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Clinical Trial
. 2012 Apr 26;119(17):3917-24.
doi: 10.1182/blood-2011-10-383406. Epub 2012 Feb 2.

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia

Geoffrey L Uy  1 , Michael P Rettig, Ibraheem H Motabi, Kyle McFarland, Kathryn M Trinkaus, Lindsay M Hladnik, Shashikant Kulkarni, Camille N Abboud, Amanda F Cashen, Keith E Stockerl-Goldstein, Ravi Vij, Peter Westervelt, John F DiPersio
Affiliations
Clinical Trial

A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia

Geoffrey L Uy et al. Blood. .

Abstract

The interaction of acute myeloid leukemia (AML) blasts with the leukemic microenvironment is postulated to be an important mediator of resistance to chemotherapy and disease relapse. We hypothesized that inhibition of the CXCR4/CXCL12 axis by the small molecule inhibitor, plerixafor, would disrupt the interaction of leukemic blasts with the environment and increase the sensitivity of AML blasts to chemotherapy. In this phase 1/2 study, 52 patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide, and cytarabine. In phase 1, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose-limiting toxicities. In phase 2, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission and complete remission with incomplete blood count recovery rate (CR + CRi) of 46%. Correlative studies demonstrated a 2-fold mobilization in leukemic blasts into the peripheral circulation. No evidence of symptomatic hyperleukocytosis or delayed count recovery was observed with the addition of plerixafor. We conclude that the addition of plerixafor to cytotoxic chemotherapy is feasible in AML, and results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis.

Trial registration: ClinicalTrials.gov NCT00512252.

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Figures

Figure 1
Figure 1
Phase 1 mobilization kinetics. Measurement of (A) total leukocytes, and (B) AML blasts in the peripheral blood after administration of a single dose of plerixafor 0.08 mg/kg (n = 3), 0.16 mg/kg (n = 3), or 0.24 mg/kg (n = 6).
Figure 2
Figure 2
Survival. Kaplan-Meier estimates of (A) OS and (B) RFS for the phase 2 (n = 46) cohort.
Figure 3
Figure 3
Phase 2 mobilization data. (A) Change in AML blasts in the peripheral blood expressed as fold-change relative to baseline at 6 hours (n = 37) and 24 hours (n = 31) after administration of plerixafor 0.24 mg/kg. (B) Correlation between CXCR4 expression (CD184 12G5) in the peripheral blood at baseline and AML blast mobilization at 6 hours.
Figure 4
Figure 4
Expression of adhesion molecules. RMFI at baseline, 6 and 24 hours after administration of plerixafor 0.24 mg/kg for (A) 2 different mAbs against CD184 (CXCR4), 12G5, and 1D9 (n = 38) and (B) CD62L (L-selectin, n = 24), CD49d (VLA-4, n = 38), and CD123 (IL3RA, n = 38). (C) Migration of PBMCs to CXCL12 (200 ng/mL) compared with no CXCL12 in transwell assay at baseline and 6 hours after administration of plerixafor (n = 10).
Figure 5
Figure 5
Surface expression of CXCR4 after in vitro culture with plerixafor. Cord blood CD34+ HSPCs or PBMCs from normal healthy donors or AML patients were incubated overnight at 37°C in the presence or absence of OP9 stromal cells and plerixafor (1μM) as indicated. Cells were harvested with accutase, washed, stained with Abs to CD45 and CD184 (clone 1D9), and subjected to flow cytometry. Lymphocytes and AML blasts were discriminated by their CD45/SSC characteristics. (A) Relative changes in the amount of cell-surface–expressed CXCR4. RMFI ratios were calculated by dividing the MFI of CD184 by the MFI of a rat IgG2a isotype control. (B) Representative flow cytometric profiles. The flow cytometric histograms show overlays of CXCR4 surface expression on each cell type in the different culture conditions. The data (mean ± SD) are representative of 1 of 2 independent experiments, in which each condition was tested in duplicate or triplicate; *P < .05, **P < .01, ***P < .001.
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Comment in

  • Get out--and stay out.
    Attar EC. Attar EC. Blood. 2012 Apr 26;119(17):3869-70. doi: 10.1182/blood-2012-02-410357. Blood. 2012. PMID: 22538491

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