HLA-Matched Sibling Donor Stem Cell Mobilization Can Be Safely and Effectively Reduced from a Five Day to a One Day Process by a Direct Antagonist of the CXCR4/SDF-1 Interaction.
Authors: Devine Steven M. , Vij Ravi , Todt Laura , McLaughlin Kiley , Fisher Nicholas , Morris Natalie , Link Daniel C. , Calandra Gary , Bridger Gary , DiPersio John F. 
Published: October 2019

Abstract
The vast majority of matched sibling donor allografts are now procured following mobilization with granulocyte-colony stimulating factor (G-CSF). G-CSF (G) induces stem and progenitor cell mobilization by indirectly disrupting the interaction between the chemokine receptor CXCR4 and its ligand SDF-1. This requires 5–6 days of treatment for maximal effect. We have recently developed a protocol for the mobilization and collection of CD34+ cells from HLA-matched sibling donors that requires only 1–2 days of treatment using a direct antagonist of CXCR4/SDF-1 called AMD3100 (A). We have treated 19 HLA-matched sibling donors with AMD3100 at a dose of 240ug/kg by subcutaneous injection. Blood was collected via leukapheresis (LP) just 4 hours following a single dose of A. The median donor age was 51 (range 24–62). 16 donors were males. Two donors did not tolerate LP and were removed from study. Of the remaining 17, 12 collected an allograft with a CD34+ cell dose sufficient for transplantation after just one dose of A. The remaining 5 required a second day of A. Mobilization with A was safe and no donor experienced more than grade 1 toxicity. To date, 15 patients (pts) have received allografts collected after A alone that contained median CD34+ and CD3+ cell doses of 2.9×10e6/kg (range 1.9–6.3) and 4.5×10e8/kg (range 1.5–7.8), respectively. 8 donors mobilized with A alone were subsequently mobilized with G alone in order to perform internal comparisons of graft content. Allografts collected following A contained significantly less CD34+ cells (p=0.05) but more CD3+ (p=0.04) and CD4+ (p=0.02) cells compared to G mobilized grafts. The median age of the 15 pts transplanted for a variety of hematological malignancies was 52 years (range 32–62). 10 had high risk disease. All pts were conditioned with a myeloablative regimen containing cyclophosphamide (120mg/kg) and single dose total body irradiation (550cGy). Single agent cyclosporine was the sole agent used for GVHD prophylaxis. All pts engrafted neutrophils (ANC>500/ul) and platelets (>20,000/ul) at a median of 10 and 17 days, respectively. All pts who remained in remission achieved and sustained full donor peripheral blood chimerism in both the myeloid and T-lymphoid compartments up to one year post transplant. Acute GVHD grades 2–4 and 3–4 occurred in 20% and 6% of pts, respectively. Chronic GVHD developed in 3 of 8 evaluable pts. Treatment related mortality was observed in 1 of 15 pts. Two pts have relapsed. With a median follow-up of 173 days (range 44–782), 12 of 15 pts (80%) are surviving progression free. In summary, allografts mobilized just 4 hours following A alone are functionally competent and appear qualitatively similar to allografts mobilized following 5 days of G. While this novel mobilization regimen requires optimization, these early data suggest mobilizing HLA-matched sibling donors by directly targeting CXCR4/SDF-1 with A alone may be an effective, safer, and less cumbersome alternative to the traditional method of mobilizing donors with G-CSF.