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1.
Br J Haematol ; 170(1): 96-109, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25891346

RESUMO

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Depsipeptídeos/efeitos adversos , Epigenômica , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/patologia
3.
Blood ; 117(22): 5827-34, 2011 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-21355097

RESUMO

Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacocinética , Depsipeptídeos/farmacocinética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Neoplasias Cutâneas/tratamento farmacológico , Taxa de Sobrevida , Distribuição Tecidual , Resultado do Tratamento
4.
Biol Blood Marrow Transplant ; 18(3): 432-40, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21801703

RESUMO

Clofarabine is a novel purine nucleoside analog with immunosuppressive and antileukemia activity. We performed a phase I study of the combination of clofarabine plus melphalan as a reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with acute myelogenous leukemia. Patients over age 18 in complete remission or with active disease (up to 50% marrow blasts) who had a matched related or unrelated donor were eligible. The conditioning regimen consisted of escalating doses of clofarabine plus melphalan, followed by allogeneic stem cell transplantation. Sixteen patients (median age, 63 years) were treated at 3 dose levels; 4 of these patients had primary induction failure, and 3 were in first relapse. One patient at dose level 2 and 1 patient at dose level 3 died of multiorgan toxicity; no other dose-limiting toxicities were seen. All other patients at both doses of clofarabine studied demonstrated complete engraftment by day 30, with a median time to absolute neutrophil count recovery of 14 days, and 16 days for platelet recovery. With a median follow-up of 17 months, only 2 patients relapsed, and 4 patients died. Clofarabine plus melphalan at dose level 2 is a well-tolerated conditioning regimen with activity in patients with advanced acute myelogenous leukemia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Idoso , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Clofarabina , Terapia Combinada , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/cirurgia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo
6.
Leuk Lymphoma ; 57(10): 2307-14, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26895565

RESUMO

We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Monitoramento de Medicamentos , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Ribonucleotídeo Redutases/antagonistas & inibidores , Resultado do Tratamento
7.
Leuk Lymphoma ; 55(10): 2301-4, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24369094

RESUMO

We performed a phase II study of belinostat in patients with acute myeloid leukemia (AML). In this open label phase II study (NCT00357032), patients with relapsed/refractory AML, or newly diagnosed patients with AML over the age of 60, were eligible. Belinostat was administered intravenously (IV) at a dose of 1000 mg/m(2) daily on days 1-5 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was complete response (CR) rate, with secondary endpoints of overall response rate (CR + partial response [PR]), time to treatment failure (TTF), overall survival and safety. Twelve eligible patients with AML were enrolled, of whom six had received at least one prior line of therapy. No CR or PR was seen. Four patients had stable disease for at least five cycles. Grade 3 non-hematological toxicities occurred in four patients. Belinostat as monotherapy has minimal single-agent effect in AML on this dosing schedule.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Sulfonamidas/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento
8.
Leuk Res ; 38(3): 329-33, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24411921

RESUMO

We report on 348 patients ≥ 70 years (median age 78 years) with acute myeloid leukemia (>50% with secondary AML) randomized to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1-21 or days 1-7 and 15-21, repeated every 28 days (4 treatment regimens). Responses were seen in all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients receiving tipifarnib 300 mg twice daily on days 1-21. Toxicities were acceptable. Unless predictors of response to tipifarnib are identified, further study as a single agent in this population is unwarranted.


Assuntos
Farnesiltranstransferase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Quinolonas/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Farnesiltranstransferase/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento
9.
Clin Cancer Res ; 20(2): 490-8, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24178622

RESUMO

PURPOSE: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. EXPERIMENTAL DESIGN: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. RESULTS: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Feminino , Genes ras , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/genética
12.
Leuk Lymphoma ; 53(2): 259-62, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21823829

RESUMO

We performed a phase II study of oral vorinostat (200 mg twice daily, days 1-14 of a 21-day cycle), a histone and protein deacetylase inhibitor, to examine efficacy and tolerability in patients with relapsed/refractory Hodgkin lymphoma (HL) with ≤ 5 prior therapies. The primary endpoint was the objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), safety and tolerability. A two-stage design was used for patient accrual. Twenty-five eligible patients were accrued in the first stage. Median time on treatment was 3.8 months. The ORR was 4% (one partial response). Median PFS was 4.8 months. The drug was well tolerated. The second stage of accrual was not opened due to few objective responses. Oral vorinostat has limited single-agent activity in relapsed/refractory HL. There was one partial response, while seven other patients had stable disease for > 1 year, including two with stable disease for nearly 3 years, suggesting that further studies in combination with other active agents in this setting may be warranted.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Doença de Hodgkin/tratamento farmacológico , Ácidos Hidroxâmicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Administração Oral , Adulto , Idoso , Feminino , Seguimentos , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Vorinostat , Adulto Jovem
13.
Cancer Res ; 71(11): 3912-20, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21502403

RESUMO

MK-0457 and MK-5108 are novel aurora kinase inhibitors (AKi) leading to G(2)-M cell-cycle arrest. Growth and survival of multiple lymphoma cell lines were studied with either drug alone or in combination with vorinostat, a histone deacetylase inhibitor (HDACi), using MTS and Annexin V assays, followed by molecular studies. Either of the AKi alone at 100 to 500 nmol/L resulted in approximately 50% reduced cell growth and 10% to 40% apoptosis. Addition of vorinostat reactivated proapoptotic genes and enhanced lymphoma cell death. Quantitative PCR and immunoblotting revealed that epigenetic and protein acetylation mechanisms were responsible for this activity. The prosurvival genes Bcl-X(L) and hTERT were downregulated 5-fold by combination drug treatment, whereas the proapoptotic BAD and BID genes were upregulated 3-fold. The p53 tumor suppressor was stabilized by an increased acetylation in response to vorinostat and a reduced Ser315 phosphorylation in response to aurora kinase A. Vorinostat or trichostatin A decreased MYC mRNA and protein as well as c-Myc-regulated microRNAs. MYC is a critical gene in these responses, as MYC knockdown combined with the expression of the c-Myc antagonist MXD1 raised cell sensitivity to the effects of either AKi. Thus, the HDACi vorinostat leads to both transcriptional and posttranscriptional changes to create a proapoptotic milieu, sensitizing cells to mitosis-specific agents such as AKis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Linfoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aurora Quinase A , Aurora Quinases , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Immunoblotting , Linfoma/genética , Linfoma/metabolismo , Linfoma/patologia , MicroRNAs/biossíntese , MicroRNAs/genética , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Telomerase/biossíntese , Telomerase/genética , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Vorinostat
14.
J Clin Oncol ; 27(32): 5410-7, 2009 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-19826128

RESUMO

PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.


Assuntos
Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Área Sob a Curva , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacocinética , Fadiga/induzido quimicamente , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Leucemia/induzido quimicamente , Linfoma Cutâneo de Células T/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
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