Rituximab, Bevacizumab (Avastin) and CHOP (RA-CHOP) for Patients with Diffuse Large B-Cell Lymphoma (DLBCL).

Abstract

IntroductionBevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Non-Hodgkin's lymphoma (NHL) patients with a high serum VEGF levels have an inferior overall survival compared to patients with low VEGF levels. Rituximab plus CHOP (R-CHOP) prolongs time to treatment failure and survival in patients with DLBCL. But further improvement is needed, particularly with patients with high-intermediate and high risk international index disease. This study was designed to assess the feasibility of the combination of bevacizumab plus R-CHOP (RA-CHOP).MethodBevacizumab was administered at 15 mg/kg IV on day 1 of each cycle over 30–90 minutes. R-CHOP was administered on day 2 of cycle 1 and on day 1 of subsequent cycles. Patients were monitored for cardiac function with echocardiogram and for proteinuria. Serum levels of bevacizumab and rituximab were measured to assess pharmacokinetics. Serum and urine samples were also analyzed for circulating VEGF. Tumor samples were stained for VEGF by immunohistochemistry.ResultsTwelve patients (10 males, and 2 females) with newly-diagnosed DLBCL were enrolled. The median age was 48 years (range 29–63). Three patients had stage II primary mediastinal, 2 stage III, and 7 stage IV disease. ECOG performance status ranged from 0–1. Nine patients had an elevated LDH with a median international index score of 2 (range 0–3). Nine patients had an international index score of 2–3. A total of 80 cycles (range 2–8; median 7) of RA-CHOP was administered. Bevacizumab was held in 5 cycles in 3 patients-due to 1) elevated liver enzymes in the setting of positive hepatitis C serology, 2) transient proteinuria, and 3) DVT associated with central line. The following grade 3 toxicities were observed: 4 febrile neutropenia with infection related to central line, 2 DVT (both central line associated), 1 elevated liver enzymes, and 2 transient hypertension. Grade 4 toxicities included 3 absolute neutropenia with 2 febrile neutropenia, and 1 HSV esophagitis. Two patients are too early to assess response. Best response included CR in 3, PR in 4 (2 with normal PET scans), SD in 1. One patient progressed and another achieved a PR after 4 cycles but further treatment was not given due to severe depression.ConclusionIn this patient population, treatment with RA-CHOP did not result in any grade 3 or 4 proteinuria, heart failure or bleeding. Hypertension was transient and thrombosis was associated with central line placement. Correlative studies and pharmacokinetics are being analyzed and will be available for presentation.