Phase 1 trial of bortezomib plus R‐CHOP in previously untreated patients with aggressive non‐Hodgkin lymphoma

BACKGROUND: Bortezomib has preclinical and clinical in B‐cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) in patients with untreated diffuse large B‐cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). METHODS: Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29‐84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R‐CHOP was administered on a 21‐day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m 2 [n = 4 patients], 1.0 mg/m 2 [n = 9 patients], or 1.3 mg/m 2 [n = 7 patients]) administered on Days 1 and 4 of each cycle. RESULTS: The maximum tolerated dose of bortezomib with R‐CHOP was not reached, and the 1.3‐mg/m 2 dose level had acceptable tolerability. A dose‐limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m 2 of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow‐up of 56 months, overall survival at 4 years was 75% and progression‐free survival was 58%. CONCLUSIONS: Bortezomib at a dose of 1.3 mg/m 2 twice per cycle can be added to R‐CHOP chemotherapy with acceptable toxicity. Multi‐institutional and cooperative group follow‐up studies of this regimen are currently ongoing. Cancer 2010. © 2010 American Cancer Society.