RESUMEN
Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor κB. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210.
Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Sirtuinas/metabolismo , Acetilación/efectos de los fármacos , Adulto , Anciano , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Concentración 50 Inhibidora , Linfoma de Células B Grandes Difuso/patología , Masculino , Ratones , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/farmacología , Niacinamida/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pralatrexate is a novel antifolate, which shows increased antitumor activity in human tumor xenograft studies in mice compared with methotrexate. We investigated the effects of pralatrexate in a patient with adult T-cell lymphoma/leukemia with significant skin involvement. Atypical lymphocytes in epidermal Pautrier microabscesses were positive for HTLV-1. After the patient presented with leukemic conversion and with worsening of an erythematous generalized papular rash, he received one dose of pralatrexate. Within one week, his skin developed innumerable small erosions limited to the areas of the papular rash, sparing unaffected skin. Here we present in vivo evidence that pralatrexate-induced erosions in skin affected by adult T-cell lymphoma/leukemia are a manifestation of apoptosis of tumor cells infiltrating the epidermis and are not the result of cytotoxicity by pralatrexate on keratinocytes. This distinction is critical and may profoundly influence the clinical decision to continue pralatrexate treatment. Pralatrexate-induced skin erosions may indicate response to treatment.
Asunto(s)
Aminopterina/análogos & derivados , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Epidermis/efectos de los fármacos , Exantema/inducido químicamente , Antagonistas del Ácido Fólico/farmacología , Leucemia-Linfoma de Células T del Adulto/patología , Adulto , Aminopterina/farmacología , Aminopterina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Ciclofosfamida/administración & dosificación , Diagnóstico Diferencial , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Erupciones por Medicamentos/diagnóstico , Epidermis/patología , Etopósido/administración & dosificación , Exantema/diagnóstico , Antagonistas del Ácido Fólico/uso terapéutico , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/radioterapia , Masculino , Prednisona/administración & dosificación , Proteínas Recombinantes , Vincristina/administración & dosificación , Zidovudina/administración & dosificaciónRESUMEN
Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0.02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Pirazinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/efectos adversos , Pirazinas/administración & dosificación , Pirazinas/efectos adversosRESUMEN
The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enrolled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively (P = 0.74), while both populations of patients exhibited essentially similar progression-free survival (PFS; 5.6 months vs. 3.9 months, P = 0.81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7.8 months vs. 8.4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross-resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib.
Asunto(s)
Antineoplásicos/administración & dosificación , Ácidos Borónicos/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteasas/administración & dosificación , Pirazinas/uso terapéutico , Antineoplásicos/uso terapéutico , Bortezomib , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Múltiples Medicamentos , Femenino , Humanos , Masculino , Inhibidores de Proteasas/uso terapéutico , Inducción de RemisiónRESUMEN
OBJECTIVE: T-cell lymphomas (TCLs) classically have a poorer response to therapy when compared with B-cell lymphomas and account for only 10-15% of all lymphoid malignancies. Hepatosplenic TCLs are a rare subset of this group that usually present with hepatosplenomegaly, B-symptoms, and only rarely with lymphadenopathy. BACKGROUND: This disease process, also known as gamma/delta (gamma/delta) TCL because of the expression of the T-cell receptor gamma/delta chain, tends to present in young male patients. Hepatosplenic TCLs have recently gained notoriety because of the realization that patients with long-term treatment of some immunomodulators can develop this potentially fatal disease. These facts are exacerbated by the fact that patients with this disease rarely enjoy remissions of more than brief duration with common chemotherapeutic agents or bone marrow transplants. A novel agent, pralatrexate, has recently been found to have a dramatic activity in this patient population with refractory/relapsed disease. Unfortunately, patients with hepatosplenic TCL often present with thrombocytopenia and this new agent is contraindicated in these patients because of the potential exacerbation of thrombocytopenia with this agent. METHODS: Because of this we attempted a laparoscopic-assisted splenectomy in one patient with grade 4 thrombocytopenia. RESULTS: Postoperatively the patient's thrombocytopenia resolved, permitting him to begin treatment with this potentially life-saving agent. CONCLUSION: Due to the lethality of this disease and potential efficacy of new therapies, we believe splenectomy should be considered in patients with hepatosplenic lymphoma in an effort to improve the treatment options and survival of patients with this challenging disease.
