How I Treat Patients Who Mobilize Hematopoietic Stem Cells Poorly

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 transplantations. 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.

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 transplantations,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. ϩ therapy.37 The efficacy of biosimilar G-CSF is still to be confirmed. Cells supporting the niche cells: A population of CD68 ϩ SCF (ancestim) exists as a soluble form as well as a surface CD169 phagocytic macrophages are adjacent to MSCs and molecule on BM stromal cells. It binds to c-kit on HSCs and osteoblasts that form the HSC niche. These macrophages are modulates proliferation and adhesion. As a single agent SCF has necessary for niche cells to express hematopoietic cytokines and 58,59 limited efficacy in HSC mobilization; however, synergy between CXCL12 and are critical for the functional integrity of niches. SCF and G-CSF has been noted in animal models38 and in human Ablation of these macrophages disrupts niche function, resulting in subjects.39 SCF at 20 ␮g/kg subcutaneously was started 4 days a dramatic down-regulation of VCAM-1, SDF-1, and SCF expres- 58,59 before the start of G-CSF and continued with the G-CSF until the sion and concomitant HSC mobilization (Figure 1). end of apheresis. Antihistamine and anti–5-hydroxytryptamine blocking agents should be administered concurrently to reduce the Mechanisms of mobilization risks of anaphylactic reactions. In failed mobilizers SCF plus Mobilization is the iatrogenic augmentation of HSC recirculation G-CSF with or without chemotherapy enabled adequate mobiliza- that occurs at low levels in steady state. Murine experiments within ϳ 40 tion in 50% of patients. In prior fludarabine-exposed patients the past decade have identified several pathways that lead to HSC SCF with high-dose G-CSF resulted in a 63% success rate, almost mobilization. 23 doubling that in historical controls that used G-CSF alone. It is G-CSF not available in many countries, including the United States. The role of proteases: Chemotherapy and G-CSF produce Sargramostim, GM-CSF, is not more effective than G-CSF alterations in the composition of the HSC niches, including a alone, has no synergy with G-CSF, and is limited by dose-related marked down-regulation of adhesion and chemokine processes 41 toxicities. Now, GM-CSF is rarely used. such as VCAM-1, SDF-1, and SCF.58,60,61 Initial investigations Plerixafor suggested that granulocytes and their progenitors release large amounts of proteases such as neutrophil elastase, cathepsin G, and Plerixafor,42 a CXCR4 antagonist, reduces the binding and che- matrix metalloproteinase-9 in the mobilized BM, which in concert motaxis of HSCs to the BM stroma. It is used at 240 ␮g/m2 with other proteases such as CD26 (expressed at the surface of From bloodjournal.hematologylibrary.org at UCLA on November 22, 2011. For personal use only. 4532 TO et al BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17

Figure 1. Model of HSC niche regulation in steady state. (A) Perivascular niches harboring active HSCs that regenerate the hematopoietic system. Active HSCs are in contact with perivascular nestinϩ MSCs and sinusoidal endothelial cells. Both MSCs and sinusoidal endothelial cells express SDF-1, transmembrane SCF, and VCAM-1 that retain HSCs within the niche via adhesive and chemotactic interactions. (B) Endosteal niches harboring quiescent HSCs. Quiescent HSCs are in contact with nestinϩ MSCs or osteoprogenitors or both. (C) Interactions between niches cells, HSCs, and adrenergic neurons. CD68ϩ CD169ϩ macrophages and osteomacs forming support function of nestinϩ MSCs, osteoprogenitors and osteoblasts which in turn maintain HSCs in steady state (stimulating feed-back illustrated by green arrow). Sympathetic ␤3 adrenergic nerves inhibit SDF-1 secretion by MSCs and osteoblasts after a circadian pulse (negative pulse illustrated by dotted red bars).

