Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies

Owen A. O'Connor, Steven Horwitz, Paul Hamlin, Carol Portlock, Craig H. Moskowitz, Debra Sarasohn, Ellen Neylon, Jill Mastrella, Rachel Hamelers, Barbara MacGregor-Cortelli, Molly Patterson, Venkatraman E. Seshan, Frank Sirotnak, Martin Fleisher, Diane R. Mould, Mike Saunders, Andrew D. Zelenetz

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157 Scopus citations

Abstract

Purpose: To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and Methods: Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle. Results: The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. Conclusion: Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

Original languageEnglish (US)
Pages (from-to)4357-4364
Number of pages8
JournalJournal of Clinical Oncology
Volume27
Issue number26
DOIs
StatePublished - Sep 10 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    O'Connor, O. A., Horwitz, S., Hamlin, P., Portlock, C., Moskowitz, C. H., Sarasohn, D., Neylon, E., Mastrella, J., Hamelers, R., MacGregor-Cortelli, B., Patterson, M., Seshan, V. E., Sirotnak, F., Fleisher, M., Mould, D. R., Saunders, M., & Zelenetz, A. D. (2009). Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. Journal of Clinical Oncology, 27(26), 4357-4364. https://doi.org/10.1200/JCO.2008.20.8470