Asunto(s)
Neoplasias Hepáticas/cirugía , Linfoma de Células T/cirugía , Esplenectomía , Neoplasias del Bazo/cirugía , Trombocitopenia/tratamiento farmacológico , Aminopterina/análogos & derivados , Aminopterina/uso terapéutico , Resultado Fatal , Fármacos Hematológicos/uso terapéutico , Humanos , Laparoscopía , Neoplasias Hepáticas/diagnóstico , Linfoma de Células T/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias del Bazo/diagnóstico , Trombocitopenia/etiología , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma. EXPERIMENTAL DESIGN: Patients with follicular lymphoma (FL), marginal zone lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia were eligible for study. Bortezomib was given at a dose of 1.5 mg/m(2) as an i.v. push on days 1, 4, 8, and 11 of a 21-day cycle. Eligibility included the following: (a) no more than three prior therapies, (b) at least 1 month since prior chemotherapy, (c) measurable disease, and (d) an absolute neutrophil count of >1,000/microL and a platelet count >50,000/microL for the first dose of any cycle. RESULTS: Seventy-seven patients were registered, of which 69 were assessable for response based on the completion of two cycles of therapy. Subtypes included FL (59.5%), mantle cell lymphoma (52%), small lymphocytic lymphoma/chronic lymphocytic leukemia (16.2%), marginal zone lymphoma (21.6%), and one Waldenstrom's macroglobulinemia. The median number of prior therapies was three. The most common grade 3 toxicity was lymphopenia (35%) and thrombocytopenia (31%). Twenty-five patients experienced grade Asunto(s)
Ácidos Borónicos/uso terapéutico
, Linfoma de Células B/tratamiento farmacológico
, Linfoma Folicular/tratamiento farmacológico
, Pirazinas/uso terapéutico
, Adulto
, Anciano
, Anciano de 80 o más Años
, Bortezomib
, Progresión de la Enfermedad
, Supervivencia sin Enfermedad
, Femenino
, Humanos
, Linfoma de Células B/diagnóstico
, Linfoma de Células B/mortalidad
, Linfoma de Células B/patología
, Linfoma Folicular/diagnóstico
, Linfoma Folicular/mortalidad
, Linfoma Folicular/patología
, Masculino
, Persona de Mediana Edad
, Recurrencia
, Análisis de Supervivencia
, Factores de Tiempo
, Resultado del Tratamiento
RESUMEN
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.
Asunto(s)
Aminopterina/análogos & derivados , Linfoma de Células T/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminopterina/administración & dosificación , Aminopterina/efectos adversos , Aminopterina/uso terapéutico , Estreñimiento/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Fatiga/inducido químicamente , Femenino , Antagonistas del Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/uso terapéutico , Humanos , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Estomatitis/inducido químicamente , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacos , Adulto JovenRESUMEN
T-cell lymphomas (TCLs) are characterised by poor responses to therapy with brief durations of remissions. An early phase study of pralatrexate has demonstrated dramatic activity in patients with relapsed/refractory disease. Of the first 20 lymphoma patients treated, 16 had B-cell lymphoma and four had refractory aggressive TCL. All four patients with TCL achieved a complete remission. Patients with B-cell lymphoma achieved stable disease at best. For each TCL patient, the response was more durable than their best response with chemotherapy. This early experience is the first to document this unique activity of pralatrexate in TCL.
Asunto(s)
Aminopterina/análogos & derivados , Antineoplásicos/uso terapéutico , Antagonistas del Ácido Fólico/uso terapéutico , Linfoma de Células T/tratamiento farmacológico , Adulto , Anciano , Aminopterina/metabolismo , Aminopterina/uso terapéutico , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Antagonistas del Ácido Fólico/metabolismo , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células T/diagnóstico por imagen , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non-Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy. Punch biopsy in six patients revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, consistent with a non-necrotising cutaneous vasculitis. The combined overall response rate was 41%. The response in the 26 patients who developed a rash was 73%, compared with 33% in patients who did not. The odds ratio for response given the development of a rash was 4.6 (95% CI, 1.7-12.4, P = 0.001). This is the first report to characterise a vasculitic rash associated with bortezomib, and to show a relationship between development of the rash and response to treatment. Unlike classic hypersensitivity type reactions, this vasculitic rash may not necessarily prompt cessation of drug. In fact, the development of an isolated cutaneous vasculitis may portend a better clinical response to bortezomib in some patients.