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.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.


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/microL, and a platelet count greater than 50,000/microL 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.


CONCLUSIONS
Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
O'Connor
Owen A
OA
Lymphoid Development and Malignancy Program, Lymphoma Service, Columbia University, Herbert Irving Comprehensive Cancer Center, 1130 St Nicholas Ave, New York, NY 10032, USA. oo2130@columbia.edu
Horwitz
Steven
S
Hamlin
Paul
P
Portlock
Carol
C
Moskowitz
Craig H
CH
Sarasohn
Debra
D
Neylon
Ellen
E
Mastrella
Jill
J
Hamelers
Rachel
R
Macgregor-Cortelli
Barbara
B
Patterson
Molly
M
Seshan
Venkatraman E
VE
Sirotnak
Frank
F
Fleisher
Martin
M
Mould
Diane R
DR
Saunders
Mike
M
Zelenetz
Andrew D
AD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000630:Aminopterin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003248:Constipation / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects; D055815:Young Adult
C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D000630:Aminopterin