Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL.

Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m²IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual.

Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths.

The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted.

Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.