HSCs62) complement cascade proteins C3 and C563,64 and the peak.70 In a retrospective study comprising 85 healthy mobilized plasmin activation cascade,65 cleave and inactivate VCAM-1, donors, this peak was in the afternoon with 85% higher CD34ϩ SDF-1, CXCR4, c-Kit, and SCF. Indeed, mice rendered neutro- yields than in the morning.72 The ␤2 agonist clenbuterol also penic by antibody treatment or deletion of the G-CSF receptor increases mobilization in mice.73 Therefore, time of collection and (Csf3r) gene mobilize poorly in response to G-CSF or cyclophosph- ␤2 agonists could be 2 simple strategies to further increase amide.66,67 However, the physiologic signiﬁcance of proteases mobilization yields. remains uncertain because mice lacking genes encoding some of Hence, it is increasingly apparent that the mobilization response these proteases will still mobilize normally in response to G-CSF.68 to G-CSF involves both macrophage-mediated and adrenergic The role of BM macrophages: The importance of CD68ϩ sympathetic pathways (Figure 2). Targeting these 2 pathways to CD169ϩ BM macrophages in G-CSF mobilization was discovered improve mobilization efﬁciency is an interesting avenue to explore. recently.58,59,69 G-CSF administration causes the loss of these Cyclophosphamide. HSC mobilization occurs during the macrophages, resulting in down-regulation of SDF-1, SCF, and recovery phase after cyclophosphamide. A marked reduction of VCAM-1 expression by niche cells.58,59,69 It was therefore con- osteoblasts, osteoblast-supportive endosteal macrophages (osteo- cluded that the loss of these niche-supportive macrophages results macs), and CXCL12 expression results in the disruption of the in inhibition of bone formation and HSC-supportive niche function CXCL12 gradient (Winkler IG, Petit AR, Raggatt LI, Bendall LJ, and contributes to G-CSF–induced mobilization.58,59,69 Jacobsen R, Barbier V, Nowlan B, Cisterre A, Shen Y, Sims NA, The role of complement, the thrombolytic pathway, and chemot- Levesque JP, manuscript in preparation). Unlike G-CSF, however, actic gradients of SDF-1 and sphingosine-1-phosphate: G-CSF cyclophosphamide does not down-regulate the expression of KIT administration activates the complement cascade63,64 and thrombo- ligand, enabling rapid recruitment of HSCs into proliferation to lytic pathway,65 both shown to play a role in the mobilizing restore BM cellularity (Winkler IG, Petit AR, Raggatt LI, Bendall response to G-CSF. Complement activation also causes the release LJ, Jacobsen R, Barbier V, Nowlan B, Cisterre A, Shen Y, Sims NA, of erythrocytes sphingosine-1-phosphate (S1P) into the plasma. Levesque JP, manuscript in preparation). The synergism with S1P is a lipid that is highly chemoattractant to HSCs. S1P G-CSF may result from a more complete down-regulation of accumulates in plasma of mobilized mice, forming a counter CXCL12 combined with enhanced number of BM HSCs because gradient that chemoattracts HSCs into the circulation.70 Therefore, of the induction of HSC self-renewal in response to chemotherapy. mobilization could result from the simultaneous weakening of the CXCR4 antagonists. Because the chemotactic interaction SDF-1 gradient released by niche cells, weakening of adhesive between SDF-1 and its receptor CXCR4 is critical to HSC retention interactions mediated by VCAM-1 and transmembrane SCF, within the BM, CXCR4 blockade with antagonists or administra- together with the formation of a counter gradient of S1P caused by tion of stable analogs of SDF-1 effectively mobilizes HSCs. complement activation. Plerixafor is the only CXCR4 antagonist currently available. The role of ␤-adrenergic sympathetic nerves: In mice and Alone, plerixafor rapidly mobilizes HSCs, peaking at 6-9 hours.43-45 humans the steady state recirculation of HSCs follows a circadian Plerixafor directly binds to CXCR4 and inhibits chemotactic rhythm under the control of sympathetic adrenergic nerves that signaling in cells.74,75 Plerixafor also promotes the release of SDF-1 promote rhythmic oscillations in the production of SDF-1 by HSC from CXCR4ϩ osteoblastic and endothelial cells into the circula- niche cells and CXCR4 expression by HSCs themselves.71,72 tion.76 It therefore seems to counter the chemotactic SDF-1 Consequently in mice, SDF-1 expression in the BM and CXCR4 gradient between the BM stroma and the circulation, favoring the expression on HSCs is lowest 5 hours after the onset of light when egress of HSCs from the BM. Of note, the down-regulation of HSCs in the peripheral circulation peak. In mice mobilized with SDF-1 in response to G-CSF is always partial and at best G-CSF or plerixafor, more HSCs were harvested at this circadian 80%.58,73,77,78 Unlike G-CSF, plerixafor bypasses the macrophage 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 4533

