A phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma: Southwest oncology group study S0108

Abstract

Purpose In a phase II trial, SWOG S0108, patients with relapsed, aggressive non-Hodgkin lymphoma were treated with single agent bevacizumab. The primary endpoint was 6 month progression free survival (PFS) with secondary endpoints including response rate, toxicity, and laboratory correlative studies. Patients and Methods 52 patients in first or second relapse with diffuse large B-cell or mantle cell lymphoma were enrolled. 45 patients were eligible. Patients were treated with bevacizumab at 10mg/kg every 2 weeks with disease assessments every 8 weeks. Biomarkers analyzed included plasma VCAM, urine VEGF, circulating endothelial cells (CEC), and VEGF and VEGF receptor expression in lymphoma specimens. Results Therapy was well tolerated with no unexpected toxicities observed. 6 month PFS was 16% with a response rate of 2%. 11 patients had prolonged stable disease. The median duration of response or stable disease was 5.2 months (range 3.5 – 72.7). VEGF and VEGF receptor expression was observed in 70% and 65% of specimens, respectively. There was excellent concordance between expression of VEGF and VEGF receptors. Baseline urine VEGF and VCAM levels correlated with survival. CEC levels decreased in patients with elevated baseline values. Conclusion Bevacizumab, as a single agent, is well-tolerated in patients with relapsed aggressive NHL, but has little single agent activity. Laboratory correlative studies and prolonged PFS in several patients suggest the VEGF pathway may play an important role in aggressive NHL. Future trials should test the hypothesis that antiangiogenic therapies will synergize with chemotherapy regimens in improving response rates and overall survival of patients with aggressive NHL.

Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes

“…12 Drawing parallels from the extensive literature on solid malignancies, antiangiogenic lymphoma therapy has focused largely on vascular endothelial growth factor (VEGF), which can drive proliferation of both tumor and endothelial cells. 12,13 However, small phase II clinical studies with the anti-VEGF monoclonal antibody bevacizumab have thus far shown equivocal efficacy in aggressive NHL, 14,15 suggesting that non-VEGF angiogenic pathways may be highly relevant.…”

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

“…Although the objective response rate (ORR) was low (2%, one partial response (PR) in a patient with DLBCL), singleagent activity was not anticipated given its mechanism of action; combination therapy trials were thus deemed appropriate. 15 The anti-CD20 monoclonal antibody rituximab used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy is standard treatment for DLBCL. [16][17][18][19][20][21][22] However, there is a need to further improve treatment outcomes, as the 2-year PFS rate of a large populationbased analysis of R-CHOP was only 69%.…”

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

“…Elevated levels of plasma angiogenic factors, including VEGF and VCAM, are associated with poor overall survival (OS) and progression-free survival (PFS) in clinical trials and VEGF, and its receptors are frequently expressed in lymphoma specimens by immunohistochemistry or gene expression profiling. [1][2][3][4][5][6] Resistance to chemotherapy has also been correlated with high levels of VEGF expression in non-Hodgkin lymphoma (NHL) and in xenograft models. [7][8][9][10] Treatment with anti-VEGF therapy plus rituximab or chemotherapy yielded superior antitumor responses compared with either therapy alone.…”