Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone

Abstract

Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting.

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy

“…To estimate the frequency of SRC in UM171-expanded CD34 + CD38 − HSPCs, we performed limiting-dilution statistics on the “t0 equivalent” cell doses that were transplanted in four replicate experiments (Figure 4F). Estimated SRC frequency was 1 in 10,700 (95% confidence interval: 5,500–21,100), which compares with a recently reported SRC frequency of ∼1 in 141,203 in uncultured CD34 + cells from G-CSF-mPB (Lidonnici et al., 2016). Taken together, these data indicate that our protocol allows ex vivo expansion of genetically engineered mPB CD34 + CD38 − cells with SCID-repopulating potential and warrants further protocol optimization for clinical application.…”

Reduced‐dose plerixafor as a mobilization strategy in autologous hematopoietic cell transplantation: a proof of concept study

“…However, most of these patients have been previously exposed to chemotherapy, radiation, or medications that affect bone marrow function; therefore, obtaining the necessary number of HSCs is a challenge in these patients. Although the optimal amount of CD34+ cells for autologous transplant is 5 × 10 6 /kg, a dose of at least 2 × 10 6 /kg CD34+ cells is required to ensure engraftment, lower doses may delay recovery of blood cells . Many risk factors have been associated with poor stem cell mobilization, including age, obesity, the underlying diagnosis (myeloma and lymphoma), previous radiotherapy or chemotherapy, disease status, among others .…”

“…In the field of autologous stem cell transplantation (ASCT) it is accepted that the ideal number of CD34+ HSCs necessary to ensure the recovery of hematopoietic function is approximately 5 × 10 6 per kg of body weight . Although the minimum number of cells required to guarantee engraftment is unknown, most authors agree that 2 × 10 6 /kg is sufficient, as lower doses may delay platelet and neutrophil engraftment . Lymphoma and myeloma are the most frequent contemporary indications of ASCT, with peripheral blood as the preferred source of HSCs for its faster hematopoietic and immune reconstitution, lower cost and greater donor comfort .…”

“…Poor mobilization can be defined as the inability to collect the number of HSCs necessary to guarantee hematological recovery 15 days after transplantation (≤2 × 10 6 /kg BW). Different strategies have been used to reduce this probability, including different growth factors, such as filgrastim, lenograstim, or sargramostim; chemotherapy plus granulocyte colony‐stimulating factor (G‐CSF); chemotherapy plus pegfilgrastim; and, more recently, plerixafor as a single agent or combined with G‐CSF . Plerixafor is a molecule that binds reversibly to CXC motif, receptor 4 (CXCR4), an adhesion molecule expressed in hematopoietic cells that plays an important role in their retention in the bone marrow, antagonizing the union of stromal cell‐derived factor‐1 (SDF‐1).…”

“…Plerixafor is a molecule that binds reversibly to CXC motif, receptor 4 (CXCR4), an adhesion molecule expressed in hematopoietic cells that plays an important role in their retention in the bone marrow, antagonizing the union of stromal cell‐derived factor‐1 (SDF‐1). This results in the mobilization of cells to the peripheral blood . Different studies have shown that plerixafor is well tolerated and highly effective in mobilizing HSCs, resulting in a higher proportion of CD34+ PBSC being collected, even in heavily pretreated patients .…”