Phase I Study of Bortezomib in Combination with Gemcitabine in Relapsed/Refractory Intermediate Grade B-Cell and Mantle Cell Non-Hodgkin's Lymphoma.

The outlook for patients with relapsed or primary progressive intermediate to high grade Non Hodgkin's Lymphoma (NHL) remains problematic. The current best strategy is to to identify potential chemosensitive patients who may respond to autologous transplant, by use of high dose chemotherapy protocols However, approximately fifty percent of those who undergo high-dose therapy, and the majority of patients treated with standard salvage regimens alone, will ultimately show progression or relapse; newer regimens are necessary. In-vitro data in a number of tumor cell types shows enhanced activity of gemcitabine (gem) when combined with the proteasome inhibitor bortezomib (B).

Patients with intermediate to high grade relapsed or refractory B cell NHL or mantle cell lymphoma who had been treated with up to 4 prior regimens including autologous transplant were eligible. Starting dose of gemcitabine was 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with bortezomib starting at 1 mg/m2 on days 1, 4, 8, 11. CT (and PET when possible) were performed after cycle 4 and after cycle 6. Patients were allowed to continue therapy in the event of clinical benefit.

28 patients were enrolled overall, of whom 24 are evaluable for response. 3 of the patients had mantle cell lymphoma. Median Age was 63 (range 34-77). 20 were male, 8 female. Four patients were enrolled on dose level 1, of whom three were evaluable for toxicity. All 3 showed DLT (neutropenia and thrombocytopenia) so enrollment continued at dose level -1 (gem 800 days 1 and 8, B 1.0 mg/m2 d1, 4, 8, 11). One DLT was seen in the five patients treated. In order to make the regimen more easily tolerable, the regimen was changed to increase the time between doses so that dose escalations would begin from gem 800 given on days 1 and 15 and B 1.0 given on days 1 and 15 only, on a 28 day cycle. Dose escalation to the target dose of gem 1000 mg/m2 and B 1.3 mg/m2 was achieved without DLT, and this level was expanded to six patients. A second group of six patient was treated on this dose level with the addition of rituxan 375 mg/m2 given on days 1 and 15 with no DLT seen. Grade 4 toxicities seen on the study were neutropenia (4 pts), and thrombocytopenia (2). Grade 3 toxicities were neutropenia (6) thrombocytopenia (5) and febrile neutropenia (1). Other toxicities of grade 2 or less included elevated transaminases, fatigue, diarrhea, and peripheral neuropathy (grade 2: 3 pts grade 1: 3 patients). 24 patients were evaluable for response. Complete Remission was seen in 3 patients, one at dose level 1, one at dose level 5B (gem 1000 mg/m2 d1 and 15, B 1.3 mg/m2 d1 and 15) and one at dose level 5B1 (5B plus rituxan 375 mg/m2 d1 and 15).

The combination of gemcitabine 1000 mg/m2 combined with bortezomib 1.3 mg/m2 with or without rituxan 375 mg/m2 on a day 1, 15 schedule shows activity in patients with relapsed/refractory B cell NHL, and was well tolerated. A phase II study of this combination is ongoing.

Off Label Use: bortezomib in lymphoma.