RESUMO
T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.
Assuntos
Micose Fungoide/terapia , Síndrome de Sézary/terapia , Neoplasias Cutâneas/terapia , Corticosteroides/uso terapêutico , Idoso , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Bexaroteno/uso terapêutico , Biomarcadores Tumorais/sangue , Ensaios Clínicos como Assunto , Terapia Combinada , Diagnóstico Tardio , Diagnóstico Diferencial , Elétrons/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Micose Fungoide/diagnóstico , Micose Fungoide/patologia , Micose Fungoide/fisiopatologia , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/patologia , Terapia PUVA , Fotoferese , Prognóstico , Retinoides/uso terapêutico , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/patologia , Síndrome de Sézary/fisiopatologia , Transdução de Sinais , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/patologiaAssuntos
Antineoplásicos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Recidiva Local de Neoplasia , Niacinamida/uso terapêutico , Projetos Piloto , Sorafenibe , Resultado do TratamentoRESUMO
Pralatrexate is a folate analogue metabolic inhibitor manufactured by Allos Therapeutics, Inc., a wholly-owned subsidiary of Spectrum Pharmaceuticals, Inc. In both preclinical and clinical studies, pralatrexate demonstrated activity in lymphoma. Pralatrexate was US FDA approved for the treatment of relapsed/refractory peripheral T-cell lymphoma in 2009. Approval was based on data from the PROPEL trial that demonstrated an overall response rate of 29% in a heavily pretreated patient population. The dose and schedule of pralatrexate is 30-mg/m(2) weekly for 6 weeks, given in 7-week cycles. Folate and vitamin B12 supplementation are required to minimize toxicity. The most common toxicities are mucositis, thrombocytopenia, nausea and fatigue.
Assuntos
Aminopterina/análogos & derivados , Antineoplásicos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Aminopterina/efeitos adversos , Aminopterina/química , Aminopterina/farmacocinética , Aminopterina/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , RecidivaRESUMO
INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of T-cell neoplasms. Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem-cell transplantation. Pralatrexate, a novel antifolate chemotherapeutic agent, was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase (DHFR) and to be more efficiently internalized into tumor cells. Pralatrexate is the first drug that is FDA approved for patients with relapsed and refractory PTCL. AREAS COVERED: Pralatrexate has been used as a single agent and in combination with other agents in clinical trials for non-Hodgkin's lymphoma and Hodgkin's disease as well as in solid tumors. This review will cover the development of pralatrexate, the pharmacokinetics of pralatrexate, preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies. EXPERT OPINION: Pralatrexate has significant activity in vitro, and in early Phase I/II trials, responses were noted in patients with aggressive T-cell lymphomas. The Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T-cell lymphoma subtypes, and studies in cutaneous T-cell lymphoma have shown efficacy at different doses and schedules. The most frequent adverse events in these trials were mucositis, reversible thrombocytopenia and fatigue.
Assuntos
Aminopterina/análogos & derivados , Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Linfoma de Células T/tratamento farmacológico , Aminopterina/efeitos adversos , Aminopterina/farmacocinética , Aminopterina/farmacologia , Aminopterina/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/uso terapêutico , HumanosRESUMO
Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.
Assuntos
Síndrome de Sézary/patologia , Síndrome de Sézary/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Alquilantes/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Quimioterapia Combinada , Medicina Baseada em Evidências , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Metotrexato/uso terapêutico , Micose Fungoide/patologia , Micose Fungoide/terapia , Qualidade de Vida , Retinoides/uso terapêutico , Síndrome de Sézary/imunologia , Neoplasias Cutâneas/imunologiaRESUMO
The National Comprehensive Cancer Network (NCCN) practice guidelines for peripheral T-cell lymphoma (PTCL) accentuate the lack of standard treatment options for this disease. Outcomes with conventional therapies, many of which are borrowed from B-cell lymphoma, are poor. Strategies to enhance existing approaches include creating a new platform for first-line therapy and adding novel agents, such as denileukin diftitox, to existing chemotherapy platforms. Furthermore, to improve outcomes, patients must reach transplant through effective first-line therapies. Additionally, treatment should be individualized based on histopathologic subtype, as all PTCL patients will not respond to the same treatment regimen.
