Sargramostim (GM-CSF) Combined with IV Plerixafor to Mobilize Peripheral Blood Stem Cells (PBSC) from Normal HLA-Matched Allogeneic Sibling Donors

We have previously reported a lower than expected incidence of acute GVHD in recipients of sibling donor allogeneic HSC transplants mobilized with GM-CSF alone (Devine et al. BMT 2005). However, the use of GM-CSF as a single agent for stem cell mobilization has been limited by a high (~30%) incidence of failure to mobilize and collect adequate stem cell numbers in a single apheresis procedure. Based on observed synergy between GM-CSF and plerixafor for HSC mobilization in mice, we hypothesized that this combination in humans might overcome the low stem cell yields observed with either agent alone and result in a PBSC product enriched in Tregs and MDSCs that could reduce GvHD after transplant.  The efficacy of GM-CSF (initially given 10 mcg/kg SC daily x 5 – 6 days but reduced to 5mcg/kg daily secondary to toxicity), and plerixafor (320 mcg/kg IV daily starting on day 5) was tested in a phase II trial.

The primary objective of this trial was reduction in the day 1 mobilization failure rate from 33% to <10%.  We planned to enroll 17 donor recipient pairs.  Donors failing to reach 20L apheresis volume were replaced. To date 22 donors (4 at 10mcg/kg GM-CSF and 18 at 5mcg/kg GM-CSF) have been mobilized and 19 recipients transplanted. Initial mobilization with GM-CSF 10mcg/kg was complicated by catheter and IV tubing-associated thrombosis at the time of apheresis in 4/4 donors. Because of this, GM-CSF dose was reduced to 5 mcg/kg SC daily x 5–6 days.  Since this dose reduction, access complications have occurred in 3/18 donors that precluded a full 20 L apheresis. There has been no grade 3–4 adverse events related to mobilization.

Analysis of mobilization in 15 donors with a 20 L apheresis volume on day 1 demonstrated a failure to collect ≥2x10⁶ CD34/kg recipient weight in 2/15 donors (13.3%). The mean CD34/Kg recipient weight collected from these donors was 3.97 x 10⁶ CD34/Kg. No donor regardless of day one apheresis volume failed to reach this goal after two days of apheresis.

All recipients engrafted. The median time to neutrophil engraftment was 13 days (range 11 - 22 days), and median time to platelet engraftment >50K was 24 days (range 15 - 106).  14/18 (78%) recipients had 100% donor chimerism at day 30 post transplant. Of the 14 evaluable recipients receiving mobilized products from donors mobilized with 5mcg/kg GM-CSF+plerixafor, the incidence of grades II–IV and III-IV acute GvHD was 35.7% and 21.2%. Of all evaluable recipients (n=18) treated on study, the incidence of grades II-IV and III-IV acute GvHD were 44% and 22.2%. The incidence of cGvHD for all recipients surviving past 100 days (n = 13) was 61.5%. CMV viremia occurred in 10/15 (66.6%) of recipients and CMV disease was identified or suspected in 5/15 (33.3%).

GM-CSF at 5mcg/kg combined with IV plerixafor is a feasible combination to overcome low apheresis CD34 yields observed with either agent alone.  Phenotypic and functional studies of cellular graft content are ongoing.