Mobilization regimens prior to stem-cell collection in patients with lymphoma: How to choose?

High-dose chemotherapy supported by autologous stem-cell transplantation has an established therapeutic role in various hematological malignancies. Peripheral blood stem-cells (PBSC) have largely replaced bone-marrow as the source of autologous stem-cells since they provide more rapid recovery of hematopoiesis after transplantation resulting in reduced treatment-related complications, and since the collection procedure is more convenient [1]. Under steady-state conditioning, hematopoietic progenitor cells circulate in the peripheral blood at a low frequency. In order to collect an adequate number of stem-cells, they must be mobilized from the marrow to the peripheral blood. The mobilization process is a complex interplay between hematopoietic stem-cells, stromal cells, extra-cellular matrix, vascular endothelium, as well as cytokines, chemokines, adhesion molecules and their receptors. Mobilization mimics the physiological release of stem-cells from the marrow in response to stress signals. G-CSF induces proliferation of progenitor/ stem cells as well as activation of mature neutrophils resulting in release of proteases such as elastase, cathepsin G, and various metalloproteases. This proteolytic activity disrupts the anchoring signals between stromal cells and stem-cells such as VCAM1/ VLA-4 interaction and most importantly SDF-1/ CXCR4 interaction. It also disrupts the extra-cellular matrix and opens endothelial gaps for migration of stem-cells from the marrow to peripheral blood [2]. Current mobilization regimens include hematopoietic cytokines, such as G-CSF, as single agent or in combinations, chemotherapy followed by cytokines, or chemokine combinations. The probability of achieving successful mobilization and the number of stem-cells collected depends on several factors including the mobilization regimen used, age, the amount and type of prior chemotherapy and radiation therapy administered, and bone-marrow involvement. Chemotherapy plus cytokines generally mobilize greater number of PBSC than either alone. Myelosuppressive chemotherapy simulates the stress signals that result in stem-cell proliferation and egress to peripheral blood and this process is enhanced by growth factors. In one study, high-dose cyclophosphamide plus G-GCF resulted in a threefold increase in CD34þ cell yield compared with GCSF alone in patients with lymphoma [3]. No single mobilization chemotherapy has been clearly superior to others. However as a rule, higher doses of chemotherapy have been associated with better yield in some, but not all, studies. Intensive combination chemotherapy has been associated with better mobilization effect than single agents; however intensive regimens are more toxic [4]. Similarly, a dose-response phenomenon has been observed for cytokine dose in some studies [5] but this may not be applicable when administering intensive chemotherapy. In most studies, the ability to collect a larger number of PBSC with more effective regimens did not have a clinically significant advantage in engraftment kinetics. A recent study observed improved survival in super mobilizers compared with standard mobilizers; however it is not clear whether improved survival was related to administration of a larger graft or to favorable patient characteristics that are associated with mobilization of a large graft [6].