A Phase I Trial of Bortezomib Plus CHOP Every 2 Weeks in Patients with Advanced Stage Diffuse Large B-Cell Lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma. Recently, with new treatment strategies including the addition of rituximab to CHOP and dose-dense CHOP therapy there has been much progress in the treatment for these patients. Nonetheless, there is still significant opportunity for improving survival in DLBCL. Bortezomib is a small molecule proteasome inhibitor as a novel agent to treat human malignancies. Its antitumor activity was reported in a variety of tumor model and human malignancies, both as a single agent and in combination with chemotherapy. In this study, we tried to add bortezomib to dose-dense CHOP every 2 weeks which has potential to have promising activity to DLBCL as a first-line treatment, and to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of bortezomib in this regimen. Patients with advanced stage (stage III, IV or non-contiguous stage II) DLBCL and age 70 years or less who previously untreated were eligible for enrollment. All patients received CHOP (cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, vincristine 1.4 mg/m² IV on day 1, and prednisone 100mg PO on days 1 to 5) and granulocyte colony-stimulating factor at a dose of 5μg/kg from days 4 to 13 every 2 weeks. Bortezomib was administered twice weekly (day 1 and 4) with a 1-week recovery period. Three cohorts of 3 to 6 patients were planned with bortezomib 1.0, 1.3 or 1.6 mg/m²/day in order to determine the MTD. Toxicity was assessed using NCI-CTC, version 3.0. DLT was defined as grade 4 neutropenia associated with fever lasting ≥ 3 days, grade 4 neutropenia lasting ≥10 days, grade 3,4 thrombocytopenia with grade 2 hemorrhage or any grade 3,4 non-hematologic toxicity except for nausea, vomiting and diarrhea in the absence of prophylactic and/or symptomatic treatment. Nine patients were enrolled from December, 2006 to April, 2007 at two study centers. No patient at any dose level of bortezomib was developed DLT based on 1st cycle treatment. No escalation was planned beyond 1.6 mg/m² of bortezomib. Total 49 cycles of treatment were done to 9 patients. Seven of 9 patients finished the planned 6 cycles of treatment. One patient experienced disease progression after 5 cycles of treatment and one patient couldn’t continue treatment due to prolonged grade 3 abdominal pain after 2 cycles. Nine episodes of grade 3 toxicity(3 hematologic grade 3 toxicity after 1st cycle) were seen in 5 patients including thrombocytopenia, pneumonia, febrile neutropenia, anorexia, vomiting and abdominal pain. One episode of grade 4 neutropenia and thrombocytopenia was developed in one patient during 2nd cycle of treatment. Other grade 1 or 2 toxicities were anemia, anorexia, fatigue, constipation and peripheral neuropathy. Eight of 9 evaluable patients had a complete response. Bortezomib plus dose-dense CHOP every two weeks in patient with advanced DLBCL as a first-line treatment was safely administered in this study with promising antitumor activity. Further testing in phase II trial is worthwhile and underway.