Assuntos
Linfoma de Células T Periférico/terapia , Terapias em Estudo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/radioterapia , Linfoma de Células T Periférico/cirurgia , Subpopulações de Linfócitos T/patologiaRESUMO
Primary cutaneous T-cell lymphomas are a heterogenous group of non-Hodgkin lymphomas. The characteristic clinicopathologic and immunophenotypic features and prognoses of the various cutaneous lymphomas have been recently described by the World Health Organization and European Organization for Research and Treatment of Cancer. Cutaneous T-cell lymphoma variants include mycosis fungoides and Sezary syndrome, which are generally associated, respectively, with indolent and aggressive clinical courses and are the subject of this review. Currently utilized treatments for cutaneous T-cell lymphoma include skin-directed therapies (topical agents such as corticosteroids, mechlorethamine, carmustine, and retinoids, phototherapy, superficial radiotherapy, and total skin electron beam therapy), systemic therapies (photophoresis, retinoids, denileukin diftitox, interferons, and chemotherapy), and stem cell transplantation (autologous and allogeneic). This review will describe recent advances in our understanding of the biology (immunologic, cytogenetic, and genetic) of cutaneous T-cell lymphomas and discuss the efficacy and tolerability of the current therapeutic options for cutaneous T-cell lymphomas. Disease progression in over 20% of patients with early stages of disease and the current lack of a definitive treatment which produces durable responses in advanced stages of disease indicates a critical unmet need in CTCL. New insights into the molecular and immunologic changes associated with cutaneous T-cell lymphomas should ultimately lead to the identification of novel therapeutic targets and the development of improved therapeutic options for patients with these malignancies.
Assuntos
Micose Fungoide/terapia , Síndrome de Sézary/terapia , Neoplasias Cutâneas/terapia , Humanos , Resultado do TratamentoRESUMO
There are now a wide variety of therapeutic options for managing patients with cutaneous T-cell lymphoma-related symptoms. These include skin-directed therapies such as psoralen with UVA irradiation (PUVA), topical chemotherapies such as mechlorethamine (nitrogen mustard) and carmustine (BCNU), electron beam radiation, and systemic therapies such as chemotherapy, photopheresis, and interferons. Although treatment algorithms exist for patients with early stage disease, often treatments are individualized, based on patient specific factors, cost, and accessibility of referral centers for specialized therapies. This article provides details of five real-life case studies to illustrate how cutaneous T-cell lymphoma management can be tailored to the needs of each individual patient.
Assuntos
Dermatite Esfoliativa/tratamento farmacológico , Eritema Nodoso/tratamento farmacológico , Linfoma Cutâneo de Células T/tratamento farmacológico , Micose Fungoide/tratamento farmacológico , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Antineoplásicos/uso terapêutico , Carmustina/uso terapêutico , Terapia Combinada , Feminino , Ficusina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Terapia PUVA , FototerapiaRESUMO
Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos/uso terapêutico , Toxina Diftérica/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-2/uso terapêutico , Receptores do Ácido Retinoico/efeitos dos fármacos , Proteínas Recombinantes de Fusão/uso terapêutico , Retinoides/farmacologia , Fatores de Transcrição/efeitos dos fármacos , Alitretinoína , Linfócitos B/efeitos dos fármacos , Bexaroteno , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Receptores de Interleucina-2/efeitos dos fármacos , Receptores de Interleucina-2/genética , Receptores do Ácido Retinoico/fisiologia , Receptores X de Retinoides , Linfócitos T/efeitos dos fármacos , Tetra-Hidronaftalenos/farmacologia , Fatores de Transcrição/fisiologia , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
OBJECTIVE: This was a phase II study of perillyl alcohol in the treatment of advanced ovarian cancer. The primary endpoint was to evaluate the 6-month progression-free rate of perillyl alcohol as compared with historic controls. Secondary objectives were to evaluate the objective response rate, time to progression and survival, dropout rate, and number of cycles administered; define the qualitative nature of acute and chronic toxicities; and evaluate the effect of perillyl alcohol on triglycerides and total, HDL, and LDL cholesterol levels. Methods. Women who had received prior platinum-based therapy and had residual or recurrent disease were eligible. Perillyl alcohol was administered orally, four times daily, at a dose of 1200 mg/m(2). This was repeated until disease progression or unacceptable toxicity was experienced. RESULTS: The 6-month progression-free rate was 17%. None of the patients achieved a complete or partial response. The median progression-free survival was 1.7 months. The median overall survival was 9.1 months. Compliance was greater than 90% but gastrointestinal toxicity (grade 1-2 nausea, satiety, eructation in 70%) and fatigue (grade 1-2 in 40%) were common and limited the ability to escalate the dose from 1200 to 1500 mg/m(2). CONCLUSION: Perillyl alcohol administered at this dose and formulation did not exhibit signs of extending the time-to-progression in patients with advanced ovarian carcinoma.