Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Geoffrey L. Uy1,
  2. Michael P. Rettig1,
  3. Ibraheem H. Motabi1,
  4. Kyle McFarland1,
  5. Kathryn M. Trinkaus2,
  6. Lindsay M. Hladnik1,
  7. Shashikant Kulkarni3,
  8. Camille N. Abboud1,
  9. Amanda F. Cashen1,
  10. Keith E. Stockerl-Goldstein1,
  11. Ravi Vij1,
  12. Peter Westervelt1, and
  13. John F. DiPersio1,*
  1. 1 Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States;
  2. 2 Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States;
  3. 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
  1. * Corresponding author; email: jdipersi{at}dom.wustl.edu

Abstract

The interaction of 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 I/II study, fifty-two patients with relapsed or refractory AML were treated with plerixafor in combination with mitoxantrone, etoposide and cytarabine. In the phase I, plerixafor was escalated to a maximum of 0.24 mg/kg/d without any dose limiting toxicities. In the phase II, 46 patients were treated with plerixafor 0.24 mg/kg/d in combination with chemotherapy with an overall complete remission rate (CR+CRi) of 46%. Correlative studies demonstrated a two-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, results in encouraging rates of remission with correlative studies demonstrating in vivo evidence of disruption of the CXCR4/CXCL12 axis. This study was registered at ClinicalTrials.gov, number: NCT00512252.

  • Submitted October 18, 2011.
  • Accepted January 26, 2012.