A Phase I/II Study of Chemosensitization with the CXCR4 Antagonist Plerixafor in Relapsed or Refractory AML.

Abstract 787 The interaction between leukemic blasts and the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although many candidate receptor/ligand pairs have been implicated, the CXCR4 / SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. We hypothesized that disruption of the CXCR4 / SDF-1 axis with plerixafor (Mozobil ® ), a small molecule inhibitor of CXCR4, may sensitize AML to the effects of chemotherapy. We conducted an open label, phase I/II study in patients with relapsed or refractory AML in which plerixafor was administered prior to salvage chemotherapy. A test dose of plerixafor was administered SQ followed by a 24 hour observation period to analyze its effects on AML blasts in the absence of chemotherapy. Plerixafor was then given 4 hours prior to MEC chemotherapy (mitoxantrone 8 mg/m 2 /d, etoposide 100 mg/m 2 /d and cytarabine 1,000 mg/m 2 /d) daily for 5 days. Forty pts have been enrolled in the study with median age of 49 yrs (range 19-71). Baseline characteristics include 6 pts (15%) with secondary AML, 4 (10%) with prior transplant, 24 (60%) with intermediate and 10 (25%) with poor risk cytogenetics. Thirty-six pts (90%) received plerixafor + MEC as their 1st salvage regimen for relapsed disease with 21 (53%) having a CR1 duration of 500/mm 3 , median 27d, range 21-37) or platelet recovery (plt >50k/mm 3 , median 26d, range 20-40d) were observed. Of the 32 pts currently evaluable for response at the 240 mcg/kg dose level, a complete remission (CR+CRi) has been achieved in 50% of pts (CR=13, CRi=3) which compares favorably to historical CR rates of 25-35%. Treatment failure was due to persistent disease in 14 pts (44%) and early death due to complications from infection in 2 pts (6%). One year KM estimate of overall survival is currently 56%. Correlative studies demonstrate that plerixafor mobilizes AML blasts (mean 2.5-fold increase, range 0.9-7.3 fold) into the peripheral circulation peaking at 6-8 hours after administration. FISH performed in pts with informative cytogenetic abnormalities indicates that mobilization occurs equally in both non-leukemic and leukemic populations. Higher baseline surface CXCR4 expression correlated with increased mobilization of AML blasts (Pearson9s r=0.53, p=0.023) into the PB at 6 hrs post-plerixafor. In addition, a strong correlation was also observed between baseline CXCR4 expression and % SDF-1 migration in transwell assays (r=0.84, p=0.0013). Furthermore analysis of AML PB blasts at 6 hrs post-plerixafor demonstrate increased CXCR4 expression as well as increased chemotaxis in response to an SDF-1 gradient in transwell assays compared to baseline (64% vs 38%, p=0.0006). We conclude that plerixafor can be safely administered in combination with cytotoxic chemotherapy in patients with AML. Based on encouraging preliminary evidence of efficacy and in vivo evidence of CXCR4/SDF-1 blockade, confirmatory randomized studies of plerixafor for chemosensitization in AML are being planned. Disclosures: Uy: Genzyme: Consultancy, Speakers Bureau. Off Label Use: Plerixafor for AML. Abboud: Genzyme: Consultancy. Vij: Genzyme: Consultancy. DiPersio: Genzyme: Consultancy, Honoraria.