A Phase II Trial of Bendamustine, Bortezomib, and Rituximab in Patients with Previously Untreated Low Grade Lymphoma

Introduction: Rituximab and bendamustine combination regimens have demonstrated high activity in non-Hodgkin’s lymphoma (NHL). Phase III trials evaluating bendamustine plus rituximab as first-line therapy for patients (pts) with indolent and mantle cell lymphoma have shown equivalent or superior results when compared to R-CHOP or R-CVP as first-line treatment for indolent lymphoma. The proteasome inhibitor, bortezomib, has shown substantial activity in multiple myeloma and has demonstrated synergy and/or ability to overcome resistance to a variety of current and investigational treatments for lymphoma. A Phase II study of the combination of bendamustine, bortezomib, and rituximab (BBR) in relapse/refractory indolent and mantel cell NHL pts resulted in an ORR of 83% and 47% 2yr PFS (Friedberg, Blood 2011). This Phase II trial evaluated the activity of BBR in patients with previously untreated low-grade lymphoma.

Methods: Eligible patients had histologically-confirmed follicular center cell lymphoma (FL) (grade 1 or 2), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), or lymphoplasmacytic lymphoma (LPL); lymph node biopsy containing CD20+ B-cells; Ann-Arbor Stage 2, 3, or 4 disease; no previous systemic treatment for lymphoma; bi-dimensional measurable disease with at least 1 lesion measuring > 2.0 cm in a single dimension; ECOG PS 0-2. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m² IV on days 1, 8, and 15 of cycle 1 (cycles 2-6, rituximab only on day 1); bendamustine 90 mg/m² IV on days 1 and 2; and bortezomib 1.6 mg/m²IV on days 1, 8, and 15. Response evaluations were performed after cycle 3 and cycle 6. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments have been conducted. The primary endpoint was to determine the CR rate in this patient population. Secondary endpoints were to assess the ORR, PFS and to characterize the toxicity of this drug combination. 

Results: Between 3/2010 and 11/2011, 55 patients were enrolled, median age of 64 years (range 30-89), 51% male, 85% stage III or IV. Diagnoses were: FL, 38pts (69%); MZL, 8pts (15%); LPL, 5pts (9%); SLL, 4pts (7%). FLIPI risk for FL pts was low 14 pts (37%), intermediate 18 pts (47%), and high 6 pts (16%). Forty-four pts (80%) completed 6 cycles of BRR, and 67% continued to maintenance rituximab with 35% completing maintenance. The most common grade (G) 3/4 hematologic toxicities were leukopenia (29%), neutropenia (29%) and lymphopenia (16%), and the most common G 3/4 non-hematologic toxicities were neuropathy (9%), diarrhea (7%), and fatigue (7%) (See Table 1).  There were no treatment-related deaths and 1 unrelated death on study (embolic stroke). Treatment discontinuation due to toxicity occurred in 11% of pts (2 pts neuropathy, 1 pt each: pancreatitis, atrial fibrillation, erythemia multiforme, and diarrhea). Fifty-one pts were evaluable for response, including 36 FL pts. The overall response rate was 94% (CR 65%, PR 29%) for all pts and 94% (CR 67%, PR 27%) for FL pts. The median FU was 34.8 months (range 9-49). Kaplan-Meier estimates of all pts for progression-free survival (PFS) and overall survival (OS) at 36 mos were 75% and 88% respectively. The 36 mo PFS and OS estimates for FL pts were 73% and 89% respectively.

Conclusion: BBR was well tolerated, produced high CR and OR rates and response compares favorably with Phase III of BR. No unforeseen toxicities were noted with this combination. Further study of this regimen in patients with previously untreated low-grade lymphoma is warranted.

Table 1 G3/4 Toxicity

Hematologic	G3	G4	Total
Leukopenia	14 (26%)	2 (4%)	16 (29%)
Neutropenia	11 (20%)	5 (9%)	16 (29%)
Febrile Neutropenia	1 (2%)	0	1 (2%)
Lymphopenia	7 (13%)	2 (4%)	9 (16%)
Thrombocytopenia	3 (6%)	1 (2%)	4 (7%)
Anemia	1 (2%)	1 (2%)	2 (4%)
Non-Hematologic
Peripheral Neuropathy	5 (9%)	0	5 (9%)
Diarrhea	4 (7%)	0	4 (7%)
Fatigue	4 (7%)	0	4 (7%)
Cough	3 (6%)	0	3 (6%)
Rash	2 (4%)	0	2 (4%)
Syncope	2 (4%)	0	2 (4%)