Figure 2. G-CSF deregulates niches and causes HSC mobilization. (A) G-CSF activates CD68ϩ CD169ϩ macrophages in perivascular niches. This suppresses macrophage supportive function for MSCs. Conse- quently, expression of CXCL12, SCF, and VCAM-1 is down-regulated. Complement cascade is activated, lead- ing to erythrocyte lysis and release of S1P in the blood, creating a chemotactic counter gradient. Active HSCs are mobilized. (B) G-CSF suppresses osteomacs in endosteal niches. Osteoblasts are lost, bone formation stops, and expression of CXCL12, SCF, and VCAM-1 by MSCs and osteoprogenitors is down-regulated. Dormant HSCs are mobilized. (C) Schematic representation of interactions in response to G-CSF. ␤-adrenergic neuron activation by G-CSF inhibits SDF-1 production by MSCs, osteoprogenitors, and osteoblasts and inhibits bone formation by osteoblasts (solid red bars). Stimulation of osteomacs and CD169ϩ macrophages by G-CSF (solid red bars) suppresses their supportive function for MSCs and osteoblasts. Consequently, expression of SDF-1, Kit ligand, and VCAM-1 by osteoprogenitors and MSCs is down-regulated. Complement cascade is activated by G-CSF, resulting in S1P release into the blood.

pathway and does not promote the loss of endosteal osteomacs and but the therapeutic approach to correct them may be specific to osteoblasts (Winkler IG, Petit AR, Raggatt LI, Bendall LJ, Jacob- each one. sen R, Barbier V, Nowlan B, Cisterre A, Shen Y, Sims NA, Levesque JP, manuscript in preparation). Because of their different Effect of underlying disease and complementary mechanisms of action, plerixafor shows marked BM involvement by disease is associated with poor yields.82,83 44,45 synergism with G-CSF. Although plerixafor represents a land- There may be reduced HSC numbers partly related to the impair- mark development in improving HSC mobilization strategies, it is ment of healthy niches by malignant cells in the BM84 or direct important to note that 30% of patients failing G-CSF containing competition between HSCs and malignant cells for a limited mobilization protocols still fail to mobilize adequately to this number of niches.85 Moreover, non-Hodgkin versus Hodgkin combination. lymphoma,86 indolent lymphoproliferative disease,82 and acute ␣4 Integrin (CD49d) antibodies. Integrin ␣4␤1 mediates leukemia87 have all been identified as independent risk factors. HSC adhesion to VCAM-1, a key adhesive interaction for HSC Whether there are specific aspects of the pathophysiology of these retention within the BM stroma.79 A single dose of natalizumab diseases that influence mobilization is still to be determined. (300 mg), a humanized function-blocking anti-CD49d antibody prescribed to patients with relapsing multiple sclerosis, was found Effect of prior treatment to increase circulating CD34ϩ cells 5-fold 1 day after antibody Mobilization failure in autologous donors correlates with the infusion.80 In mice, a single dose of the small ␣4␤1 integrin number of prior lines of treatment with chemotherapy. Most inhibitor BIO5192 mobilizes HSC/progenitor cell at 6 hours after a cytotoxic treatments and molecules used in targeted therapies can single dose and is additive to the effect of plerixafor.81 Therefore, have deleterious effects on HSCs and the niches in which they ␣4␤1 blockers may be of interest in patients who fail to mobilize reside. However, DNA cross-link agents such as melphalan or adequately in response to G-CSF and plerixafor. carmustine,88 and purine analogs such as fludarabine are associated with a very high risk of mobilization failure.89 Cytotoxic drugs that do not specifically target cell progressing through the S phase of the cell cycle (eg, anthracyclines, cisplatin, Poor mobilization: clinical risk factors and fludarabine, carmustine, melphalan) could potentially kill quies- mechanistic understanding cent HSCs and niche cells, thereby reducing the HSC reserve. Fludarabine is toxic to hematopoietic progenitors as well as to the Clinical risk factors for poor mobilization with conventional niche, a double hit on the mechanisms of mobilization.90 Alkylating regimens have been well described (Table 1). Poor mobilization agents such as chlorambucil given in a continuous manner may still may be innate and inherent to a particular genetic combination be toxic on HSCs. specific to a person or acquired as a consequence of aging, prior Highly intensive, dose-dense regimens such as the hyper-CVAD treatments, or disease. The possible defects could be at one or more (hyperfractionated cyclophosphamide, vincristine, doxorubicin, of three levels: (1) insufficient number of HSCs because of HSC and dexamethasone with methotrexate and cytarabine) regimen are intrinsic factors, (2) insufficient HSC number because of low associated with a high risk of mobilization failure beyond the first number or defective niches, or (3) inadequate number or response 2-4 cycles of therapy.91 Successive cycles of chemotherapy recruit of effector/supporter cells such as BM macrophages or ␤-adrener- more and more HSCs into the cell cycle, and in mice such forced gic nerves. These possible defects are not mutually exclusive, HSC cycling leads to rapid exhaustion of HSC self-renewal and From bloodjournal.hematologylibrary.org at UCLA on November 22, 2011. For personal use only. 4534 TO et al BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17

