Abstract LB-162: Targeting CXCR4 for treatment of relapsed or refractory AML.
Authors: Uy Geoffrey L. , Rettig Michael P. , McFarland Kyle , DiPersio John F. 
Published: August 2014

In AML, the interaction of leukemic blasts with the bone marrow (BM) microenvironment is an important mediator of resistance to chemotherapy and disease relapse. The chemokine receptor, CXCR4, expressed on both normal HSCs and AML blasts, and serves as the principal regulator of stem cell homing and retention in the BM. We previously demonstrated in a murine model that blockade of CXCR4 by the small molecule inhibitor, plerixafor, mobilizes AML blasts into the peripheral circulation and sensitizes leukemic cells to chemotherapy (Nervi et al, Blood 2009). Furthermore, chemoprotection is mediated by bone marrow derived soluble factors which inhibits equilibrative nucleoside transporter 1 (ENT1) activity and cellular uptake of cytarabine (Nervi et al, PLoS One 2012). Based on these preclinical data, we have embarked on a series of studies combining plerixafor with chemotherapy for the treatment of AML. Our initial study combining plerixafor with chemotherapy demonstrated a CR rate of 46% in adults with relapsed or refractory AML (Uy et al, Blood 2012).

Methods. In this follow-up study, we sought to maximize CXCR4/CXC12 blockade by 1) adding G-CSF which downregulates CXCL12 production and 2) escalating the dose of plerixafor. G-CSF 10 mcg/kg was administered for 4 days prior to plerixafor and chemotherapy consisting of mitoxantrone 8 mg/m2, etoposide 100 mg/m2 and cytarabine 1000 mg/m2 IV x 5 days. Peripheral blood was collected at baseline, after G-CSF on day 3, and after both G-CSF and plerixafor on day 4 to study the effects on leukemic cell mobilization.

Results. In the Phase I, plerixafor was successfully escalated from 0.24 to 0.75 mg/kg/day. Peak mobilization of AML blasts occurred 4-6 hours post-plerixafor and remain elevated at 24 hours. We observed a unique pattern of CXCR4 expression using 2 monoclonal antibodies to CXCR4. The 12G5 mAb recognizes an epitope involving the first and second extracellular domains and inhibits plerixafor binding to CXCR4. In contrast, the 1D9 mAb binds to the N-terminus and is not affected by plerixafor. 12G5 binding decreased on CD45dimssclo AML blasts from baseline to 6 hours and an increase from 6 to 24 hours toward baseline. In contrast, we identified an increase in the binding of surface 1D9 after plerixafor occurring between pretreatment and 24 hours. Overall, these results indicate successful CXCR4 blockade by plerixafor in vivo with subsequent mobilization of AML blasts . The phase II is currently enrolling and will treat up to 46 patients. The completed phase II will allow us to determine the contribution of G-CSF and increased doses of plerixafor to both tumor mobilization and sensitivity to chemotherapy.

Citation Format: Geoffrey L. Uy, Michael P. Rettig, Kyle McFarland, John F. DiPersio. Targeting CXCR4 for treatment of relapsed or refractory AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-162. doi:10.1158/1538-7445.AM2013-LB-162