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1.
Transplant Cell Ther ; 30(5): 544.e1-544.e8, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38417677

RESUMO

Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Doadores não Relacionados , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Adulto , Doença Enxerto-Hospedeiro/prevenção & controle , Grupos Minoritários/estatística & dados numéricos , Estudos de Coortes , Antígenos HLA/imunologia , Idoso
2.
Clin Cancer Res ; 29(15): 2774-2780, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37341641

RESUMO

PURPOSE: Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression. PATIENTS AND METHODS: This is a retrospective, single-center analysis of patients with AML, MDS, or chronic myelomonocytic leukemia treated with a once-weekly LDDec/VEN regimen. We also compare this regimen with a cohort treated with standard dosing HMA/VEN. RESULTS: In a retrospective cohort of 39 patients, the overall response rate for patients receiving LDDec/VEN for first-line AML and MDS was 88% and 64%, respectively. In patients with TP53 mutations, the composite complete response rate was 71% and the median overall survival was 10.7 months. When compared with 36 patients receiving standard dose HMA/VEN, the LDDec/VEN patients had a longer time on therapy (175 vs. 78 days; P = 0.014) and a trend toward a higher rate of transfusion independence (47% vs. 26%; P = 0.33). Neutropenic fever occurred in 31% of patients, with a median of one hospitalization at any point during treatment. CONCLUSIONS: This preliminary clinical experience, although retrospective, provides proof-of-activity of noncytotoxic DNA methyltransferase 1-targeting by allowing frequent, sustained drug exposure often not possible with standard HMA/VEN regimens.

3.
Blood ; 139(8): 1135-1146, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-34543383

RESUMO

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glicolipídeos/administração & dosagem , Leucemia Mieloide Aguda , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glicolipídeos/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Taxa de Sobrevida
4.
Mol Cancer Ther ; 17(2): 554-564, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29142066

RESUMO

Treatment choices for acute myelogenous leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. IL3 receptor alpha (IL3Rα, or CD123) is expressed on the majority of AML blasts, and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here, we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate using the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation. Mechanistically, SGN-CD123A induces activation of DNA damage response pathways, cell-cycle changes, and apoptosis in AML cells. In vitro, SGN-CD123A-mediated potent cytotoxicity of 11/12 CD123+ AML cell lines and 20/23 primary samples from AML patients, including those with unfavorable cytogenetic profiles or FLT3 mutations. In vivo, SGN-CD123A treatment led to AML eradication in a disseminated disease model, remission in a subcutaneous xenograft model, and significant growth delay in a multidrug resistance xenograft model. Moreover, SGN-CD123A also resulted in durable complete remission of a patient-derived xenograft AML model. When combined with a FLT3 inhibitor quizartinib, SGN-CD123A enhanced the activity of quizartinib against two FLT3-mutated xenograft models. Overall, these data demonstrate that SGN-CD123A is a potent antileukemic agent, supporting an ongoing trial to evaluate its safety and efficacy in AML patients (NCT02848248). Mol Cancer Ther; 17(2); 554-64. ©2017 AACR.


Assuntos
Imunoconjugados/farmacologia , Subunidade alfa de Receptor de Interleucina-3/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Células CHO , Linhagem Celular Tumoral , Cricetulus , Humanos , Imunoconjugados/imunologia , Leucemia Mieloide Aguda/imunologia , Camundongos , Camundongos SCID , Células THP-1 , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Curr Hematol Malig Rep ; 11(6): 545-552, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27734262

RESUMO

While antibody-based therapies have emerged as clinically effective approaches for several hematologic and solid malignancies, they have not played a significant role to date in the treatment of acute myeloid leukemia (AML). More recently, improvements in antibody-drug conjugate technology, bispecific antibodies, as well as identification of novel AML antigens have re-invigorated enthusiasm for antibody-based therapies for AML. This review describes experiences with former and existing antibody-based therapies for AML, including unconjugated antibodies, antibody-drug conjugates (ADCs), radio-labelled antibodies, and immune-engaging antibodies, and discusses the promise and challenges associated with each.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Aminoglicosídeos/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Gemtuzumab , Humanos , Imunoconjugados/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3/imunologia , Radioimunoterapia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia
6.
Clin Lymphoma Myeloma Leuk ; 15 Suppl: S91-3, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26297287

