic lymphoma kinase protein-positive large-cell lymphoma, standard chemotherapy provides dismal long-term outcomes when compared with NHLs with B-cell immunophenotype. DESIGN: We review the literature on the role of high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in T-cell NHLs both as up-front treatment and in the salvage setting. The role of allogeneic transplantation will also be reviewed. RESULTS: Results from five prospective, nonrandomized and six retrospective studies evaluating the role of HDT and ASCT in the up-front setting show that patients in first complete or partial remission especially those who present with advanced disease and high prognostic index of peripheral T-cell lymphoma score may benefit from this approach. In the relapsed and/or refractory setting, most series show results that are comparable with those seen in patients with B-cell lymphomas if transplanted with chemosensitive disease. There is limited evidence to suggest that an immune-mediated graft-versus-lymphoma effect may result in long-term disease remissions in some patients after allogeneic transplantation. CONCLUSIONS: Randomized studies comparing HDT and ASCT with conventional chemotherapy are needed in T-cell lymphomas.
Assuntos
Linfoma não Hodgkin/terapia , Linfoma de Células T/terapia , Transplante de Células-Tronco , Humanos , PrognósticoRESUMO
Although the immune system has long been implicated in the control of cancer, evidence for specific and efficacious immune responses in human cancer has been lacking. In the case of chronic myelogenous leukemia (CML), either allogeneic bone marrow transplant (BMT) or interferon-alpha2b (IFN-alpha2b) therapy can result in complete remission, but the mechanism for prolonged disease control is unknown and may involve immune anti-leukemic responses. We previously demonstrated that PR1, a peptide derived from proteinase 3, is a potential target for CML-specific T cells. Here we studied 38 CML patients treated with allogeneic BMT, IFN- alpha2b or chemotherapy to look for PR1-specific T cells using PR1/HLA-A*0201 tetrameric complexes. There was a strong correlation between the presence of PR1-specific T cells and clinical responses after IFN-alpha and allogeneic BMT. This provides for the first time direct evidence of a role for T-cell immunity in clearing malignant cells.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Serina Endopeptidases/imunologia , Linfócitos T Citotóxicos/imunologia , Circulação Sanguínea , Transplante de Medula Óssea , Citotoxicidade Imunológica , Efeito Enxerto vs Leucemia , Humanos , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Mieloblastina , Fragmentos de Peptídeos/imunologia , Indução de RemissãoRESUMO
BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma; treatment with standard anthracycline-containing chemotherapy regimens has been disappointing, and an optimal treatment strategy for this patient population has not yet been determined. METHODS: We identified 15 cases of pathologically confirmed HSTCL in the institution's database. Clinical characteristics and treatment results were reviewed. RESULTS: Complete responses (CRs) were achieved in 7 of 14 patients who received chemotherapy. Achievement of CR was followed by hematopoietic stem-cell transplantation in three patients. Median duration of CR was 8 months (range 2 to 32+ months) with four patients currently alive and in CR at 5, 8, 12, and 32 months, respectively. Median overall survival (OS) was 11 months (range 2 to 36+ months). Patients who achieved a CR had a median OS of 13 months, compared with 7.5 months in patients who did not achieve a CR. Risk factors associated with worse outcome included male gender, failure to achieve a CR, history of immunocompromise, and absence of a T-cell receptor gene rearrangement in the gamma chain. CONCLUSION: A better understanding of the pathophysiology of HSTCL and new therapeutic strategies are needed.
Assuntos
Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
In the Philadelphia chromosome (Ph1) of chronic myelogenous leukemia (CML), the c-abl gene on chromosome 9 is translocated to bcr on chromosome 22. This results in the expression of a chimeric bcr-abl message that encodes the P210bcr-abl tyrosine kinase. The cells of 10% of acute lymphocytic leukemia patients (ALL) carry a cytogenetically similar Ph1 translocation. We report that Ph1-positive ALL cells express unique abl-derived tyrosine kinases of 185 and 180 kilodaltons that are distinct from the bcr-abl-derived P210 protein of CML. The appearance of the 185/180-kilodalton proteins correlates with the expression of a novel 6.5-kilobase messenger RNA. Thus, similar genetic translocations in two different leukemias result in the expression of distinct c-abl-derived products.
Assuntos
Leucemia Linfoide/enzimologia , Leucemia Mieloide/enzimologia , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proto-Oncogenes , DNA de Neoplasias/genética , Humanos , Leucemia Linfoide/genética , Leucemia Mieloide/genética , Peso Molecular , Fragmentos de Peptídeos/análise , Cromossomo Filadélfia , Fosfoproteínas/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Translocação GenéticaRESUMO
PATIENTS AND METHODS: We present a retrospective analysis of 99 consecutive patients with relapsed non-Hodgkin's lymphomas who were older than 65 years at the time of high-dose chemotherapy and autologous progenitor cell transplantation. RESULTS: Median age at transplant was 68 years (range 65-82). Thirty-six percent of patients had a hematopoietic cell transplantation comorbidity index of >2 at the time of transplantation. The cumulative nonrelapse mortality was 8% [95% confidence interval (CI) 4-17] at 26 months and the 3-year overall survival (OS) was 61% (95% CI 49-71). On multivariate analysis, disease status at transplant and lactate dehydrogenase (LDH) > normal were significant predictors for OS (P = 0.002). Comorbidity index of >2 did not impact OS but did predict for higher risk of developing grade 3-5 toxicity (P = 0.006). Eight patients developed secondary myelodysplastic syndrome/acute myelogenous leukemia after transplantation (cumulative incidence 16%). CONCLUSIONS: Patients with relapsed lymphomas who are >65 years of age should be considered transplant candidates, particularly if they have chemosensitive disease and normal LDH levels at the time of transplantation. Patients with comorbidity index of >2 can also undergo transplantation with acceptable outcomes but may be at higher risk for developing toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/terapia , Recidiva Local de Neoplasia/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Estudos Retrospectivos , Transplante AutólogoRESUMO
The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133+ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained <2 x 10(7) total nucleated cells (TNCs) per kilogram pre-expansion. All donor-recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2-620). Mean increase of CD34+ cell count was 6 (over the CD34+ cell content in the entire unit). Despite the low TNCs per kilogram infused (median=1.8 x 10(7)/kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16-46) and 48 (range, 35-105) days. There were no cases of grades 3-4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.
