Bortezomib In Combination with Rituximab, Cyclophosphamide, and Prednisone with or without Doxorubicin Followed by Rituximab Maintenance In Patients with Relapsed or Refractory Follicular Lymphoma: Results of a Phase 2 Study.

Non-Hodgkin's lymphoma is the most common hematologic malignancy, with an estimated >65,000 new cases in the US in 2010. The indolent follicular lymphoma (FL) and marginal zone lymphoma (MZL) subtypes account for approximately 22% and 10% of cases, respectively. Rituximab, cyclophosphamide, vincristine, and prednisone, with doxorubicin (R-CHOP) or without (R-CVP) are the most common regimens used for frontline and relapsed/refractory FL. Bortezomib (VELCADE^®) has shown activity alone and with rituximab in relapsed/refractory FL/MZL, and also in combination with chemo-immunotherapy regimens such as R-CHOP. However, overlapping peripheral neuropathy (PN) with vincristine may limit bortezomib dosing. Thus, the aim of this phase 2, two-arm, non-randomized, multicenter study was to evaluate the safety and efficacy of administering bortezomib in place of vincristine in the R-CHOP and R-CVP regimens.

Patients aged ≥18 years with relapsed or refractory FL (including transformed FL) or MZL following ≥1 prior chemotherapy, ≥1 measurable tumor mass, ECOG performance status ≤2, no grade ≥2 residual toxicity from previous therapy/surgery, no grade ≥2 PN, and adequate hematologic, renal, and hepatic function were eligible. Based on investigator preference, patients received up to six 21-day cycles of bortezomib 1.6 mg/m² IV on days 1 and 8, rituximab 375 mg/m² IV on day 1, and prednisone 100 mg PO on days 1–5, plus either cyclophosphamide 1000 mg/m² IV (VR-CP arm), or cyclophosphamide 750 mg/m² IV and doxorubicin 50 mg/m² IV (VR-CAP arm) on day 1. All patients then received rituximab 375 mg/m² IV every 3 months for ≤2 years as maintenance. The primary endpoint was complete response (CR) rate, determined after all patients completed the 12-week follow-up visit. Secondary endpoints included overall response rate (ORR; CR + partial response [PR]), duration of response (DOR), progression-free survival (PFS), and safety/tolerability. Response was assessed by investigators using modified International Workshop Response Criteria. Toxicities were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

A total of 55 patients have been enrolled, 48 to VR-CP and 7 to VR-CAP; reasons for selecting VR-CP included extent of prior anthracycline therapy (56%), study center preference (25%), response to prior R-CVP (13%), and age (10%). Of the 48 VR-CP patients, 50% were male, 88% were white, median age was 63.5 years (range 40–85), 47 had FL (52/33/15% grade 1/2/3; 19/43/38% low/intermediate/high risk by FL International Prognostic Index [FLIPI]), and 1 had MZL. Median number of prior lines of therapy was 2 (range 1–10), which included R-CHOP in 27 (56%), rituximab in 19 (40%), and R-CVP in 7 (15%) patients. Of 47 evaluable patients, 14 (30%) achieved CR and 23 (49%; including 1 MZL) PR (ORR 79%). Median DOR and PFS have not been reached. Patients received a median of 6 (range 2–6) cycles of VR-CP; 40 (83%) received all 6 cycles, and 28 (58%) have continued into the rituximab maintenance phase. All patients reported ≥1 adverse event (AE), including 65% with grade ≥3 AEs, and 25% with serious AEs. Most common AEs included diarrhea (52%), nausea (46%), fatigue (44%), neutropenia (31%), constipation, and vomiting (each 23%); grade ≥3 AEs included neutropenia (27%), lymphopenia (10%), and thrombocytopenia (6%). The incidence of PN was 21% (2% grade ≥3). Four (8%) patients discontinued due to AEs. Of 7 VR-CAP patients (2 male, 7 white, median age 57 years [range 55–73]), 4 had FL (3 grade 1, 1 unknown; all FLIPI high-risk), 2 MZL, and 1 chronic lymphocytic leukemia. Median number of prior lines of therapy was 1 (range 1–8). Of 6 response-evaluable patients, 0/4 achieved CR/PR (3 FL, 1 MZL; ORR 67%). Five patients received all 6 cycles; 4 have continued into rituximab maintenance. AEs included fatigue (n=5), alopecia, neutropenia (each n=4), anemia, constipation, nausea, rigors, and thrombocytopenia (each n=3). Neutropenia (n=4) was the only grade ≥3 AE reported in >1 patient. PN was seen in 2 patients (no grade 3). Two patients had serious AEs. There have been no on-study deaths in either arm.

These results indicate that VR-CP is active, with a 30% CR rate, in patients with relapsed or refractory FL/MZL, including those who had received prior chemo-immunotherapy. Prolonged follow-up is required to evaluate DOR and PFS; updated results will be presented.

Craig:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Use of bortezomib in combination in follicular lymphoma and marginal zone lymphoma. Cabanillas:Celgene: Consultancy, Research Funding; Bayer: Research Funding; Pfizer: Research Funding. Parasuraman:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. O'Connor:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.