Table 1. Risk factors, mechanisms, and strategies to optimize collection in predicted poor mobilizer patients Risk factor Postulated mechanism Mobilization strategy

Low steady-state platelet counts Reflects overall HSC reserve Regimen promoting HSC proliferation, eg, SCF, cyclophosphamide and PB CD34ϩ level Low steady-state TNF-␣ level May reflect niche dysfunction, including the macrophage Regimen bypassing the macrophage-dependent pathways, eg, response to G-CSF plerixafor-containing regimen Increasing age Reduced HSC reserve because of the following: Regimen promoting HSC proliferation, eg, SCF, cyclophosphamide Age-related HSC senescence Add risk-adapted plerixafor to augment niche response to G-CSF Age-related loss or dysfunction of HSC niche Bisphosphonate treatment continued throughout collection PTH of Age-related bone loss or altered bone metabolism interest in experimental models Underlying disease Paraneoplastic niche dysfunction Aim to clear BM of disease before collection Loss of niche to mass effect of tumor Prior extensive radiotherapy Direct HSC toxicity Rainy day collection before extensive RT when possible (RT) to red marrow Toxicity to HSC niche Risk-adapted plerixafor Regimen promoting HSC proliferation, eg, SCF, cyclophosphamide Prior chemotherapy Melphalan Direct HSC toxicity Avoid melphalan until autologous cells collected Fludarabine Direct HSC toxicity, niche damage Collect HSCs early, after Ͻ 4 cycles of fludarabine Intensive chemotherapy Dose-dense cycles may cause niche damage, and Use SCF or preemptive risk-adapted plerixafor for fludarabine- (eg, hyper-CVAD) HSCs forced into cell cycle may not engraft as well exposed and heavily pretreated patients Prior lenalidomide Possible effects on HSC motility Collect HSC early, after Ͻ 4 cycles of treatment Possible dysregulated HSC niche because of Temporarily withhold lenalidomide during collection. antiangiogenic effects

