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.

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/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. CONCLUSION: Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma.

Twice-weekly bortezomib has proven activity in mantle cell (MCL) and indolent lymphomas. This study explored a weekly schedule of bortezomib in follicular lymphoma (FL) and MCL. Although weekly bortezomib was better tolerated, the overall response rate (ORR) was inferior (18% vs. 50%, P = 0.02) with no complete remissions (CR) (compared with 18% CR for the twice-weekly schedule). Progression-free survival (PFS) was not different. The weekly schedule of bortezomib was less toxic, but yielded fewer and lower quality responses than twice-weekly bortezomib. Given the similar PFS, the weekly schedule may still be appropriate for some patients.

Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre Phase 2 clinical trial.

The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enrolled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively (P = 0.74), while both populations of patients exhibited essentially similar progression-free survival (PFS; 5.6 months vs. 3.9 months, P = 0.81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7.8 months vs. 8.4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross-resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib.