From bloodjournal.hematologylibrary.org at UCLA on November 22, 2011. For personal use only. How I treat How I treat patients who mobilize hematopoietic stem cells poorly L. Bik To,1,2 Jean-Pierre Levesque,3,4 and Kirsten E. Herbert5 1Haematology, Institute of Medical and Veterinary Science/SA Pathology and Royal Adelaide Hospital, Adelaide, Australia; 2School of Medicine, University of Adelaide, Adelaide, Australia; 3Mater Medical Research Institute, South Brisbane, Australia; 4School of Medicine, University of Queensland, Brisbane, Australia; and 5Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia -Transplantation with 2-5 ؋ 106 mobilized niche integrity and chemotaxis. Poor mo- To maximize HSC harvest in poor mobiliz -CD34؉cells/kg body weight lowers trans- bilization affects patient outcome and in- ers the clinician needs to optimize cur plantation costs and mortality. Mobiliza- creases resource use. Until recently in- rent mobilization protocols and to inte- tion is most commonly performed with creasing G-CSF dose and adding SCF grate novel agents such as plerixafor. recombinant human G-CSF with or with- have been used in poor mobilizers with These include when to mobilize in rela- out chemotherapy, but a proportion of limited success. However, plerixafor tion to chemotherapy, how to schedule patients/donors fail to mobilize sufficient through its rapid direct blockage of the and perform apheresis, how to identify cells. BM disease, prior treatment, and CXCR4/CXCL12 chemotaxis pathway and poor mobilizers, and what are the criteria age are factors influencing mobilization, synergy with G-CSF and chemotherapy for preemptive and immediate salvage but genetics also contributes. Mobiliza- has become a new and important agent use of plerixafor. (Blood. 2011;118(17): tion may fail because of the changes for mobilization. Its efficacy in upfront 4530-4540) affecting the HSC/progenitor cell/BM and failed mobilizers is well established. Introduction Hematopoietic stem cell transplantation (HSCT) has revolution- engraftment19 and better survival in allogeneic transplantations,20 ized the curative approach to a number of malignancies and BM and it is probable that higher cell doses (eg, Ն 5 ϫ 106 CD34ϩ failure syndromes by providing hematopoietic and immune rescue cells/kg BW) may be similarly beneficial in mismatched transplan- after high-dose cytoreductive therapy and, in allogeneic transplan- tations. In haplotype mismatched transplantations doses of tations, graft-versus-tumor effect.1-4 Ն 10 ϫ 106 CD34ϩ cells/kg BW are often used.21 With the The term “mobilization” was first used to describe a 4-fold extension of transplantation to selected elderly patients,22 the increase of circulating myeloid progenitors (granulocyte macro- improved safety is vital. phage CFU [CFU-GM]) after the administration of endotoxin to G-CSF–based mobilization regimens have a 5%-30% failure healthy volunteers in 1977.5 High levels of CFU-GM after recovery rate among healthy donors and patients, but Յ 60% in high-risk from myelosuppressive chemotherapy in humans was first de- patients such as those exposed to fludarabine.23-25 A conservative scribed in 1976.6 However, it was not until the 1980s that the use of estimate of the number of patients who failed mobilization chemotherapy-mobilized HSCs for transplantation was estab- annually on the basis of the number of transplantations globally and lished.7-9 Subsequently, a single high-dose cyclophosphamide was the rate of failed mobilization is 5000-10 000 each year. Poor developed as a generic mobilizer.10 mobilization has significant consequences for the patient with Prof Metcalf led the study that showed the potential of G-CSF potential loss of the transplant as a treatment option. Repeated in mobilization.11 Subsequently, 2 Australian centers in Melbourne attempts at mobilization increase resource use, morbidity, and and Adelaide showed for the first time the use of G-CSF–mobilized patient/donor inconvenience. There is thus much interest in the HSCs for transplantation,12 and reports of combined G-CSF and prevention and salvage of mobilization failure with novel chemotherapy mobilization soon followed.13 Now, virtually all strategies. autologous and three-quarters of allogeneic transplantations are Understanding the mechanism of mobilization is fundamental performed with mobilized HSCs (CIBMTR reports).14,15 to develop novel strategies. The first reports of mobilization of The cell dose effect of HSCT describes a threshold of HSCs HSCs in humans were empirical observations, and the hypothesis, that, when transplanted, is associated with rapid and sustained untested, was that mobilization was a result of HSC proliferation. blood count recovery.16 The benefits of rapid recovery are reduced Mechanistic understanding of mobilization emerged when animal hospitalization, blood product usage, and infections.12,17 The mini- studies started.26 A number of pathways have been described, so it mum threshold for autologous transplantation is currently defined is timely to evaluate the risk factors for failed mobilization and how as 2 ϫ 106 CD34ϩ cells/kg body weight (BW).18 Many centers use optimized protocols involving conventional and new agents could a minimum of 3 ϫ 106 CD34ϩ cells/kg BW for myeloablative and be developed. nonmyeloablative allogeneic and matched unrelated transplanta- This article will not cover the mobilization of other cells such as tions. Furthermore, Ͼ 5 ϫ 106 CD34ϩ cells/kg BW is associated endothelial and mesenchymal progenitors, dendritic, or other with even lower resource use and faster and more complete platelet immune or malignant cells. Submitted May 30, 2011; accepted July 29, 2011. Prepublished online as Blood © 2011 by The American Society of Hematology First Edition paper, August 10, 2011; DOI 10.1182/blood-2011-06-318220. 