levoleucovorin and 10-propargyl-10-deazaaminopterin

Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.

Topics: Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Folic Acid Antagonists; Humans; Leucovorin; Lymphoma, T-Cell; Male; Neoplasm Recurrence, Local

Peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) are rare, heterogeneous non-Hodgkin lymphomas with poor prognoses. Pralatrexate has demonstrated efficacy in T-cell lymphomas; however, mucositis has been reported as the most common dose-modifying adverse event. Leucovorin has been shown to minimize mucositis incidence, without sacrificing pralatrexate efficacy. We retrospectively studied 34 patients (7-PTCL/27-CTCL) treated with pralatrexate alone or pralatrexate and leucovorin. Leucovorin was administered preemptively prior to any mucositis occurrence. Pralatrexate dosing ranged from 10-30 mg/m

Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Female; Humans; Leucovorin; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Mucositis; Neoplasm Staging; Premedication; Retrospective Studies; Skin Diseases; Treatment Outcome

To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.. H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.. In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.. High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.

Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Leucovorin; Mesothelioma; Methotrexate; Mice, Nude; Pemetrexed; Time Factors; Tumor Burden; Vitamin B Complex; Xenograft Model Antitumor Assays

Balancing efficacy and safety of drugs is key for successful cancer therapy, as adverse reactions can prohibit the use of efficacious treatments. Pralatrexate (PDX) is a novel antifolate with a higher affinity for tumor cells than methotrexate, Food and Drug Administration (FDA) approved for use in relapsed and refractory peripheral T-cell lymphoma (PTCL) and transformed mycosis fungoides (T-MF). Patients with T-MF have a higher incidence of adverse events than patients with other lymphomas, necessitating a lower recommended dose of 15 mg/m(2) (vs. 30 mg/m(2) for PTCL). Dose-limiting toxicity (DLT) mucositis occurs in about 25% of patients with T-MF, but milder mucositis is observed in almost all patients with T-MF, frequently leading to therapy discontinuation despite clinical response. Leucovorin rescue is the standard of care for high-dose methotrexate therapy, but has not been studied or recommended for use with PDX. We report our clinical experience using leucovorin with PDX (30 mg/m(2)) with good clinical response and no DLTs. Prophylactic leucovorin deserves further investigation in prospective clinical trials to allow patients with cutaneous lymphomas to receive the full benefit of PDX therapy without intolerable toxicity.

Topics: Adult; Aged; Aged, 80 and over; Aminopterin; Female; Folic Acid Antagonists; Humans; Leucovorin; Lymph Nodes; Lymphoma, T-Cell, Peripheral; Male; Mycosis Fungoides; Premedication; Skin; Tomography, X-Ray Computed