A Phase I/II Study of Chemosensitization with the CXCR4 Antagonist Plerixafor in Relapsed or Refractory AML.
Authors: Uy Geoffrey L. , Rettig Michael P. , McFarland Kyle , Hladnik Lindsay , Kulkarni Shashikant , Abboud Camille N. , Cashen Amanda F , Stockerl-Goldstein Keith , Vij Ravi , Westervelt Peter , DiPersio John F. 
Published: October 2019

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/m2/d, etoposide 100 mg/m2/d and cytarabine 1,000 mg/m2/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 < 12 months and 9 pts (6%) for primary refractory disease. The remaining four pts (10%) received the regimen as their 2nd salvage regimen. Three dose levels of plerixafor: 80 mcg/kg, 160 mcg/kg and 240 mcg/kg were tested in the phase I dose escalation. In the phase II, a total of 34 patients have been treated at the 240 mcg/kg dose level. Common grade ≥ 3 adverse events consisted primarily of cytopenias and infections. No evidence of hyperleukocytosis or significant delays in neutrophil recovery (ANC >500/mm3, median 27d, range 21-37) or platelet recovery (plt >50k/mm3, 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 (Pearson's 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.