CHOP-R + Bortezomib as Initial Therapy for Mantle Cell Lymphoma (MCL).

Bortezomib is a proteasome inhibitor with single agent activity in mantle cell lymphoma. Preclinical studies have demonstrated that addition of bortezomib to chemoimmunotherapy can enhance antitumor effects. We report findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab (R) in previously untreated MCL patients.

From 6/2004 to 10/2007, 36 patients with previously untreated MCL received standard CHOP-21 with rituximab (375 mg/m² per cycle) plus bortezomib at 1.0 mg/m² (n=4) or 1.3 mg/m² (n=32) on days 1 and 4 of each cycle for a total of 6 cycles. Study endpoints included safety and efficacy assessment.

At study entry, median age (n=36) was 66 years (range 45–80), and M:F ratio was 5:1. Thirty-four subjects (94%) had stage III/IV disease, and 18 (50%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores (42% with IPI of 2, and 47% with IPI of 3–5), as well as MIPI scores (28% with intermediate risk and 39% with high risk). Treatment was generally well tolerated. Peripheral neuropathy (sometimes reversible) occurred in 20 subjects (56%) with 16 grade 1, 3 grade 2, and 1 grade 3. Grade 3/4 cytopenias included anemia (11%), neutropenia (23%) and thrombocytopenia (14%). At a median followup of 30 months (range 8–61 months), 32 patients are evaluable for efficacy. For all patients (n=36), the intent-to-treat (ITT) overall response rate (ORR) is 81% with 64% CR/CRu. For evaluable patients (n=32), the ORR is 91%, and CR/CRu 72%. The median progression free survival for all patients (n=36) is 21 months (95% CI 17-29) by Kaplan-Meier estimate, and 2 year overall survival is 86% (95% CI 69–94%). Currently eight patients remain in ongoing response (range 15–39 months). In a univariate Cox regression analysis, IPI correlated with PFS (HR 1.85, p=0.023), while MIPI correlated with both PFS (HR 1.81, p=0.027) and OS (HR 2.6, p=0.033).

Bortezomib in conjunction with R-CHOP-21 can be safely administered in an outpatient regimen to previously untreated MCL patients, including the elderly. Further evaluation of combinations of bortezomib with R-CHOP is warranted.

Vose:Genentech, Inc.: Consultancy, Research Funding. Coleman:Millenium: Speakers Bureau. Leonard:Millenium: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Biogen Idec: Consultancy, Honoraria.