4530 BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17 From bloodjournal.hematologylibrary.org at UCLA on November 22, 2011. For personal use only. BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17 HOW I TREAT POOR HSC MOBILIZERS 4531 subcutaneously the evening before the scheduled apheresis because ϩ Current mobilization regimens it generates peak CD34 levels 6-9 hours after administration.43-45 It synergizes with G-CSF and chemotherapy. Plerixafor is the latest G-CSF–based mobilization protocols addition to the list of mobilizing agents and the first driven by understanding how mobilization occurs. G-CSF with or without myelosuppressive chemotherapy has been the most commonly used mobilization protocols since the 1990s.12,13 When used alone, in both autologous12 and allogeneic transplanta- tions,27 G-CSF is given at 10 ␮g/kg per day subcutaneously with How HSC mobilization occurs apheresis beginning on the fifth day until the yield target is reached. HSC niche and microvascular recirculation There is no compelling evidence that twice daily administrations give a higher yield than a once-daily schedule.28 The HSC niche. HSCs reside within specific BM niches, an- Combining G-CSF with chemotherapy achieves the twin aims chored by adhesive interactions, and supported by stromal niche of mobilization and antitumor activity and has been shown to result cells that provide ligands for adhesion as well as signals for HSC in a higher CD34ϩ cell yield than G-CSF alone.29 Regimens such as functions such as quiescence, proliferation, and self-renewal. Two cyclophosphamide, doxorubicin, vincristine, and prednisone/ anatomical HSC niches have been described in mouse BM: a dexamethasone, high-dose cytarabine, and cisplatin or cyclophos- vascular niche in which HSCs are in contact with perivascular phamide 1-5 g/m2 have been used with G-CSF that starts 1-3 days mesenchymal stem cells (MSCs) and sinusoidal endothelial cells,46,47 after cyclophosphamide. Apheresis is usually started when leuko- and an endosteal niche in which HSCs are located within 2 cell cyte count reaches Ͼ 2 ϫ 109/L. The benefit of higher mobilization diameters from osteoblasts covering endosteal bone surfaces48-50 yield with higher doses of chemotherapy needs to be balanced and MSCs. An emerging model is that active HSCs that proliferate against more red cell and platelet transfusions, and, frequently, to renew the hematopoietic system are preferentially located in hospitalization for febrile neutropenia,30 and it is more justified perivascular niches, whereas dormant HSCs that maintain a reserve when significant antitumor effects exist. are preferentially located in poorly perfused, hypoxic endosteal A prospective study that compared 5 versus 10 ␮g/kg per day niches.51-53 after standard chemotherapy was inconclusive.31 G-CSF 5 ␮g/kg The “players” in the HSC niche per day is used in most units for combined G-CSF/chemotherapy The physical niche: Perivascular pluripotent MSC and their mobilization. osteogenic progenies form the physical niche in which the HSC The pegylated form of G-CSF (pegfilgrastim) showed similar resides.54 kinetics of mobilization as filgrastim.32 A phase 1/2 study in healthy The adhesive and chemotactic interactions: Perivascular MSCs, donors reported suboptimal mobilization with a dose of 6 mg but sinusoidal endothelial cells, and osteoprogenitors express adhesion satisfactory yield with 12 mg.33 Such dose dependence was not molecules such as (1) VCAM-1/CD106 that binds its receptor seen when pegfilgrastim was used with cyclophosphamide.34 integrin ␣4␤1 expressed by HSCs, and (2) transmembrane SCF (kit Lenograstim is a glycosylated form of G-CSF, whereas filgrastim is ligand) that binds its receptor c-Kit (CD117) on HSCs. Another nonglycosylated. Several prospective studies have shown higher mobili- essential interaction is the chemotactic factor stromal cell–derived zation yield with lenograstim.35,36 Posthoc analysis indicated that factor-1 (SDF-1/CXCL12) secreted by niche cells and its receptor this was because of better mobilization with lenograstim in males.36 CXCR4 on HSCs. Inducible deletion of any of these genes,55,56 or In contrast to healthy donors, CD34ϩ cell yield appears similar in blockade of the relevant proteins with antagonists,44,57 induces patients receiving either lenograstim or filgrastim after chemo- HSC mobilization in the mouse.