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 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

Research output: Contribution to journalArticle

150 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Reduced Folate Carrier Protein
Lymphoma
Appointments and Schedules
T-Lymphocytes
Stomatitis
Maximum Tolerated Dose
T-Cell Lymphoma
Neoplasms
Methylmalonic Acid
10-propargyl-10-deazaaminopterin
B-Cell Lymphoma
Homocysteine
Vitamin B 12
Platelet Count
Folic Acid
Positron-Emission Tomography
Neutrophils

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Journal of Clinical Oncology, Vol. 27, No. 26, 10.09.2009, p. 4357-4364.

Research output: Contribution to journalArticle

O'Connor, OA, Horwitz, S, Hamlin, P, Portlock, C, Moskowitz, C, Sarasohn, D, Neylon, E, Mastrella, J, Hamelers, R, MacGregor-Cortelli, B, Patterson, M, Seshan, VE, Sirotnak, F, Fleisher, M, Mould, DR, Saunders, M & Zelenetz, AD 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, vol. 27, no. 26, pp. 4357-4364. https://doi.org/10.1200/JCO.2008.20.8470
O'Connor, Owen A. ; Horwitz, Steven ; Hamlin, Paul ; Portlock, Carol ; Moskowitz, Craig ; Sarasohn, Debra ; Neylon, Ellen ; Mastrella, Jill ; Hamelers, Rachel ; MacGregor-Cortelli, Barbara ; Patterson, Molly ; Seshan, Venkatraman E. ; Sirotnak, Frank ; Fleisher, Martin ; Mould, Diane R. ; Saunders, Mike ; Zelenetz, Andrew D. / 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. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 26. pp. 4357-4364.
@article{f435dc29d47347f5a9893e0a4f250051,
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/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.",
author = "O'Connor, {Owen A.} and Steven Horwitz and Paul Hamlin and Carol Portlock and Craig Moskowitz and Debra Sarasohn and Ellen Neylon and Jill Mastrella and Rachel Hamelers and Barbara MacGregor-Cortelli and Molly Patterson and Seshan, {Venkatraman E.} and Frank Sirotnak and Martin Fleisher and Mould, {Diane R.} and Mike Saunders and Zelenetz, {Andrew D.}",
year = "2009",
month = "9",
day = "10",
doi = "10.1200/JCO.2008.20.8470",
language = "English (US)",
volume = "27",
pages = "4357--4364",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "26",

}

TY - JOUR

T1 - 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

AU - O'Connor, Owen A.

AU - Horwitz, Steven

AU - Hamlin, Paul

AU - Portlock, Carol

AU - Moskowitz, Craig

AU - Sarasohn, Debra

AU - Neylon, Ellen

AU - Mastrella, Jill

AU - Hamelers, Rachel

AU - MacGregor-Cortelli, Barbara

AU - Patterson, Molly

AU - Seshan, Venkatraman E.

AU - Sirotnak, Frank

AU - Fleisher, Martin

AU - Mould, Diane R.

AU - Saunders, Mike

AU - Zelenetz, Andrew D.

PY - 2009/9/10

Y1 - 2009/9/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70349310325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349310325&partnerID=8YFLogxK

U2 - 10.1200/JCO.2008.20.8470

DO - 10.1200/JCO.2008.20.8470

M3 - Article

VL - 27

SP - 4357

EP - 4364

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 26

ER -