RESUMO

Effective treatment options for adults with therapy-related AML continues to be an area of unmet need. Genetic and molecular changes within these leukemias confer resistance to standard chemotherapy regimens. Emerging developmental therapeutics in this area has focused on several approaches. These include; novel delivery of chemotherapy as well as newer DNA-damaging agents delivered through antibody-drug conjugates, increased use of hypomethylating agents, and molecularly-directed small molecules against specific mutations commonly occurring in secondary AML. Results of this efforts are encouraging, but to date, no clear improvements have been demonstrated in this most difficult to treat population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Humanos , Resultado do Tratamento
7.
Cancer ; 121(2): 234-42, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25223583

RESUMO

BACKGROUND: CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. METHODS: This phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point. RESULTS: Patient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%). CONCLUSIONS: Taken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Aminoglicosídeos/administração & dosagem , Amsacrina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Cladribina/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Gemtuzumab , Humanos , Injeções , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Lipossomos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Recidiva , Indução de Remissão , Medição de Risco , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
8.
Leuk Lymphoma ; 56(2): 395-400, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24794806

RESUMO

There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose.


Assuntos
Leucemia Mieloide/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Leucemia Mieloide/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
9.
J Clin Oncol ; 32(33): 3723-8, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25245447

RESUMO

PURPOSE: Arsenic trioxide (ATO) is a highly effective agent for the treatment of acute promyelocytic leukemia (APL). QT interval prolongation is common with ATO and can pose a barrier to effective administration. The objective of this study was to characterize the prevalence, management, and clinical consequences of QT prolongation in a large cohort of patients treated with ATO. PATIENTS AND METHODS: We analyzed 3,011 electrocardiograms from 113 patients with non-APL acute myeloid leukemia and myelodysplastic syndrome who were treated on a previously reported clinical trial. QT intervals were assessed using four different correction formulas, and data were correlated with clinical parameters and treatment with ATO. RESULTS: There were no clinically significant cardiac events in the study population. Of those receiving ATO therapy, 29 patients (26%) had rate-uncorrected QT values above 470 ms and 13 (12%) had values exceeding 500 ms. With the commonly used Bazett rate correction formula, 102 patients (90%) had QTc greater than 470 ms, including 74 (65%) above 500 ms. By using alternative rate correction formulas, only 24% to 32% of patients had rate-corrected QT intervals above 500 ms. CONCLUSION: QT interval prolongation is common with ATO treatment, but clinically significant arrhythmias are rare and can be avoided with appropriate precautions. Use of the Bazett correction may result in unnecessary interruptions in ATO therapy, and alternative rate correction formulas should be considered for routine electrocardiographic monitoring.


Assuntos
Antineoplásicos/efeitos adversos , Arsenicais/efeitos adversos , Eletrocardiografia/efeitos dos fármacos , Óxidos/efeitos adversos , Idoso , Trióxido de Arsênio , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
10.
Blood ; 123(21): 3239-46, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24687088

RESUMO

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos , Masculino , Pessoa de Meia-Idade
11.
Cancer Chemother Pharmacol ; 72(4): 897-908, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23949430

RESUMO

PURPOSE: Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro. METHODS: Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m(2) given as a 2-h infusion every 21 days. RESULTS: Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients' peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill. CONCLUSIONS: While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Compostos de Piridínio/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Linhagem Celular Tumoral , Óxidos N-Cíclicos , Esquema de Medicação , Feminino , Humanos , Indolizinas , Infusões Intravenosas , Leucemia Mieloide Aguda/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Poli(ADP-Ribose) Polimerases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Compostos de Piridínio/efeitos adversos , Compostos de Piridínio/farmacocinética , Fatores de Tempo , Resultado do Tratamento
13.
Leuk Lymphoma ; 54(9): 2003-7, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23270581

RESUMO

Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m(2) administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Estudos de Coortes , Decitabina , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Resultado do Tratamento
14.
Leuk Lymphoma ; 54(4): 799-806, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22916826

