A B S T R A C T PurposeTo determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and MethodsPralatrexate, 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/L, and a platelet count greater than 50,000/L for the first dose of any cycle. ResultsThe 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. ConclusionPralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.

Key Points Treatment of DLBCL with the combination of sirtuin and DAC inhibitors leads to synergistic cytotoxicity and acetylation of Bcl6 and p53. The overall response rate of relapsed lymphoma patients treated with vorinostat and niacinamide was 24%, and an additional 57% achieved stable disease.

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.

Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma Based on the most recent surveillance epidemiology and end results registry data (Morton et al, 2005), it is estimated that there are 114 548 cases of lymphoid neoplasms per year in the United States, of which 87 666 (about 76%) are B-cell lymphoid neoplasms and 10 042 are Hodgkin lymphoma. Only 5-6% of lymphoid malignancies (6228 cases per year) are T/natural killer (NK) cell neoplasms. A series of other studies have found T-cell lymphomas (TCLs) to constitute a small fraction of total non-Hodgkin lymphomas (NHLs) in the US, with reports typically ranging from 10 to 15% (Devesa & Fears, 1992) In general, TCLs carry a worse prognosis than B-cell lymphomas. In a retrospective analysis of sequential Groupe d'Etudes des Lymphomes de l'Adulte trials for aggressive lymphomas (Gisselbrecht et al, 1998), the 5-year survival rate for patients with 1, 2 or 3 risk factors with B-versus TCL was 63% vs. 60%, 53% vs. 36% and 35% vs. 23% respectively. Similar adverse results for TCL were also observed for the rate of complete remission (CR). Furthermore, the International Lymphoma Study Group classification project found that peripheral TCL (PTCL) and precursor T-lymphoblastic leukaemia/lymphoma (T-ALL) had some of the worst outcomes of any subtype of lymphoma, with a 5-year survival rate of 26% following treatment with standard doxorubicin containing regimens (Rudiger et al, 2002). There are indolent subtypes of TCL, such as mycosis fungoides and primary cutaneous anaplastic large cell lymphoma (ALCL), which do not follow this universally poor prognosis. Among the aggressive TCLs,

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 Mantle cell lymphoma (MCL) represents an aggressive form of non-Hodgkin lymphoma. The disease often responds to initial combination chemotherapy but is characterized by inevitable relapse. In the relapsed and refractory states, the disease is characterized by partial responses with typically short durations of benefit. Most patients are treated with a cyclophosphamide-based regimen at presentation, with or without a peripheral blood stem cell transplant. Second line SummaryThe 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 enroled 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 = 0AE74), while both populations of patients exhibited essentially similar progressionfree survival (PFS; 5AE6 months vs. 3AE9 months, P = 0AE81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7AE8 months vs. 8AE4 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 crossresistance 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.