Abstract

Recent studies suggest G-CSF induces stem cell mobilization by indirectly targeting the interaction between the chemokine stromal derived factor 1 (SDF-1) and its receptor CXCR4. Here we report preliminary results using a direct antagonist of the SDF-1/CXCR4 interaction, AMD3100, as a single agent to procure MPB from allogeneic donors. Nine HLA identical siblings received one or two doses of AMD3100 at 240mcg/kg subcutaneously followed four hours later by leukapheresis (LP). After successful collection and a one week washout period, the same donors were remobilized using a standard G-CSF dose and schedule. The results of the mobilizations and allograft composition are presented in the table.

Allograft Characteristics

Cell Type AMD3100 G-CSF 
Values are medians with range 
CD34(x10e6/kg) 2.6 (2–6.3) 3.3 (2.5–18.7) 
CD3 (x10e8/kg) 4.3 (1.5–7.8) 1.3 (0.7–2.2) 
CD4 (x10e8/kg) 2.8 (1.0–5.6) 0.9 (0.5–1.4) 
CD8 (x10e8/kg) 1.0 (0.4–3.4) 0.4 (0.2–0.8) 
CD19 (x10e8/kg) 1.1 (0.2–2.3) 0.4 (0.3–0.6) 
CD16/56 (x10e7/kg) 3.4 (0.2–8.1) 1.9 (1.3–2.3) 
Cell Type AMD3100 G-CSF 
Values are medians with range 
CD34(x10e6/kg) 2.6 (2–6.3) 3.3 (2.5–18.7) 
CD3 (x10e8/kg) 4.3 (1.5–7.8) 1.3 (0.7–2.2) 
CD4 (x10e8/kg) 2.8 (1.0–5.6) 0.9 (0.5–1.4) 
CD8 (x10e8/kg) 1.0 (0.4–3.4) 0.4 (0.2–0.8) 
CD19 (x10e8/kg) 1.1 (0.2–2.3) 0.4 (0.3–0.6) 
CD16/56 (x10e7/kg) 3.4 (0.2–8.1) 1.9 (1.3–2.3) 

Eight of the nine donors mobilized following AMD3100 collected at least 2.0x 10e6 CD34+ cells/kg recipient weight following 1 (n=5) or 2 (n=4) LP procedures. The same donors mobilized allografts containing >2.0x 10e6 CD34+ cells/kg following G-CSF in either 1 (n=7) or 2 (n=1) LP procedures. Allografts mobilized following AMD3100 contained less CD34+ cells but proportionately greater numbers of T-,B-, and NK-cells compared to G-CSF allografts. AMD3100 was well tolerated and no donors experienced any greater than grade 1 toxicity. To date, seven patients have been transplanted using the AMD3100 mobilized allografts and six are evaluable for engraftment. Two patients did not receive allografts due to progressive disease. The median age of the recipients is 45 years (range 32–53). Three had AML in CR1 or 2, one with ALL in CR1, one advanced CLL, and two advanced non-Hodgkins lymphoma. With a median follow up of 200 days (range 5 to 396 days), all six evaluable pts have engrafted neutrophils > 500/ul at a median of 11 days (range 8–13) and platelets > 20,000/ul at a median of 19 days (range 17 – 25). Acute GVHD prophylaxis employed single agent cyclosporine only. Despite transplanting higher numbers of T-cells, only one of six patients to date has experienced grade 2–4 acute GVHD. Two of four evaluable patients have experienced extensive chronic GVHD requiring immunosuppresive therapy. Chimersim studies of peripheral T- and and myeloid cell compartments performed on days 28, 84 and 180 have revealed essentially 100% donor chimerism at all time points. All patients currently survive in remission with full trilineage hematopoiesis. In summary, grafts mobilized following AMD3100 differ from G-CSF mobilized allografts in the content of CD34+ and immune effector cells yet appear to reconstitute hematopoiesis similarly. The risk of GVHD does not appear to be increased despite the transplantation of higher T-cell doses. This is the first study to demonstrate that a chemokine antagonist given alone can safely and rapidly induce the mobilization of a functionally competent hematopoietic allograft. Further details will be presented.

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