How I treat patients who mobilize hematopoietic stem cells poorly

Abstract

Transplantation with 2-5 ؋ 10 6 mobilized CD34 ؉ cells/kg body weight lowers transplantation costs and mortality. Mobilization is most commonly performed with recombinant human G-CSF with or without chemotherapy, but a proportion of patients/donors fail to mobilize sufficient cells. BM disease, prior treatment, and age are factors influencing mobilization, but genetics also contributes. Mobilization may fail because of the changes affecting the HSC/progenitor cell/BM niche integrity and chemotaxis. Poor mobilization affects patient outcome and increases resource use. Until recently increasing G-CSF dose and adding SCF have been used in poor mobilizers with limited success. However, plerixafor through its rapid direct blockage of the CXCR4/CXCL12 chemotaxis pathway and synergy with G-CSF and chemotherapy has become a new and important agent for mobilization. Its efficacy in upfront and failed mobilizers is well established.To maximize HSC harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor. These include when to mobilize in relation to chemotherapy, how to schedule and perform apheresis, how to identify IntroductionHematopoietic stem cell transplantation (HSCT) has revolutionized the curative approach to a number of malignancies and BM failure syndromes by providing hematopoietic and immune rescue after high-dose cytoreductive therapy and, in allogeneic transplantations, graft-versus-tumor effect. [1][2][3][4] The term "mobilization" was first used to describe a 4-fold increase of circulating myeloid progenitors (granulocyte macrophage CFU [CFU-GM]) after the administration of endotoxin to healthy volunteers in 1977. 5 High levels of CFU-GM after recovery from myelosuppressive chemotherapy in humans was first described in 1976. 6 However, it was not until the 1980s that the use of chemotherapy-mobilized HSCs for transplantation was established. [7][8][9] Subsequently, a single high-dose cyclophosphamide was developed as a generic mobilizer. 10 Prof Metcalf led the study that showed the potential of G-CSF in mobilization. 11 Subsequently, 2 Australian centers in Melbourne and Adelaide showed for the first time the use of G-CSF-mobilized HSCs for transplantation, 12 and reports of combined G-CSF and chemotherapy mobilization soon followed. 13 Now, virtually all autologous and three-quarters of allogeneic transplantations are performed with mobilized HSCs (CIBMTR reports). 14,15 The cell dose effect of HSCT describes a threshold of HSCs that, when transplanted, is associated with rapid and sustained blood count recovery. 16 The benefits of rapid recovery are reduced hospitalization, blood product usage, and infections. 12,17 The minimum threshold for autologous transplantation is currently defined as 2 ϫ 10 6 CD34 ϩ cells/kg body weight (BW). 18 Many centers use a minimum of 3 ϫ 10 6 CD34 ϩ cells/kg BW for myeloablative and nonmyeloablative allogeneic and matched unrelated transplantations. Furthermore, Ͼ 5 ϫ 10 6 CD3...

Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation

“…However, a high proportion of cancer patients with prior repeated high dose-chemotherapy cycles fail to mobilize sufficient HSC numbers in response to G-CSF to enable subsequent autologous transplantation. 2 Conditioning with chemotherapy, particularly with the alkylating agent cyclophosphamide (CYP), before G-CSF infusion increases the mobilizing response thereby enabling some poor mobilizers to reach the minimum threshold of 2 Â 10 6 CD34 þ HSPC/kg. However, the unpredictability of the kinetics and extent of mobilization renders this method difficult to implement.…”

“…Furthermore, genetically modified C57BL/6 mice lacking some of these proteases mobilize normally in response to G-CSF. 10 In the past 5 years, it has emerged that G-CSF mobilizes in part by (1) blocking proliferation and osteogenic differentiation of mesenchymal stem cells (MSC), 11 (2) inducing osteoblast apoptosis 12 and (3) blocking bone formation. 13,14 This results in a dramatic reduction in the expression of chemokines and cytokines necessary to maintain and retain HSC in their endosteal and perivascular niches such as CXCL12, kit ligand (KL) and angiopoietin-1.…”

“…As AMD3100 is progressively replacing CYP as adjuvant to G-CSF to mobilize HSC in lymphoma and multiple myeloma patients who previously failed to mobilize in response to G-CSF alone, 2 we compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts and HSC niche function.…”

The impact of CD34+ cell dose on engraftment after SCTs: personalized estimates based on mathematical modeling

“…1 Clinical trials have confirmed the impact of transplant size on fast and sustained engraftment. 2 Accordingly, lower bounds on the number of transplanted cells have been defined to ensure safe treatment. Nevertheless, individual engraftment times differ widely and delayed engraftment occurs.…”

“…[16][17][18] In almost every trial, there exist patients with recovery times distant from average. The dose of transplanted cells has an impact on the time to neutrophil reconstitution 2,19 and is a tunable parameter; therefore, it is important to know whether slowly reconstituting patients might benefit from increased numbers of transplanted cells. As such patients cannot be identified before transplantation, it is difficult to apply prospective clinical trials.…”