Pralatrexate (10-Propargyl-10-Deazaaminopterin (PRX)), a Novel Antifolate, Effects Durable Complete Remissions (CR) in Patients with a Diversity of Drug Resistant T-Cell Lymphomas with Minimal Toxicity.

PRX belongs to a new class of anti-folates designed to have improved affinity for the reduced folate carrier. A phase 2 study at 135 mg/m² given on an every other week (w) basis treated 16 patients, including Hodgkin’s Disease (HD) (n=5), aggressive B-cell lymphoma (BCL) (n=8), mantle cell lymphoma (n=2) and peripheral T-cell lymphoma (PTCL). A higher than anticipated incidence of stomatitis (6 of 16 patients with Grade 3 or 4 stomatitis) was associated with marked increase in stomatitis occurred in patients with Hcy and MMA less than 10 mM and 200 nM respectively. Patients with elevated Hcy and MMA who developed stomatitis with PRX did not develop advanced grade stomatitis after normalization of their Hcy and MMA with vitamins. The patient with chemotherapy refractory T-cell lymphoma attained a PET negative CR after one dose, while the other patients had stable/progressive disease. The study was amended to a weekly phase I study based on laboratory data. The dose escalation study was: 30 mg/m² w x 3 every 4 w; 30 mg/m² w x 6 every 7 w, then increasing by 15 mg/m² on the 7 week schedule. To date, eleven patients have been accrued to the amended study, including 7 patients with T-cell lymphoma (PTCL, angioimmunoblastic lymphoma (n=2), acute T-cell acute lymphoblastic lymphoma; HTLV-1 associated adult T-cell leukemia/lymphoma (ATLL), panniculitic T-cell lymphoma, and a NK-T cell lymphoma). In total, 8 patients with T-cell lymphoma have been treated with PRX, with 5 of the 8 evaluable for response. 4 of 5 evaluable patients with T-cell lymphoma achieved a CR within the first cycle, despite being chemotherapy refractory. The one patient with NK-T cell lymphoma had a mixed response. 3 of 4 patients remain in CR at 4 to 9 mo. and remain on treatment. Patients with BCL and HD attained stable disease. Normalization of Hcy and MMA pre-treatment with vitamins abrogated the stomatitis. Little hematological toxicity (grade 2 thrombocytopenia in 2 patients) has been observed. PRX has achieved a remarkably high CR rate among patients with drug resistant T-cell lymphoma in this phase I study. The ongoing trial will identify the MTD on the weekly schedule, the DLT, and to define the scope of PRX activity in T-cell lymphomas.