RESUMO

Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent pathogens. However, little is known about their emergence in patients with hematologic malignancies. We identified 18 patients with hematologic malignancies over 3.5 years who developed bloodstream infections (BSIs) caused by CRE. Fourteen BSIs were caused by Klebsiella pneumoniae, three by Enterobacter cloacae, and one was polymicrobial. Initial empirical antimicrobial therapy was active in two patients (11%), and a median of 55 h elapsed between culture collection and receipt of an active agent. Ten patients (56%) died, including nine (69%) of 13 neutropenic patients, with a median of 4 days from culture collection until death. CRE isolates were analyzed for carbapenemase production, ß-lactamase genes and outer membrane porin deletions and characterized by multilocus sequence typing and pulsed-field gel electrophoresis (PFGE). Carbapenem resistance mechanisms included Klebsiella pneumoniae carbapenemase production and CTX-M-15 production with an absent outer membrane porin protein. No isolate had ≥95% homology on PFGE, indicating a heterogeneous, non-outbreak population of isolates. CRE BSIs are emerging in patients with hematologic malignancies and are associated with ineffective initial empirical therapy, long delays in administration of active antimicrobials and high mortality rates. New diagnostic, therapeutic and preventive strategies for CRE infections in this vulnerable population are needed.


Assuntos
Bacteriemia/complicações , Infecções por Enterobacteriaceae/complicações , Enterobacteriaceae , Neoplasias Hematológicas/complicações , Resistência beta-Lactâmica , Adulto , Idoso , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Enterobacteriaceae/classificação , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/epidemiologia , Feminino , Genótipo , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Filogenia , Adulto Jovem , Resistência beta-Lactâmica/genética
15.
Leuk Res ; 36(4): 407-12, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22325245

RESUMO

This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥ 60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Gemtuzumab , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Quinolonas/administração & dosagem , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
16.
Leuk Res ; 36(2): 156-62, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21983176

RESUMO

We treated 37 patients with polycythemia vera with imatinib mesylate (IM). The overall response rate was 49%. Thirty percent had a complete response, and 19%, a partial response. Thirty-one patients were treated for >120 days. Frequent side effects included nausea, diarrhea, edema, and skin rash. Whereas IM was effective in controlling erythropoiesis and reducing spleen size it was ineffective in controlling thrombocytosis. Normocellular marrow developed in 4 patients who had a complete response. Progression to overt myelofibrosis occurred in 3. Nevertheless, 6 patients have had a sustained complete response while on IM for >6 years. These patients were young, had high phlebotomy requirements, and only slightly elevated platelet counts. Therefore, we believe there may be a role for IM in patients with these characteristics whose disease cannot be controlled by, or as an alternative to, other myelosuppressive treatments.


Assuntos
Antineoplásicos/uso terapêutico , Piperazinas/uso terapêutico , Policitemia Vera/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Relação Dose-Resposta a Droga , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Policitemia/tratamento farmacológico , Prognóstico , Trombocitose/tratamento farmacológico
17.
Blood ; 119(1): 55-63, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22001391

RESUMO

Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Farmacogenética , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Proteínas Nucleares/genética , Prognóstico , Quinolonas/administração & dosagem , RNA Mensageiro/genética , Indução de Remissão , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
18.
Best Pract Res Clin Haematol ; 24(4): 523-6, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22127315

RESUMO

Do patients with therapy-related acute myeloid leukemia (t-AML) have a poor prognosis independent of other predictive variables such as cytogenetics or molecular determinants? Limited data exist to answer this question in part because t-AML is often considered together with AML following myelodysplastic syndromes (MDS) in the category of secondary AML. This discussion provides some insight, based primarily on two published retrospective reviews of the German cooperative groups, into the question of whether t-AML is an independent adverse variable.


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Adenina , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citogenética , Feminino , Alemanha , Humanos , Leucemia Mieloide Aguda/induzido quimicamente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Naftalimidas/administração & dosagem , Naftalimidas/uso terapêutico , Naftiridinas/administração & dosagem , Naftiridinas/uso terapêutico , Organofosfonatos , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico
19.
Blood ; 118(6): 1472-80, 2011 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-21613261

RESUMO

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m² by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m² for 7 days) and daunorubicin (60 mg/m² × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Decitabina , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Febre/induzido quimicamente , Humanos , Infecções/induzido quimicamente , Estimativa de Kaplan-Meier , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neutropenia/induzido quimicamente , Resultado do Tratamento , Adulto Jovem
20.
J Clin Oncol ; 29(8): 979-85, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-21282541

RESUMO

PURPOSE: This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. PATIENTS AND METHODS: CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. RESULTS: The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. CONCLUSION: The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Lipossomos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva , Terapia de Salvação , Resultado do Tratamento , Adulto Jovem
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