The CXCR4-Antagonist AMD3100 Augments the Number of Mobilized Peripheral Blood Progenitor Cells (PBPC) When Added to a G-CSF Standard Mobilization Regime and AMD3100-Mobilized PBPC Result in Rapid Hematopoietic Reconstitution after Autologous Transplantation.

Abstract

Sufficient mobilization of peripheral blood progenitor cells (PBPC) is pivotal for successful autologous transplantation. G-CSF has gained a confirmed and dominant role in standard mobilization regimens. Recent reports provided evidence for the importance of the SDF1/CXCR4 axis in hematopoietic stem cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We initiated a phase II study assessing the safety and potential of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). At the time of the report 6 patients with MM and 4 patients with NHL were enrolled (5 female, 5 male; age median 44, range 44–71 yrs; prior chemotherapy regimens median 3, range 1–8). All patients with MM were in stage IIA or IIIA. Patients with NHL were in stage IIB, IIIA, IIIE or IV. Mobilization treatment consisted of 5 days G-CSF (10 μg/kg, s.c. AM) and a single dose of AMD3100 (240 μg/kg, s.c.) in the evening of day 4, 10–11 hours prior to leukapheresis. As expected, following 4 days of G-CSF treatment the CD34+ cell count in the peripheral blood increased 22-fold (range 7,8–33) and there was a correlation between baseline and day 4 PB CD34+ counts (r=0,88). Addition of AMD3100 led almost to a tripling of circulating CD34+ cells within 10 h after administration (2,8-fold increase, range 1,85–4,74). On the other hand, there was no mobilization of B-cells (CD19) -thus giving no indication for the co-mobilization of tumor cells- and no mobilization of NK/T-cell subsets (CD2, CD3, CD4, CD8). Patients with low starting PB CD34+ counts profited most. There was no association between the SDF1 1-3A polymorphism and the mobilization efficiency following AMD3100+G-CSF vs. G-CSF mobilization: 21% of patients showed the heterozygous G/A phenotype and the remainder the G/G phenotype. Interestingly, SDF1-serum levels in patients increased significantly after addition of AMD3100. Per leukapheresis procedure 4,3 (range 2,6–12,1) * 10e6 CD34+ cells/kg body weight (bw) were collected. Adverse effects were mild, one patient reported of nausea and emesis, WHO grade I. To date, four patients have been transplanted after high-dose chemotherapy (Melphalan 200mg/m2 or BEAM) with 4,7 (range 2,4–6,05) * 10e6 CD34+ cells/kg bw. Hematopoietic reconstitution (leukocytes >1/nl and thrombocytes >20/nl) was observed within a median of 14 (range 12–17) and 13 (range 10–15) days, respectively and is sustained in all patients. Thus CD34+ cells mobilized with AMD3100 appear to be fully functional. In conclusion AMD3100 is a seminal new drug development in the field of stem cell transplantation with the highest potential in poorly mobilizing patients.