Stem cells stat, please!

Over the past decade, cytokine-mobilized peripheral blood stem cells have largely replaced bone marrow as a source of stem cells for both autologous and allogeneic stem cell transplantation. Only 2 cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage–CSF (GM-CSF), have been approved by the Food and Drug Administration (FDA) for stem cell mobilization. Their use for stem cell mobilization is limited by their cost, the need for multiple injections, toxicity to the donor (bone pain), and most importantly by their failure to mobilize a minimum number of progenitors (2 × 10⁶ CD34⁺/kg) necessary for consistent and rapid engraftment of neutrophils and platelets from difficult-tomobilize patients. The addition of chemotherapy to cytokines has enhanced mobilization but is also limited by significantly greater cost and morbility to the donor. Over the past decade we have witnessed the death of many exciting new cytokines that were marketed and tested as stem cell mobilizing agents. These include stem cell factor, daniplestim (interleukin 3 [IL-3] agonist), chimeric cytokines, thrombopoietin analogues, and flt-3 ligand and analogues. Their impact on mobilization has either been modest at best or they have been associated with unexpected toxicities. Chemokines such as IL-8 have been shown to rapidly (within 1-4 hours) induce the mobilization of hematopoietic progenitors in mice and nonhuman primates but directly activate mature myeloid effector cells, limiting their potential in human clinical trials due to the possibility of excessive toxicity. Liles and colleagues (page 2728) used AMD3100, a novel reversible bicyclam antagonist of CXCR4 (the receptor for stromal cell-derived factor 1 or SDF-1/CXCL12) to rapidly (3-9 hours) mobilize CD34⁺ progenitors in a dose-dependent manner from a series of healthy human volunteers. The circulating CD34/mL increased 10- to 20-fold within 6 to 9 hours after a single injection of the highest dose of AMD3100 (240 μg/kg) tested. These single injections were associated with minimal toxicities and were suffi-cient to mobilize enough stem cells for a stem cell transplantation after a single apheresis.

This exciting report raises many questions. Although comparable numbers of CD34 are mobilized 6 to 9 hours after a single subcutaneous injection of AMD3100 and after 5 days of G-CSF in healthy donors, will the same effect of AMD3100 be seen in patients who have impaired marrow reserves? Preliminary studies in patients with myeloma and non-Hodgkin lymphoma (NHL) are currently underway and the results are anxiously awaited. Since 20% to 40% of heavily pretreated patients with NHL and Hodgkin disease fail to mobilize using G-CSF, it will be extremely important to demonstrate that AMD3100 has an additive or synergistic effect with G-CSF on stem cell mobilization. Previous data¹  suggest that AMD3100 acts synergistically with G-CSF in a murine model of stem cell mobilization. Finally, are stem cells mobilized more rapidly by AMD3100 comparable or better than stem cells mobilized more slowly by G-CSF? Can dosing of AMD3100 be effectively performed in a repetitive fashion with respectable toxicities? Although initial trials in humans may provide some insights, only preclinical competitive repopulation studies in the mouse will be able to appropriately assess the short-term and long-term multilineage engraftment potential of stem cells mobilized with AMD3100 and G-CSF. Will AMD3100 be an option for the mobilization of allogeneic donors? Since CXCR4 is expressed on many cells, including CD3⁺ T cells, it is conceivable that AMD3100-mobilized T cells may alter graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) in positive or negative ways. Again, preclinical studies using AMD3100 in the allogeneic setting will be necessary prior to any future clinical trials using AMD3100 as an allogeneic stem cell mobilizing agent in humans.