Abstract
Abstract 314
We have previously reported mobilization data of hematopoietic stem and progenitor cells (HSPCs) in donors treated with IV plerixafor in a phase I/II open label trial (Rettig et al. Blood 2010 116: a2261). Here we report the final outcomes of donors and recipients of the phase II portion of the trial evaluating the use of 0.32 mg/kg plerixafor IV as a single agent for stem cell mobilization. We hypothesized, based on preclinical studies in the mouse, that IV plerixafor would have more rapid and prolonged mobilization and increase stem cell yields so that failure to collect ≥2×106 CD34+ /Kg recipient weight in one apheresis would be reduced from 33% (seen with 240 ug SC plerixafor) to 11%. We also hypothesized based on our prior observations of increased plasmacytoid dendritic cells (pDCs) in plerixafor mobilized products (Rettig et al. Blood 2009 114: a32), that peripheral blood stem cell products would be enriched in pDCs which may lead to improved immunity in the recipient after transplant and reduced incidence of CMV.
In this phase II open label trial donors were mobilized with 0.32 mg/Kg IV plerixafor (over 30 minutes), followed by a 20 L apheresis starting 4 hours after injection. The primary outcome was failure to collect ≥2×106 CD34+/Kg actual recipient weight on day 1. Secondary outcomes included donor toxicity, successful collection in 2 aphereses, pharmacodynamics of mobilization, engraftment, graft-versus-host disease (GvHD), treatment related mortality (TRM), incidence of CMV, relapse free survival, and overall survival. The study was powered to detect a difference in failure rate from 33% to 11%. Sibling donors were 18 – 70 years of age and 6/6 HLA matched with recipients. Recipients were 18 – 67 years of age with a hematologic malignancy (AML n=14, NHL n=9, CLL n=3, MDS n=3, ALL n=2, CML n=1, and HD n=1). 33 recipients were transplanted (5 reduced-intensity and 28 myeloablative conditioning). A total of 27 donor recipient pairs were initially enrolled and 7 additional pairs of subjects were enrolled to replace 6 donors who failed to collect goal apheresis volume (>17.5L) due to technical problems related to initial apheresis collections. Median follow up of recipients is 248 days (range 37–695 days).
The primary outcome of failure to reach ≥2×10e6 CD34+/Kg recipient weight was analyzed on a per protocol basis. CD34 HSPC mobilization kinetics were previously reported for the phase I cohorts (ASH 2010). 29 donors were evaluable for the primary outcome. 34% (10/29) failed to reach the day 1 collection goal of ≥2×106 CD34/Kg recipient weight. 10% (3/29) failed to reach goal after 2 apheresis procedures. Toxicity in donors was mild with the most common reported side effects being grade 1 GI toxicity of abdominal bloating (30%) and grade 1 bradycardia (30%). All recipients engrafted and there was no graft failure. The median time to neutrophil engraftment (ANC>500K/uL × 2 days) was 14 days, with 31/33 engrafting by day 21. The median time to platelet engraftment (Platelets>50K/uL × 2 days) was 25 days, with 23/33 engrafting by day 30. The incidence of grade II-IV acute GvHD was 7/33 (21%). The incidence of grade III-IV acute GvHD was 4/33 (12%). The cumulative incidence of chronic GvHD in those living beyond 100 days was 7/25 (28%) and 4/25 (16%) had severe disease. The incidence of CMV viermia >10,000 copies in at risk recipients (defined as serology positive in donor or recipient) was 3/20 (15%). The incidence of CMV disease was 1/20 (5%). Median overall survival was 258 days, with 43% one-year survival. Median relapse free survival was 238 days. The day 100 TRM was 1/33 (3%).
IV administration of plerixafor was well tolerated by donors. However, based on our prior experience with subcutaneous dosing with 0.24mg/kg (Devine et al Blood, 2008) there was no improvement in the percent of normal donors who successfully collected ≥2×106 CD34+/Kg after a single IV infusion of 0.32 mg/Kg plerixafor (67% vs. 66% respectively). Failure to reach collection goal in one apheresis procedure remains high with single agent plerixafor regardless of route of administration. Incidence of CMV viremia was low and could possibly be related to increased plasmacytoid dendritic cells in the product. The incidence of aGvHD was lower than historical controls for G-CSF mobilized peripheral blood transplantation and deserves further evaluation in future prospective trials involving CXCR4 antagonists such as plerixafor.
Schroeder:Genzyme: Research Funding. Rettig:Genzyme: Honoraria. Uy:Genzyme: Consultancy, Speakers Bureau. DiPersio:Genzyme: Honoraria.
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