Pralatrexate (PDX) Produces Durable Complete Remissions in Patients with Chemotherapy Resistant Precursor and Peripheral T-Cell Lymphomas: Results of the MSKCC Phase I/II Experience.

T-cell lymphomas (TCL) represent a diverse and heterogeneous group of diseases. The prognosis of patients with TCL is generally much worse than for patients with B-cell lymphoma (BCL). Pralatrexate is a novel 10-deazaminopoterin rationally designed to have high affinity for the reduced folate carrier (RFC-1), and is thus more efficiently internalized than other aminopterin derivatives. RFC-1 is an oncofetalprotein that is preferentially over-expressed on fetal and malignant tissues, and is known to be markedly up-regulated by a variety of oncogenes, including c-myc and H-ras. A dose escalation study of PDX were conducted in patients with lymphoproliferative malignancies on every other week (QOW) and weekly (QW) schedules in patients with non-Hodgkin’s (NHL) and Hodgkin’s Lymphoma (HL). That study demonstrated that repletion with folic acid and vitamin B12 could abrogate the previous dose limiting toxicity (DLT) of mucositis. The maximum tolerated dose (MTD) of PDX on a weekly schedule was 30 mg/m² weekly IV × 6 weeks every 7 weeks. The DLT was primarily hematologic, including thrombocytopenia. Aweekly phase 2 study has accrued 16 patients to date. In total, 49 patients have been treated with PDX on study (16 on the QOW schedule, 17 on the QW Phase 1, and 16 on the QW Phase 2). Twenty-four of the 49 patients (49%) had some form of TCL. Among the 6 patients with HL treated on study, only stable disease was appreciated. Among the 18 patients with BCL, only 1 PR was appreciated. One patient with a composite NHL experienced progression of disease (POD). Among the 24 patients with TCL, 4 are too early to judge for response, and 4 experienced toxicity following only 1–2 doses of drug, deemed possibly or unlikely related to study drug, including: septicemia following regression of infiltrated skin (HTLV-1 ATLL) and bowel (enteropathy associated TCL); persistent thrombocytopenia in 1 patient with borderline and variable platelets; and 1 patient with a colostomy who developed a fistula and other complications, including stomatitis. Of 16 patients who completed at least 2 cycles of therapy, 10 experienced a major remission (overall response rate [ORR] 63%; 9 complete remissions [CR] and 1 partial remission [PR]). Even in the intent-to-treat population, the ORR was 50%. One patient had stable disease, 5 had POD. Three of 5 patients who progressed had angioimmunoblastic TCL, 2 experienced mixed responses including one with NK/T-nasal type and one with HTLV-1 ATLL. Durable complete remissions have been documented in the following sub-types: acute lymphoblastic (12 mo.), HTLV-1 ATLL (18+ mo.), blastic NK/T (9+ mo.), ALK (+) anaplastic large cell (6+ mo), PTCL NOS (3 mo), subcutaneous panniculitis-like (3+ mo), and γ,δ-subcutaneous panniculitis-like (9 mo). Most of the responding patients had disease refractory to conventional chemotherapy, including methotrexate for the patients with ALL and γ,δ-panniculitis-like TCL. These data demonstrate that PDX exhibits significant activity in TCL, producing predominantly complete remission as the major response, the majority of which are durable. An international confirmatory trial of these data is now ongoing.