BMS-936564 (Anti-CXCR4 Antibody) Induces Specific Leukemia Cell Mobilization and Objective Clinical Responses In CLL Patients Treated Under a Phase I Clinical Trial

• Published in: Blood 2013-11, Vol.122 (21), p.4190-4190
• Main Authors: Kashyap, Manoj Kumar, Amaya-Chanaga, Carlos I., Jones, Harrison, AlMahasnah, Eiman A., Choi, Michael Y., Kuhne, Michelle R., Cohen, Lewis, Sabbatini, Peter, Kipps, Thomas J., Cardarelli, Pina M., Castro, Januario E.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.4190.4190

Expression of CXCR4 receptor (CD184) has been reported in different malignancies including Chronic Lymphocytic Leukemia (CLL) and the CXCR4-CXCL12 axis has been described to play a very important role in cancer development. Moreover, this pathway can be inhibited using CXCR4 antagonists. Previously, we have shown that BMS-936564, an anti-CXCR4 IgG4 antibody, can block in vitro the CXCR4/CXCL12 pathway in CLL overcoming stromal cell protection by inducing apoptosis, inhibiting F-actin polymerization, and migration of cells. These findings provide the rationale for an ongoing phase I clinical study in which CLL subjects received four weekly infusions of BMS-936564 antibody followed by 5 monthly cycles of bendamustine, rituximab and BMS-936564 antibody (BRB chemoimmunotherapy). Eleven (n=11) subjects with relapse / refractory disease have been enrolled and treated in this study. Here, we present correlative studies performed in three of those CLL subjects with samples collected at different time points (day 1, 2, 8, 15 and 22) during the monotherapy cycle of BMS-936564. All three subjects showed leukocytosis that was detected as early as in 4 hours following the initial BMS-936564 infusion (median increase of 64.6% above base line; range: 59.7% - 112.7%). Leukocytosis was present during the entire four weeks of monotherapy with BMS-936564. Leukocytosis in these three patients was due primarily to increase in absolute counts of CLL cells (Median increase of 129.6%; range: 95.3% - 324.8%). Interestingly, there was no evidence of increase in the absolute number of normal lymphocytes. Only one of the three patients showed an increase in neutrophil counts after infusion of BMS-936564. We observed changes in the level of CXCR4 expression after infusion with BMS-936564. All subjects showed CXCR4 down-regulation in peripheral CLL cells with a median percentage decrease in the level of expression of 106.7% (Range: 25.1% - 350.7%). We did not observe changes in CXCR4 expression in normal B cells. In contrast to our in vitro studies where we observed that all tested CLL samples underwent apoptosis after treatment with BMS-936564, only one subject showed significant increase in the percentage of apoptosis after infusion of BMS-936564 in vivo. The levels of apoptosis detected were relatively low (