Owen A O'Connor1. 1. Laboratory of Experimental Therapeutics for Lymphoproliferative Malignancies, Department of Medicine, Division of Hematologic Malignancies, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York 10021, USA. oconnoro@mskcc.org
Abstract
PURPOSE OF REVIEW: T-cell lymphomas (TCL) represent a particularly poor prognosis subgroup of lymphomas. The goal of this review is to provide emerging information on one agent demonstrating activity in these challenging diseases. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1 (RFC-1). Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against TCL. RECENT FINDINGS: The high affinity of pralatrexate for RFC-1 significantly improves its internalization into cells. Preclinical studies in models of B-cell lymphomas and TCL have demonstrated that pralatrexate demonstrates activity superior to traditional antifolates. Phase I studies have shown the dose-limiting toxicity to be stomatitis, which can be abrogated with folic acid and vitamin B12 supplementation. Early phase studies have shown marked activity across a diverse panoply of TCL. SUMMARY: Pralatrexate is an antifolate designed to be internalized more rapidly than other traditional antifolates. Preclinical studies have demonstrated its superiority to methotrexate, and early phase I and II studies have shown marked activity across many poor-risk subtypes of TCL. Future studies are directed towards understanding the pharmacokinetic features of the drug, and expanding the population of patients with TCL and B-cell lymphomas.
PURPOSE OF REVIEW: T-cell lymphomas (TCL) represent a particularly poor prognosis subgroup of lymphomas. The goal of this review is to provide emerging information on one agent demonstrating activity in these challenging diseases. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1 (RFC-1). Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against TCL. RECENT FINDINGS: The high affinity of pralatrexate for RFC-1 significantly improves its internalization into cells. Preclinical studies in models of B-cell lymphomas and TCL have demonstrated that pralatrexate demonstrates activity superior to traditional antifolates. Phase I studies have shown the dose-limiting toxicity to be stomatitis, which can be abrogated with folic acid and vitamin B12 supplementation. Early phase studies have shown marked activity across a diverse panoply of TCL. SUMMARY:Pralatrexate is an antifolate designed to be internalized more rapidly than other traditional antifolates. Preclinical studies have demonstrated its superiority to methotrexate, and early phase I and II studies have shown marked activity across many poor-risk subtypes of TCL. Future studies are directed towards understanding the pharmacokinetic features of the drug, and expanding the population of patients with TCL and B-cell lymphomas.
Authors: Birgit V Nimmervoll; Nidal Boulos; Brandon Bianski; Jason Dapper; Michael DeCuypere; Anang Shelat; Sabrina Terranova; Hope E Terhune; Amar Gajjar; Yogesh T Patel; Burgess B Freeman; Arzu Onar-Thomas; Clinton F Stewart; Martine F Roussel; R Kipling Guy; Thomas E Merchant; Christopher Calabrese; Karen D Wright; Richard J Gilbertson Journal: Clin Cancer Res Date: 2018-01-04 Impact factor: 12.531