reconstitution potential. Repetitive cycles of chemotherapy may Failed mobilization in patients with no obvious risk factors: also damage niches for HSCs and BM macrophage effector cells. constitutive poor mobilizers Lenalidomide is associated with poor mobilization, particularly Up to 5% of healthy donors fail to mobilize with conventional after Ͼ 4 cycles of treatment.92 Lenalidomide may suppress HSC regimens, and some patients with no obvious risk factors will also. motility similar to the way it reduces the motility of marrow The mechanistic understanding of these “constitutive poor mobiliz- endothelial cells in multiple myeloma.93 The antiangiogenic effect of lenalidomide could also impair mobilization.94 ers” is complex and incomplete. Different isogenic inbred mouse Long-term administration of imatinib has been associated with strains can have either very high or very low mobilizing response to reduced bone turnover,95 which could affect HSC niche function. G-CSF. Genetic linkage analyses in these inbred mouse strains 105,106 Yields were improved if the patients temporarily withheld imatinib have identified several loci linked to poor mobilization. The for 3 weeks before collection.96 mechanisms could involve qualitative and quantitative differences Prior radiotherapy to significant amounts of red marrow is in HSCs in the BM, a difference in how HSCs migrate, and how the 107 associated with mobilization failure,97 probably because of com- niches are down-regulated in response to G-CSF. These genetic bined direct HSC toxicity, niche toxicity, and toxicity to the approaches have identified the epidermal growth factor receptor niche-supporting cells. Radiotherapy may also increase the expres- pathway and the epidermal growth factor receptor tyrosine kinase sion of protease inhibitors such as ␣1-antitrypsin that would inhibitor erlotinib as an adjuvant treatment to enhance mobilization 107 diminish the protease storm during mobilization.98 in response to G-CSF in poorly responding mouse strains, although no human data are available. Genetic polymorphism analyses in humans have identified polymorphisms associated with Age-related poor mobilization mobilizing response to G-CSF in untranslated regulatory regions of genes encoding GCSFR, adhesion molecules (VCAM-1, CD44), Poor mobilization is often noted in patients Ͼ 60 years of age.86,97 and chemokines (SDF-1), which are all known to regulate HSC First, there is an age-related “senescence” of actual HSCs because trafficking.108,109 Genetic polymorphisms may predict for poor of progressive telomere shortening.99 Second, there is a reduction mobilization, yet it is premature to apply such screenings in the in the HSC reserve caused by decreased niche function in older clinic to identify poor mobilizers prospectively. mice with depletion of mesenchymal stem cells and osteoprogenitors.100 Third, aging is frequently associated with a marked decrease in bone formation and osteoblast numbers on endosteal surfaces, so endosteal osteoblastic niches for HSCs are probably Strategies to optimize current mobilization reduced.48,101 It is therefore noteworthy that boosting of bone turnover and protocols formation with a 3-week course of daily injections of parathyroid Donor screening hormone (PTH) increases HSC levels in mice102 and in a phase 1 clinical trial in patients who failed prior mobilization with G- The National Bone Marrow Program provides guidelines for CSF.103 However, the efficacy of PTH in mobilization is still to be screening of donors to ensure donor and recipient safety. Donors of proven. Interestingly, inhibition of bone degradation by a 5-day male sex, young age, and match at A, B, C, DR, and DP are pretreatment with bisphosphonates such as pamidronate and zole- preferable because of higher HSC yield and more certain engraft- dronate also increases HSC mobilization in response to G-CSF in ment. If there were any concerns about myelodysplasia/leukemia or mice.58,104 familial/inherited disorders, further screening investigations are 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 4535 warranted. For donors who failed to mobilize, the screening results Society for Cellular Therapy European Group for Blood and should be reviewed and further investigations considered. Marrow Transplantation (JACIE).

Planning of mobilization

For patients undergoing chemotherapy, collection of HSCs should Strategies to improve the likelihood of be considered early when extensive or intensive chemotherapy success in poor mobilizers such as hyper-CVAD are used and also before extensive use of fludarabine and lenalidomide. Lenalinomide and imatinib should Approaches to failed mobilization after conventional regimens be ceased 3 weeks before mobilization. It is intuitive that clearance include increased doses of G-CSF120 or combination with of BM disease is desirable. For patients undergoing extensive field SCF.39,40,121,122 However, the success rate is often still Ͻ 50%. radiotherapy, “rainy day HSC harvesting” should be considered if Currently, the combinations of G-CSF, SCF, or, more recently, autologous transplantation is a potential treatment option. Patients plerixafor with or without chemotherapy are probably the most exhibiting markers of low HSC reserve such as baseline thrombo- promising approaches. cytopenia may benefit from regimens promoting HSC proliferation such as SCF or cyclophosphamide. Plerixafor

