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      Critical appraisal of pralatrexate in the management of difficult-to-treat peripheral T cell lymphoma

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          Aggressive T cell lymphomas are a subgroup of lymphomas with a particularly poor prognosis. This is especially true for patients with recurrent or refractory disease, who typically have limited response to salvage therapy and extremely poor overall survival. For this reason, there is a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T cell lymphomas. The dose-limiting toxicity for pralatrexate is mucositis, which can be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is the first single agent approved for the treatment of patients with relapsed or refractory peripheral T cell lymphoma. This approval was based on an overall objective response rate observed in the pivotal study. The overall response rate was 29%, with a median duration of 10.1 months. This article reviews the biochemistry, preclinical experience, metabolism, and pharmacokinetics of pralatrexate, including the clinical experience with this agent in lymphoma. Future areas of development are now focused on identifying synergistic combinations of pralatrexate with other agents and the evaluation of predictive markers for clinical benefit.

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          Most cited references 36

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          A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.

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            A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

            The recognition of several new types of non-Hodgkin's lymphoma (NHL) in recent years has led to proposals for changing lymphoma classifications, including a new proposal put forth by the International Lymphoma Study Group (ILSG). However, the clinical significance of the new entities and the practical utility of this new proposal have not been studied. Therefore, we performed a clinical evaluation of the ILSG classification. A cohort of 1,403 cases of NHL was organized at nine study sites around the world and consisted of consecutive patients seen between 1988 and 1990 who were previously untreated. A detailed protocol for histologic and clinical analysis was followed at each site, and immunologic characterization as to T- or B-cell phenotype was required. Five expert hematopathologists visited the sites and each classified each case using the ILSG classification. A consensus diagnosis was also reached in each case, and each expert rereviewed a 20% random sample of the cases. Clinical correlations and survival analyses were then performed. A diagnosis of NHL was confirmed in 1,378 (98.2%) of the cases. The most common lymphoma types were diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%), whereas the new entities comprised 21% of the cases. Diagnostic accuracy was at least 85% for most of the major lymphoma types, and reproducibility of the diagnosis was 85%. Immunophenotyping improved the diagnostic accuracy by 10% to 45% for a number of the major types. The clinical features of the new entities were distinctive. Both the histologic types and the patient characteristics as defined by the International Prognostic Index predicted for patient survival. In conclusion we found that the ILSG classification can be readily applied and identifies clinically distinctive types of NHL. However, for clinical application, prognostic factors as defined by the International Prognostic Index must be combined with the histologic diagnosis for appropriate clinical decisions.
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              Epidemiology of the non-Hodgkin's lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin's Lymphoma Classification Project.

              There has been no previous systematic study of the distribution of the major subtypes of non-Hodgkin's lymphoma (NHL) across geographic regions, although there have been isolated reports of such differences. As part of a clinical evaluation of the International Lymphoma Study Group (ILSG) classification of NHL, we classified 1378 NHLs from eight different geographic sites (Omaha, NE, USA; Vancouver, BC, Canada; Capetown, South Africa; London, England; Würzburg/Göttingen, Germany; Lyon, France; Locarno/Bellinzona, Switzerland; and Hong Kong) using the ILSG classification. Substantial differences were found in the distribution of the major subtypes of NHL across geographic regions (P < 0.0001). A greater percentage of follicular lymphoma was seen in North America, London and Capetown (31% versus 14% at other sites). Peripheral T-cell lymphoma was more common in London, Capetown and Hong Kong (9%) than elsewhere (3%). In Locarno/Bellinzona, higher percentages of mediastinal large B-cell lymphoma (9% versus 2% elsewhere) and mantle cell lymphoma (14% versus 6% elsewhere) were seen. Angiocentric nasal T-/NK-cell lymphoma was only seen in Hong Kong (8%) and Lyon (2%). Our study provides evidence that the distribution of NHL subtypes differs by geographic region. These findings suggest that geographical differences in etiologic or host factors may be responsible for the observed differences in the distribution of cases across NHL subtypes.

                Author and article information

                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                07 October 2011
                : 7
                : 401-408
                Oncohematology Service, Hospital Costa del Sol, Marbella, Spain
                Author notes
                Correspondence: Antonio Rueda, Servicio de Oncohematología, Hospital Costa del Sol, Autovía A-7, Km 187, 29600 Marbella, Spain, Tel +34 951 976 192, Fax +34 951 976 473, Email arueda@ 123456hcs.es
                © 2011 Casanova et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.



                peripheral t cell lymphoma, pralatrexate


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