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 POINTSPlerixafor 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: G-CSF; MDS; Plerixafor; azacitidine.

Figure 1.

Trial schema showing cycle 1 of plerixafor, G-CSF and azacitidine. P plerixafor. V azacitidine (Vidaza).

Figure 2.. WBC and Blast Mobilization

(A) WBC count of the original study cohort of 3 patients treated with G-CSF 10 mcg/kg daily on days 1–8, plerixafor 320 µg/kg/day days 4–8, and azacitidine (arrow indicates start of plerixafor). (B) Blast fold increase in peripheral blood (by morphology) for the original study cohort (arrow indicates plerixafor administration). (C) Mean daily WBC count by plerixafor dose during cycles 1 and 2 in the revised cohorts treated with G-CSF 5 mcg/kg given daily on days 1–5, azacitidine, and plerixafor 320 µg/kg/day, 440 µg/kg/day, and 560 µg/kg/day in dose level (DL) 1, DL2, and DL3 as well as the expansion cohort treated with plerixafor 560 µg/kg/day and azacitidine without G-CSF (error bars indicate range). (D) Mean absolute peripheral blood blast count by dose level with ranges. (E) Baseline and peak WBC count during cycle 1 of assigned therapy by dose level. (F) Baseline and peak peripheral absolute blast count during cycle 1 of assigned therapy by dose level.

Figure 3.

FISH of mononuclear cells in the peripheral blood on Cycle 1 Day 3 after plerixafor administration in 13 patients with informative cytogenetics to evaluate for preferential mobilization of leukemic blasts. Lines depict the percentage of a representative cytogenetic abnormality in an individual patient.

Figure 4.

OS of all patients treated with 95% confidence intervals.