Assuntos
Técnicas de Cultura de Células , Quelantes/farmacologia , Cobre , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Etilenodiaminas/farmacologia , Sangue Fetal , Células-Tronco Hematopoéticas , Adolescente , Adulto , Antígenos de Diferenciação/metabolismo , Células Cultivadas , Criança , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Doadores de TecidosRESUMO
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
Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.
Assuntos
Antígenos CD19/imunologia , Sangue Fetal/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia , Idoso , Caspase 9/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunoterapia Adotiva/métodos , Células K562 , Leucemia/imunologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
We studied recovery of peripheral blood- and bone marrow-derived myeloid progenitor cells (CFU-G,M) in 29 patients who received bone marrow transplants 2 mo to 8.5 yr previously. All patients had normal levels of peripheral blood neutrophils, normal bone marrow cellularity, and a normal myeloid-erythroid ratio. Both peripheral blood- and bone marrow-derived CFU-G,M were markedly reduced compared with normal controls and bone marrow donors [5 +/- 1/10(6) vs. 37 +/- 4/10(6) (P less than 0.001) and 23 +/- 5/2 x 10(5) vs. 170 +/- 21/2 x 10(5) (P less than 0.001)]. Five patients had no detectable CFU-G,M even when 10(6) bone marrow cels were plated. These abnormalities of CFU-G,M were unrelated to age, sex, diagnosis, conditioning regimen, dose of bone marrow cells transplanted, and presence or absence of graft-vs.-host disease. Patients who received either autotransplants or transplants from identical twins also had decreased or absent CFU-G,M indicating that allogeneic factors and posttransplant immune suppressor with methotrexate or corticosteroids were not major determinants of this abnormality. Co-culture of normal or donor peripheral blood or bone marrow mononuclear cells with recipients peripheral blood or bone marrow mononuclear cells, purified T cells, or serum failed to show any evidence of active CFU-G,M suppression. Furthermore, the abnormality of CFU-G,M could not be corrected by the addition of normal syngeneic (donor) hematopoietic cells or serum. Depletion of T-cells from recipient bone marrow by physical techniques resulted in marked increase in CFU-G,M (36 +/- 13 vs. 138 +/- 36; P less than 0.05). The abnormality could be reproduced in vitro by readdition of autologous T cells. In contrast to results with T cell depletion by physical techniques, T cell depletion with a monoclonal anti-T antibody (B7) and complement had no effect. These data indicate that most-transplant recipients have a marked abnormality in CFU-G,M when these cells are cultured in vitro. In at least some of these patients, the decreased cloning efficiency of CFU-G,M appears to be mediated by a suppressive effect of autologous T cells.
Assuntos
Transplante de Medula Óssea , Transtornos Mieloproliferativos/fisiopatologia , Adolescente , Adulto , Ensaio de Unidades Formadoras de Colônias , Feminino , Granulócitos/citologia , Hematopoese , Humanos , Depleção Linfocítica , Macrófagos/citologia , Masculino , Pessoa de Meia-Idade , Formação de Roseta , Linfócitos T/citologiaRESUMO
Bone marrow transplant donors were immunized with tetanus/diphtheria toxoids 6-7 d before bone marrow donation to investigate the role of B cell subpopulations in reconstitution of humoral immunity. Lymphoblastoid B cells spontaneously producing IgG antitetanus and/or antidiphtheria toxoid were detected in the donor marrows at the time of transplantation. Recipients rapidly demonstrated 3-90-fold increases in serum IgG antitetanus and antidiphtheria toxoid levels. Antidiphtheria fragment A antibody in three donor/recipient pairs demonstrated spectrotypic identity indicating transfer of the donors' response. Reimmunization of three recipients 64-154 d after transplant revealed an IgG antibody response associated with reappearance of spontaneous antibody-producing B cells and an antidiphtheria fragment A response characteristics of the donor's immune response. These observations extend the understanding of the role of B cell subpopulations and provide a basis for specific modulation of immunity in the setting of bone marrow transplantation.
Assuntos
Formação de Anticorpos , Transplante de Medula Óssea , Adulto , Linfócitos B/imunologia , Toxina Diftérica/análise , Toxoide Diftérico/imunologia , Humanos , Imunização , Imunoglobulina G/análise , Imunoglobulina M/análise , Leucemia/terapia , Fragmentos de Peptídeos/análise , Toxoide Tetânico/imunologiaRESUMO
Graft failure is a life-threatening complication of allogeneic stem cell transplantation (SCT). We assessed the feasibility of performing a second SCT after such failure when fludarabine and antithymocyte globulin (ATG) are used for non-myeloablative conditioning and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. Nine patients with SCTs for various hematologic malignancies were enrolled, eight with primary and one with secondary graft failure. The median time between the first and second SCT was 53 days. Eight patients had the same donor for their second SCT, and one had a cord blood transplant. Three patients were not evaluable because of early death; the other six had evidence of donor cell engraftment. Six of the nine patients developed acute grade II-IV GVHD, the main cause of death. Overall, we found that fludarabine and ATG conditioning before a second SCT allows engraftment of donor hematopoiesis. Future studies should include more intense GVHD prophylaxis.