General AML

Chemosensitization with plerixafor plus G-CSF in R/R AML - a phase 1/2 study

Acute Myeloid Leukemia (AML) blasts express the chemokine receptor CXCR4, which interacts with the bone marrow microenvironment and contributes to evasion of chemotherapy and apoptosis. Plerixafor, an inhibitor of CXCR4, have been reported to mobilize AML blasts and enhance the anti-leukemic efficacy of chemotherapy. Additionally, administration of Granulocyte-Colony Stimulating Factor (G-CSF) along with chemotherapy has been shown to improve outcomes of AML patients.

In a Letter to the Editor of Blood Cancer Journal on 10th March 2017, Geoffrey L. Uy, from the Washington University School of Medicine, St Louis, USA, and colleagues discuss results from their phase 1/2 study (NCT00906945), which aimed to assess the combination of G-CSF and plerixafor in conjunction with mitoxantrone, etoposide, and cytarabine (MEC) for chemosensitization in adult patients with Relapsed or Refractory (R/R) AML.

Thirty-five R/R AML patients (median age = 56 years) were administered G-CSF (10 mcg/kg daily for 8 days), plerixafor (administered on days 3–8) Intravenous Infusion (IV), and MEC (administered on days 4–8). To determine the effect of G-CSF and plerixafor on leukemic cell mobilization, peripheral blood samples were collected either at baseline, after G-CSF only on day 3, or at 2, 4, 6, and 24 hours after IV plerixafor.

The key results of the study were:
  • Plerixafor was escalated to a maximum of 0.75 mg/kg/day in the phase 1 part of the trial
  • Complete Remission (CR) and CR with Insufficient Hematological Recovery (CRi) in patients (n = 20) was 30%
  • Peak mobilization of both total leukocytes and AML blasts occurred 4–6 h after plerixafor administration on day 3 of G-CSF treatment
  • After 2 days of G-CSF administration in evaluable patients (n = 31), total leukocytes and blast cell counts increased by a median of 2.4- and 3.5-fold, respectively
  • After plerixafor administration on day 3 at 6 h, circulating levels of leukocytes and blasts increased an additional 1.8- to 2.8-fold, respectively  
  • Plerixafor administration blocked CXCR4 expression in vivo
  • Plerixafor and G-CSF administration downregulated the expression of CD114 (G-CSF receptor), and CD49d (integrin alpha 6) in AML blasts

In summation, plerixafor amplifies the mobilization of AML blasts by G-CSF. However, the authors highlighted that the combination of plerixafor and G-CSF with chemotherapy “did not improve remission rates compared with historical controls”.  As a result, “the study was terminated for futility”.

References
  1. Uy G.L. et al. A phase 1/2 study of chemosensitization with plerixafor plus G-CSF in relapsed or refractory acute myeloid leukemia. Blood Cancer J. 2017 Mar 10; 7(3): e542. DOI: 10.1038/bcj.2017.21.