Optimizing apheresis to improve yield and to avoid weekend Plerixafor causes mobilization by disrupting of the SDF-1/CXCR4 apheresis interaction.123,124 It synergizes with G-CSF through its different mechanism of action. In clinical practice, plerixafor is usually adminis- The peripheral blood CD34ϩ cell count is the best predictor of tered subcutaneously at 240 ␮g/m2 in the evening 10-11 hours 110 ϩ apheresis yield, and the use of CD34 cell counts to guide before the planned first day of apheresis. More recent publications apheresis reduces costs.111 If the circulating CD34ϩ cell count is describe successful use of plerixafor with dosing at 5:00 PM dosing Ն ␮ 20/ L, 94% of collections performed the following day would the evening before apheresis.125 Peripheral blood CD34ϩ levels Ն ϫ 6 ϩ 110 be expected to yield 2.0 10 CD34 cells/kg. In general should be measured on the morning of apheresis, but commence- ϩ Ͻ ␮ terms if the CD34 cell count is 5/ L, the yield will be poor; ment of apheresis should not be delayed. Two to 3 daily doses may Ͼ ␮ therefore, apheresis not warranted. If the count is 10/ L, it may be required in some patients. take Յ 4 aphereses to collect sufficient cells for a single rescue. In healthy donors plerixafor is effective as either a single agent Studies also showed that early and late progenitors tend to or in combination with G-CSF.43 The safety and efficacy of ϩ mobilize with similar kinetics112,113 and no CD34 cell subsets plerixafor have been demonstrated in patients with lymphoma or provide additional information, so there is no need to measure multiple myeloma.126,127 However, the eventual cell yields with the different subsets. use of up-front plerixafor in all patients were the same compared In healthy donors mobilized with G-CSF alone peak CFU-GM with the use of plerixafor only in those who failed G-CSF and CD34ϩ cell counts occurred on day 5. The CD34ϩ cell peak mobilization. The disadvantage of such up-front use of plerixafor is was seen during days 4-6.114 In combined chemotherapy and increased drug costs. G-CSF mobilization one study showed that mobilization occurred Outside the United States, the mode of reimbursement varied in after day 11 after chemotherapy in 97% of patients, the median different countries and requires user-pays in others. Yet remobiliza- peak of CD34ϩ cell levels occurring on days 14-15, although tion and failed mobilization are also costly in terms of resources heavily pretreated patients mobilized later.115 On the basis of these and patient outcome. Hence, it has been suggested that the biggest data, it is possible to schedule mobilization to avoid the costs of incremental benefit of plerixafor is in the poor mobilizer popula- weekend apheresis and cryopreservation. For G-CSF alone mobili- tion.128 Risk-adapted algorithms have therefore been proposed: zation, most centers would commence G-CSF on Friday and (1) preemptive plerixafor in predicted poor mobilizers, (2) immedi- perform apheresis the following Tuesday onward. For combined ate salvage plerixafor for patients with suboptimal mobilization, chemotherapy and G-CSF mobilization, chemotherapy usually and (3) remobilization with plerixafor in failed mobilizers. starts in the latter half of the week and G-CSF started the next few The rational use of preemptive plerixafor depends on identify- days. Peripheral blood CD34ϩ cell counts should be monitored ing potential poor mobilizers. The adverse effect of BM involve- when leukocyte recovery starts, aiming for apheresis Monday/ ment and prior chemo/radiotherapy have been discussed earlier, 86 Tuesday the week after. The CD34ϩ cell threshold for starting and low marrow cellularity probably reflects poor BM reserve. ϩ However, their specificity as an indicator is low because some of apheresis is derived through a combination of CD34 cell yield these patients may still mobilize. Steady state levels of circulating target, the number of apheresis planned and the institutional HSCs significantly correlate to CD34ϩ cell yield mobilized with experience with collection efficiency.116 conventional regimens,129 with yields of 1 ϫ 106/kg CD34ϩ cells Larger volume apheresis (processing Ն 3 times the blood per apheresis procedure in 98% of patients with steady state CD34ϩ volume instead of 2 times) results in higher HSC yields and may cell levels Ͼ 2.65/␮L. However, it is not a reliable predictor of reduce the number of sessions in some cases.117 poor mobilization because 76% of patients below this threshold Applying good manufacturing practice still had adequate mobilization.129 Whether a lower cutoff will be more useful is not known, but the reproducibility and reliability of For personnel training, quality assurance, and facility accreditation, measurement at such a lower level is at the limit of technology. the readers are referred to the FACT-JACIE International Standards Requirement for G-CSF (when not given routinely) during for Cellular Therapy Products Collection, Processing and Adminis- previous chemotherapy130 may predict poor mobilization. More- tration118 and its accompanying Accreditation Manual119 produced over, baseline thrombocytopenia (quoted thresholds range from by The Foundation for the Accreditation of Cellular Therapy Ͻ 100 to Ͻ 150 ϫ 109/L)83,131 has been consistently associated (FACT) and the Joint Accreditation Committee of and International with poor mobilization. From bloodjournal.hematologylibrary.org at UCLA on November 22, 2011. For personal use only. 4536 TO et al BLOOD, 27 OCTOBER 2011 ⅐ VOLUME 118, NUMBER 17

Figure 3. Example of a proposed risk-adapted protocol for ISP in the case of suboptimal mobilization response to a conventional regimen. Triggers for ISP can be based on peripheral blood CD34ϩ counts (PB CD34) or on the daily yield from the ﬁrst day’s apheresis.

