A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515

Abstract

S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progressionfree survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1-and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinical trials.gov as #NCT00121199. (Blood. 2012; 120(6):1210-1217)

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

“…The use of bevacizumab in lymphoma patients is still under debate due to the limited efficacy and associated toxicities (47) and should be restricted to lymphoma types with proven efficacy (48). In this context, our data indicate that patients with ALK-rearranged ALCL may indeed benefit with treatment with bevacizumab.…”

R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes

“…However, we found the addition of bevacizumab to R-CHOP exacerbated the cardiac risk seen with doxorubicin alone, a risk that was also observed in a phase II trial that was published after the current study had been designed and carried out. 26 In both the RA-CHOP and R-CHOP arms, the incidence of CHF events increased beginning at a cumulative doxorubicin dose of 200 mg/m 2 . However, while the event rate plateaued in the R-CHOP group despite increasing cumulative doxorubicin doses up to 400 mg/m 2 , it continued to increase in the RA-CHOP arm, particularly beyond a cumulative dose of doxorubicin of 300 mg/m 2 .…”

“…26 Data from the SWOG 0515 trial did not become available until after the discontinuation of bevacizumab treatment in the MAIN study.…”

Imatinib tackles lymphoma via the PDGFRβ+ pericyte

“…3 However, clinical trials using an anti-vascular endothelial growth factor (VEGF) antibody (bevacizumab) in an attempt to inhibit lymphoma angiogenesis in patients with DLBCL or mantle cell lymphoma failed to show meaningful antitumor efficacy. 4,5 pericyte function. Importantly, this approach resulted in significant inhibition of human lymphoma growth in vivo.…”

“…It has been suggested that one reason anti-VEGF therapy has not succeeded in the treatment of patients with lymphoma is that other proangiogenic mechanisms were not disabled via this approach. 4 Targeting the PDGFRb 1 pericyte, which regulates multiple pathways involved in the maintenance and proliferation of vascular ECs, represents an attractive strategy to dismantle the lymphoma vasculature and, perhaps, the lymphoma itself.…”