Safety and efficacy of pralatrexate in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma

Abstract

T-cell lymphomas (TCL) are a diverse and heterogeneous group of malignancies that represent less than 15% of all non-Hodgkin lymphomas. Initial refinements of the clinical classification of these complex diseases have been made, but a better understanding of their molecular pathogenesis is still needed. Even if the paucity of insights into the underlying pathogenesis of TCLs has hindered our ability to develop rational targeted therapies, significant advances have been made. Pralatrexate (10-propargyl 10-deazaaminopterin) is a unique antifolate that has been rationally designed to have high affinity for the reduced folate receptor (RFC) and the folylpolyglutamate synthetase (FPGS) and was the first drug ever approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This review describes the preclinical development of pralatrexate that led to early-phase clinical trials in lung cancer and lymphoma and its subsequent approval in PTCL. The review also describes how pralatrexate has been combined with other agents in both the preclinical and clinical settings. FDA approval for the use of pralatrexate in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients. clinical development, pralatrexate, preclinical data, T-cell lymphoma.

Keywords: T-cell lymphoma; clinical development; pralatrexate; preclinical data.

Figure 1.

Figure 1. A: Chemical structure of pralatrexate and methotrexate; B: Internalization and retention of pralatrexate inside the cells. PDX, pralatrexate; RFC, reduced folate carrier; PDX-(G)n, polyglutamated pralatrexate; TMTX, trimetrexate; FPGS, folylpolyglutamate synthase; FPGH, folypolyglutamyl hydrolase; cMOAT, canalicular multispecific organic-anion transporter; MRP, multidrug resistance-associated protein.Illustration courtesy of Alessandro Baliani. Copyright © 2012. Adapted from Owen O’Connor’s personal slide.