Antagonizing CXCR4 accelerates CD34⁺ cell mobilization

Comment on Burroughs et al, page 4002

A novel bicyclam CXCR4 antagonist, AMD3100, appears capable of mobilizing a fully functional hematopoietic allograft within just 6 hours following a single injection.

Recent studies have demonstrated that the interaction between the chemokine stromal-derived factor 1 (SDF-1/CXCL12) and its only known receptor, CXCR4, serves as a key regulator of hematopoietic stem cell (HSC) trafficking.¹  In clinical practice, the hematopoietic cytokine granulocyte colony-stimulating factor (G-CSF) is widely used to induce the mobilization of HSCs and hematopoietic progenitor cells (HPCs) for reconstitution of hematopoiesis following myelosuppressive therapy. Several groups have demonstrated that G-CSF causes mobilization primarily through its indirect disruption of the SDF-1/CXCR4 interaction, inducing its cleavage by serine proteases or via down-regulation of SDF-1 mRNA.^2-4  Whatever the precise mechanism(s), this implies that agents that directly inhibit this interaction may be effective mobilizers. In this issue of Blood, Burroughs and colleagues have demonstrated that AMD3100, a direct antagonist of CXCR4, induces the rapid mobilization of hematopoietic cells with both short- and long-term repopulating capacity. Using a clinically relevant myeloablative canine transplantation model, they showed that a single dose of AMD3100 induces HSC and HPC mobilization within a few hours, allowing for apheresis to be performed on the same day of drug administration. Following both autologous and allogeneic transplantation, the cells collected following mobilization with AMD3100 alone were capable of reconstituting hematopoiesis with neutrophil and platelet recovery kinetics similar to those observed following transplantation of G-CSF–mobilized cells. One canine allogeneic recipient appeared to develop acute graft-versus-host disease (GVHD), but the overall incidence of this serious transplantation complication did not seem to be different from what would be expected following transplantation of G-CSF–mobilized cells. All dogs that received a transplant achieved full donor hematopoietic chimerism following myeloablative radiation.

These intriguing preliminary data suggest that by directly antagonizing CXCR4, a more rapid mobilization of clinically relevant CD34⁺ cells can be induced. This stands in stark contrast to the 4 to 5 days of G-CSF treatment normally required to mobilize sufficient HSCs and HPCs. A recent clinical trial in patients with non-Hodgkin lymphoma and multiple myeloma demonstrated that when AMD3100 is combined with G-CSF, the yield of CD34⁺ cells mobilized and available for collection is considerably greater than following G-CSF alone.⁵  These canine studies now suggest that AMD3100 could theoretically be used alone to mobilize HSCs and HPCs from healthy donors in a 1-day procedure. An ongoing trial is currently testing this hypothesis.

Despite early enthusiasm for this agent, a number of questions arise. Will blocking SDF-1/CXCR4 inhibit the normal homing and migration of stem and progenitor cells following transplantation or, alternatively, might homing of these cells be more effective? Are the qualities of the HSCs mobilized following AMD3100 similar to those mobilized by G-CSF or are there important differences? Finally, how will treatment with AMD3100 affect the quality and quantity of other important cell subsets cells mobilized in an allograft such as T and natural killer (NK) cells, and how might this influence the risk of GVHD and relapse? Ongoing studies should provide some clues over the next year. Stay tuned as the story unfolds. ▪