A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia

Abstract

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS.

Increased Serum Von Willebrand Levels in Chronic Lymphocytic Leukemia (CLL) Patients Are Related To a Shorter Time to Treatment

“…Their combination with other agents showed better results. Improved progression free survival was observed with the addition of bevacizumab to chemoimmunotherapy [6]. The same was true with the addition of rituximab to lenalidomide [7,8].…”

Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials

“…Bevacizumab was investigated in 72 trials 8 – 79 and ramucirumab was investigated in 13 trials. 80 – 92 All of the studies included 21 colorectal cancer, 8 – 26 , 85 , 86 15 breast cancer, 27 – 39 , 87 , 88 16 lung cancer, 40 – 52 , 80 – 82 three renal cell cancer, 53 , 54 two pancreatic cancer, 55 , 56 five ovarian cancer, 57 – 61 six gastric or gastroesophageal junction adenocarcinoma, 62 – 65 , 89 – 91 three glioblastoma, 66 – 68 one lymphoma, 69 one lymphocytic leukemia, 70 two melanoma, 71 , 72 two malignant mesothelioma, 73 , 74 one prostate cancer, 75 one cervical cancer, 76 one leiomyosarcoma, 77 two urothelial carcinoma, 83 , 84 two hepatocellular carcinoma, 78 , 92 and one soft tissue sarcoma. 79 In addition, 35 trials 9 , 10 , 12 – 20 , 22 – 26 , 46 , 49 , 52 , 55 , …”

Regulation and function of angiogenic factors in chronic lymphocytic leukemia

“…Bevacizumab (Avastin, AVA) is a monoclonal antibody targeting VEGF with proven antiangiogenic properties in multiple hematologic malignancies, such as acute myeloid leukemia, CLL, and non-Hodgkin's lymphoma [162][163][164] . Despite its potential relevance in the clinic, the administration of bevacizumab, as a single agent, to CLL patients has shown no significant improvement in clinical trials [165] . However, when bevacizumab was given to CLL patients in combination with other conventional therapies (pentostatin, cyclophosphamide, and rituximab), clinical trials have shown that it prolongs the progression free and treatment free survival [166] .…”