Can every patient be mobilized?

There are several ways to mobilize hematopoietic stem cells for autologous and allogeneic hematopoietic stem cell transplant by manipulating the bone marrow microenvironment. Granulocyte colony-stimulating factor (G-CSF) and chemotherapy have been commonly used to mobilize stem cells, but several new agents, such as the CXCR4 inhibitor plerixafor, inhibit stromal-stem cell interactions to improve stem cell yield. The minimum threshold for engraftment is 2 × 10? CD34+ cells/kg, but it has been shown that higher CD34+ stem cell dose, such as 5 × 10? CD34+ cells/kg, is associated with improved survival. Efforts to increase stem cell yield remain important to improve outcomes.     

UK consensus statement on the use of plerixafor to facilitate autologous peripheral blood stem cell collection to support high‐dose chemoradiotherapy for patients with malignancy

Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte‐colony stimulating factor [G‐CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re‐mobilization after a failed mobilization attempt with G‐CSF, and rescue or pre‐emptive mobilization in patients in whom mobilization with G‐CSF is likely to fail. Pre‐emptive use has the advantage that it avoids the need to re‐schedule the transplant procedure, with its attendant inconvenience, quality‐of‐life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre‐emptive plerixafor is associated with an incremental drug cost of less than £2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 µl^?1 at the time of recovery after chemomobilization or after four days of G‐CSF treatment, or an apheresis yield of <1 × 10⁶ CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre‐emptive plerixafor.     

Plerixafor for mobilization of blood stem cells in autologous transplantation: an update

Introduction: About 99% of all autologous transplants are now performed with blood stem cells. G-CSF alone or combined with chemotherapy have been used to mobilize CD34⁺ cells. Plerixafor is a novel drug used for mobilization purposes.

Areas covered: We have evaluated recent data in regard to plerixafor use in predicted or proven poor mobilizers. In addition, we have looked for preemptive strategies to optimize the use of this expensive drug. Also cost-efficacy issues and effects of plerixafor on graft composition and post-transplant outcomes will be discussed.

Expert opinion: Plerixafor added to G-CSF is superior than G-CSF alone for mobilization of CD34⁺ cells. This combination is also efficient in patients who have failed a previous mobilization attempt with other methods or in patients with risk factors for poor mobilization. Addition of plerixafor to G-CSF or chemotherapy plus G-CSF mobilization in patients who appear to mobilize poorly is under active investigation and algorithms for a preemptive use of this expensive agent have been proposed. Grafts collected after plerixafor appear to contain more lymphoid cells than the grafts collected without it. Whether this affects post-transplant outcomes such as immune reconstitution and risk of relapse needs to be evaluated.     

Plerixafor as a chemosensitizing agent in pediatric acute lymphoblastic leukemia: efficacy and potential mechanisms of resistance to CXCR4 inhibition

In spite of advances in the treatment of pediatric acute lymphoblastic leukemia (ALL), a significant number of children with ALL are not cured of their disease. We and others have shown that signaling from the bone marrow microenvironment confers therapeutic resistance, and that the interaction between CXCR4 and stromal cell-derived factor-1 (SDF-1 or CXCL12) is a key mediator of this effect. We demonstrate that ALL cells that upregulate surface CXCR4 in response to chemotherapy treatment are protected from chemotherapy-induced apoptosis when co-cultured with bone marrow stroma. Treatment with the CXCR4 inhibitor plerixafor diminishes stromal protection and confers chemosensitivity. Using xenograft models of high-risk pediatric ALL, plerixafor plus chemotherapy induces significantly decreased leukemic burden, compared to chemotherapy alone. Further, treatment with plerixafor and chemotherapy influences surface expression of CXCR4, VLA-4, and CXCR7 in surviving ALL blasts. Finally, prolonged exposure of ALL blasts to plerixafor leads to a persistent increase in surface CXCR4 expression, along with modulation of surface expression of additional adhesion molecules, and enhanced SDF-1α-induced chemotaxis, findings that may have implications for therapeutic resistance. Our results suggest that while CXCR4 inhibition may prove useful in ALL, further study is needed to understand the full effects of targeting the leukemic microenvironment.     

A novel CXCR4 antagonist for hematopoietic stem cell mobilization

Background: Hematopoietic stem cell (HSC) transplantation is a treatment option for hematological malignancies. Current mobilization regimes frequently result in inadequate numbers of HSC for transplant therefore alternative methods of mobilization are required. Objective: The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in HSC homing and mobilization. Disruption of the SDF-1/CXCR4 axis by the CXCR4 anatagonist, plerixafor, is shown to improve HSC mobilization. Methods: The molecular and in vivo pharmacology of plerixafor and subsequent clinical development is reviewed. Results/conclusion: Preclinical studies demonstrate that plerixafor is a selective antagonist of CXCR4 and can rapidly mobilize HSC. Clinical trials demonstrated improved HSC mobilization when plerixafor was included in the mobilization regimen. These data suggest the potential for a significant role for plerixafor in hematological disease.     

普乐沙福的合成工艺改进

目的：改进抗肿瘤药普乐沙福的合成工艺。方法：以丙二酸二乙酯为起始原料,经胺解、Michael加成、环合制得1,4,8,11-四氮杂-5,7,12-三氧代-环十四烷,再与α,α’-二溴对二甲苯桥连,还原制得普乐沙福。结果与结论：目标化合物的结构经1H-NMR和MS谱确证,总收率为27.5%。改进后的工艺无需柱色谱纯化,成本低廉,操作简便,有利于工业化生产。