A phase I trial evaluating the effects of plerixafor, G-CSF, and azacitidine for the treatment of myelodysplastic syndromes

Abstract

Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design. Subjects received G-CSF 10 mcg/kg D1–D8, plerixafor D4–D8, and azacitidine 75 mg/m² D4–D8, but the trial was amended to reduce G-CSF dose to 5 mcg/kg for 5 days after 2 patients had significant leukocytosis. Plerixafor was dose escalated to 560 mcg/kg/day without dose limiting toxicity. Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients, and ORR of 53% in patients receiving the triplet. Evidence of mobilization correlated with a higher ORR, 60% vs. 17%. Plerixafor, G-CSF and azacitidine appears tolerable when given over 5 days and has encouraging response rates.

KEY POINTS

• Plerixafor and G-CSF can be safely combined with azacitidine for 5 days in patients with MDS.

• The overall response rate of 53% for evaluable patients with this regimen is higher than expected and more responses were seen in patients with blast mobilization.

Keywords:

• Plerixafor
• G-CSF
• MDS
• azacitidine

Acknowledgements

We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of their core facilities. The authors would like to thank the late J Evan Sadler, M.D., Ph.D., Monica Bessler, M.D., Ph.D., and Matthew Walter, M.D. for critical feedback and mentoring.

Author contributions

Contribution: EH, MAS, MPR, KT and JFD designed and performed the research, analyzed and interpreted data and drafted the manuscript. KT performed statistical analyses. TF, ED, WS, JY, RV, KSG, AC, GU, CA and PW analyzed and interpreted data and edited the manuscript. TF, SC, KM, WCE, SK, JR and LG collected and helped analyze data. All authors reviewed the draft manuscript and approved the final version for submission.

Disclosure statement

EH, TF, JR, LG, KM, SC, WCE, KT, RR, SK, AG, CA, AFC, KSG, RV, PW and JFD have declared that no relevant conflict of interest exists. MAS, MPR, GLU, and RV report receiving honoraria from Sanofi. RV has received honoraria from Bristol Myers Squibb. This trial was developed with the support of the American Society of Hematology Clinical Research Training Institute.

Additional information

Funding

The Siteman Cancer Center is supported in part by Cancer Center Support Grant P30 CA91842 from the National Cancer Institute at the National Institutes of Health. Research reported in this publication was supported by research funding from Sanofi (JFD), National Institutes of Health grants R01 CA152329 (JFD), R21 CA141523 (JFD), R35 1R35CA210084 (JFD), and 5K12HL08710703 (MAS) and the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Support also received by MAS from CALGB/Alliance for Clinical Trials in Oncology Foundation.