TY - JOUR
T1 - Effects of plerixafor in combination with BCR-ABL kinase inhibition in a murine model of CML
AU - Agarwal, Anupriya
AU - Fleischman, Angela G.
AU - Petersen, Curtis L.
AU - MacKenzie, Ryan
AU - Luty, Samuel
AU - Loriaux, Marc
AU - Druker, Brian J.
AU - Woltjer, Randall L.
AU - Deininger, Michael W.
PY - 2012/9/27
Y1 - 2012/9/27
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-05-355396
DO - 10.1182/blood-2011-05-355396
M3 - Article
C2 - 22889761
AN - SCOPUS:84866876169
SN - 0006-4971
VL - 120
SP - 2658
EP - 2668
JO - Blood
JF - Blood
IS - 13
ER -