RESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. PATIENTS AND METHODS: Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle. RESULTS: The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. CONCLUSION: Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Assuntos
Aminopterina/análogos & derivados , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopterina/administração & dosagem , Aminopterina/efeitos adversos , Aminopterina/uso terapêutico , Constipação Intestinal/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Fadiga/induzido quimicamente , Feminino , Antagonistas do Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Estomatite/induzido quimicamente , Resultado do Tratamento , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.