Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML.
Sequestration in the bone marrow niche may allow leukemic stem cells to evade exposure to drugs. Because the CXCR4/SDF-1 axis is an important mechanism of leukemic stem cell interaction with marrow stroma, we tested whether plerixafor, an antagonist of CXCR4, may dislodge chronic myeloid leukemia (CML) cells from the niche, sensitizing them to tyrosine kinase inhibitors. We initially treated mice with retrovirally induced CML-like disease with imatinib plus plerixafor. Plerixafor mobilized CXCR4(+) cells, but no difference was observed in leukemia burden, possibly reflecting insufficient disease control by imatinib. In a second series of experiments, we tested the combination of plerixafor with dasatinib in the same as well as an attenuated CML model. Despite much improved leukemia control, plerixafor failed to reduce leukemia burden over dasatinib alone. In addition, mice receiving plerixafor had an increased incidence of neurologic symptoms in association with CNS infiltration by BCR-ABL-expressing cells. We conclude that plerixafor is ineffective in reducing leukemia burden in this model but promotes CNS infiltration. Beneficial effects of combining tyrosine kinase inhibitors with plerixafor may be observed in a situation of minimal residual disease, but caution is warranted when disease control is incomplete.
Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Anupriya
A
Agarwal
Angela G
AG
Fleischman
Curtis L
CL
Petersen
Ryan
R
MacKenzie
Samuel
S
Luty
Marc
M
Loriaux
Brian J
BJ
Druker
Randall L
RL
Woltjer
Michael W
MW
Deininger
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D001596:Benzylamines; D015153:Blotting, Western; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D000069439:Dasatinib; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D051379:Mice; D008807:Mice, Inbred BALB C; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013844:Thiazoles / Q000627:therapeutic use
D019380:Anti-HIV Agents; D001549:Benzamides; D001596:Benzylamines; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019718:Receptors, CXCR4; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib; C088327:plerixafor