Abstract 1423: The addition of bevacizumab to chemoimmunotherapy prolongs progression-free survival in patients with chronic lymphocytic leukemia (CLL) through modulation of the microenvironment
Authors: STRATI PAOLO , SHANAFELT TAIT D. , LAPLANT BETSY , PETTINGER ADAM , LESNICK CONNIE , NIKCEVICH DANIEL , CALL TIMOTHY , DING WEI , HANSON CURTIS , KAY. NEIL 
Published: July 2016

Abstract
Introduction. First-line chemoimmunotherapy (CIT) has significantly increased the complete remission (CR) rate for patients with CLL; however, relapse is a common event and strategies aimed at eradicating disease more effectively are needed. Vascular Epithelial Growth Factor (VEGF) plays a crucial role in the cross talk between CLL B cells and their microenvironment. In addition low baseline VEGF levels predict a better response to CIT. Testing the combination of an anti-VEGF agent with CIT was therefore assessed by us in upfront CLL patients.
Methods. Here we report the results of a phase II open-label randomized trial comparing the combination of bevacizumab, an anti-VEGF monoclonal antibody, with pentostatin, cyclophosphamide and rituximab (PCR-B) to PCR alone as front-line therapy in previously untreated patients with CLL. VEGF, b-fibroblast growth factor (FGF), thrombospondin (TSP)-1, chemokine ligand (CCL)-3 and CCL-4 plasma levels were measured at baseline and at time of response assessment.
Results. Between 01/2009 and 01/2013, 62 patients were accrued in the study, 32 in the arm A (PCR-B) and 30 in arm B (PCR alone). A higher rate of grade 3-4 cardiovascular toxicity was observed with the use of PCR-B (34% vs 0%, p&lt;0.001): this included 7 cases of hypertension, 2 cases of congestive heart failure, 1 myocarditis, and 1 case of torsade de point. A higher CR rate (50% vs 33%, p = 0.21) and a significantly longer median progression-free (p = 0.04) and treatment-free (p = 0.05) survival were achieved with the use of PCR-B. No difference in chemokine kinetics was observed between the 2 arms, except for VEGF, which significantly increased after PCR-B. In the PCR-B arm, chemokine kinetics for CCL-3 (median drop 5.0 vs. median drop 31.8, respectively; p = 0.02) and CCL-4 (median drop 23.8 vs. median drop 120.9, respectively; p = 0.01) were significantly associated with achievement of CR. No significant correlations were found between cytokine plasma levels and responses for patients treated in the PCR only arm.
Conclusions. The addition of bevacizumab to CIT is safe and effective, although associated with higher cardiovascular toxicity, in particular hypertension. The addition of bevacizumab produces higher CR rates, translating into improved progression-free survival, and is associated with decreased plasma levels of CCL-3 and CCL-4.
Citation Format: PAOLO STRATI, TAIT D. SHANAFELT, BETSY LAPLANT, ADAM PETTINGER, CONNIE LESNICK, DANIEL NIKCEVICH, TIMOTHY CALL, WEI DING, CURTIS HANSON, NEIL KAY. The addition of bevacizumab to chemoimmunotherapy prolongs progression-free survival in patients with chronic lymphocytic leukemia (CLL) through modulation of the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1423.