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 Article


Authors: 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.
Article Title: 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
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/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/mu L, and a platelet count greater than 50,000/mu L 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/m(2) 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.
Keywords: methotrexate; analogs; human-tumor xenografts; non-hodgkins-lymphomas; rfc-1 gene-expression; 10-deaza-aminopterin series; antifolate; 10-propargyl-10-deazaaminopterin; 10-deazaaminopterin; superior
Journal Title: Journal of Clinical Oncology
Volume: 27
Issue: 26
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2009-09-10
Start Page: 4357
End Page: 4364
Language: English
ACCESSION: ISI:000269652200022
DOI: 10.1200/jco.2008.20.8470
PROVIDER: wos
PUBMED: 19652067
PMCID: PMC3651599
Notes: --- - Article - "Source: Wos"
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    285 Seshan
  2. Carol Portlock
    178 Portlock
  3. Craig Moskowitz
    372 Moskowitz
  4. Steven M Horwitz
    351 Horwitz
  5. Andrew D Zelenetz
    550 Zelenetz
  6. Paul Hamlin
    170 Hamlin
  7. Martin Fleisher
    237 Fleisher
  8. Francis M Sirotnak
    113 Sirotnak