Lymphocyte and Hematopoietic Stem and Progenitor Cell (HSPC) Subsets Mobilized By Either Plerixafor or G-GCSF: A Retrospective Comparison of Grafts Harvested in Healthy Allogeneic Stem Cell Donors
Authors: De Greef Georgine E. , Braakman Eric , Alemayehu Wendimagegn G , Graaf Larissa De , van Geel Peter , Grootes Meriam , Engelman Carla , Petersen Eefke , Visser Otto , Vucinic Vladan , Niederwieser Dietger , Cornelissen Jan J. 
Published: November 2019

Plerixafor (PXF) is a bicyclam molecule, which acts as a reversible inhibitor of SDF-1 binding to CXCR4. A single injection results in immediate release of CD34+ cells into the peripheral blood. Sofar, PXF has been used for stem cell mobilization only in a limited number of allogeneic donors (Devine et al. Blood.2008;112(4):990)

The currently ongoing randomized phase 2 Hovon -107 study of the Dutch hemato-oncology group HOVON (www.hovon.nl) aims to compare the feasibility of intravenous (iv) versus subcutaneous (sc) PXF (Genzyme Europe BV) 320 µg/kg subcutaneously (sc) 9 hours before the planned stem cell collection or intravenously (iv) 4 hours before stem cell collection in healthy adult matched sibling donors. Concurrently, all stem cell products are evaluated for the total number of CD45+; CD34+ cells and other hematopoietic stem cell subsets, including more primitive progenitor cells (MPP/CMP: CD34+/CD45RA-/CD90- and HSC :CD34+/CD45RA-/CD90+). Furthermore, the frequency and absolute numbers of CD3+, CD4+; CD8+;CD19+; CD 3-CD16/CD56+ (NK) cells and several T cell subsets, including Foxp3+, Th1, Th2 and Th17 cells, are assessed. Thereby, the HOVON-107 study enabled us to retrospectively compare lymphocyte and CD34+ HSPC subsets in grafts harvested in healthy donors (n=27) following PXF versus a similar evaluation of those subsets in grafts (n=10) harvested following G-CSF(Neupogen) (2 x 500 ug/kg (sc) for 5 days). Data are presented with respect to the composition of stemcell harvests, obtained after a single gift of PXF (13 iv and 14 sc) followed by 15 liters leucopheresis. For comparison of the stem cell products between the two groups the Mann-Whitney U test was applied.

Results: Both groups are comparable with respect to age/sex. Mobilization with PFX resulted in similar WBC numbers as compared to G-CSF mobilization. The total number of CD34+ cells was significantly lower after PFX mobilization: median 200 x106; (range 40-560) vs 400 x106 (360-840) after G-CSF (p=0.000). However after PFX mobilization, the CD34+ cells contained a higher frequency of immature HSC and a lower frequency of MPP as compared to G-CSF mobilized grafts. The lower number of CD34+ HSPC and the higher frequency of HSC within CD34+ HSPC resulted in similar numbers of immature HSC in PXF mobilized grafts (PFX 50;1-218 x106 for G-CSF 90;11-200 x106 p=0.411).Although it is known that Plerixafor can mobilize a higher number of T-cells no data are available about the frequencies of distinct T cell subsets in the grafts. PFX mobilization resulted in higher numbers of CD3+T cells and CD19+B cells. The number of CD3-CD16/56+ NK-cells did not differ between both groups. Within the CD3+ T cell population, the CD4/CD8 ratio did not differ between both groups of mobilized grafts. While absolute numbers of T-cells were significantly increased, the frequencies of IFN-gamma+ Th1 cells, IL-4+ Th2 cells; IL-17+ Th17 cells and Foxp3+ regulatory T cells were not significantly different between both groups, resulting in increased Treg and Th1 after PFX (see Table below)

In conclusion, allogeneic stem cell grafts harvested in healthy donors following a single dose of Plerixafor contain higher numbers of primitive progenitor cells, and higher numbers of both effector and regulatory T-cells as compared to grafts harvested following G-CSF. The impact of altered subset numbers on clinical endpoints including graft versus host, engraftment, and overall outcome remain to be established. Abstract 2451. TableCD3 (x 109)CD3/4 (x 109)CD3/8 (x 109)CD19 (x 109)CD3-CD16/56+ (x 109)Treg (x 109)Th1 (x 109)Th2 (x 109)Th17 (x 109)PFXMedian Range22.7 9.8-56,7 13.2 6.3-30.56.6 2.8-22.15.7 0.6-18.11.40.5-4.30.7 0.3-2.52.8 0.3-9.30.2 0.0-1.80.20.0-6.8G-CSFMedian Range12.8 7.6-217.5 4.3-15.43.8 2.0-6.03.1 1.9-4.51.30.5-2.90.4 0.2-1.20.9 0.4-2.70.20.1-0.40.1 0.0-0.5P-value0.0010.0050.0030.0020.7320.0220.0160.2890.129

Disclosures

De Greef: Sanofi The Netherlands: Membership on an entity's Board of Directors or advisory committees. Petersen:Sanofi the Netherlands: Membership on an entity's Board of Directors or advisory committees. Visser:Sanofi the Netherlands: Membership on an entity's Board of Directors or advisory committees. Niederwieser:Novartis, Gentium, Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.