In healthy donors nearly 90% of donors who had a low TNF-␣ cell yields or both. A suggested protocol for immediate salvage level in steady state exhibited suboptimal mobilization to a G-CSF plerixafor (ISP) is presented in Figure 3. alone regimen.132 Because TNF-␣ is an essential inflammation In failed mobilizers, a remobilization regimen with the addition mediator produced by macrophages, the concentration of TNF-␣ of plerixafor enables reaching the CD34ϩ cell target in Ͼ 70% of may reflect BM macrophage activity which plays a crucial role in patients128 so there is little doubt about its efficacy. One should mobilization and niche maintenance.58,69 ensure that there is Ն 4 weeks of break before remobilization. Overall, aside from baseline thrombocytopenia, there are as yet Concerns have been raised about the higher nucleated cell content no indicators, singly or together, that identify poor mobilizers with in the apheresis product affecting apheresis and increasing the certainty. Whether low TNF-␣ levels are predictive in the autolo- infusion volume. This may be overcome by modifying the aphere- gous setting is still unknown. Hence, choosing subjects for sis software.134 preemptive plerixafor requires clinician judgment. It is noteworthy that plerixafor-containing regimens have a 30% The rational use of immediate salvage plerixafor depends on failure rate among prior failed mobilizers, probably because it real-time indicators to define “poor” and “slow” mobilizers during could not restore low or defective HSC reserve or niche. Understand- a mobilization attempt. These include a suboptimal peripheral ing how these factors operate at the molecular level and thereby blood (PB) CD34ϩ cell level or suboptimal apheresis yield or both steering the development of targeted approaches and alternative at the expected first day of apheresis which predicts failure to mobilization algorithms will define the next era of mobilization collect the target yield within an acceptable number of apheresis strategy. days. There is as yet no validated data to define cutoffs for the Salvage BM harvest addition of plerixafor; however, one published algorithm prescribes ϩ the addition of plerixafor on day 5 of G-CSF if the PB CD34 level Transplantation that use BM is generally associated with slower is Ͻ 10/␮L when collecting cells for 1 transplantation, and engraftment, particularly of platelets compared with that using Ͻ 20/␮L when collecting cells for Ͼ 1 transplantation.125 How- mobilized HSCs. This problem is magnified in patients who ever, it has been shown that a CD34ϩ cell level of Ͻ 5-6/␮L on day mobilize poorly to current regimens, whereby the use of salvage 4 of G-CSF apheresis indicates the need for salvage plerixafor, BM-derived cells is associated with a particularly high incidence of because the likelihood of achieving a level Ͼ 10/␮L by the delayed platelet engraftment and procedure-related deaths approach- following day is Ͻ 40%.133 A first-day apheresis yield of ing 50%.135,136 Poor mobilizers probably have inherently low HSC Ͻ 0.5 ϫ 106 CD34ϩ cell/kg indicates need for salvage, although numbers, possible functional HSC defects, as well as an unhealthy higher cutoffs such as a first-day apheresis of Ͻ 50% of the target BM microenvironment which together amount to adverse condi- yield are also used.125 Because institutional practices vary, indi- tions for engraftment, at times despite seemingly adequate CD34ϩ vidual centers ideally should analyze their own data to determine cell doses. Salvage BM harvests may be attempted in rare triggers for immediate salvage plerixafor that are based on different circumstances such as (1) refractory poor mobilization despite target cell yields (ie, cells for one or multiple transplantations), as novel agents, (2) when these agents are unavailable, or (3) in the defined by minimum CD34ϩ cell levels or day 1 apheresis CD34ϩ presence of contraindication to apheresis or stem cell mobilization 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 4537 regimens. In general, it is more advisable to seek enrollment on a the HSC yield that is fundamental to the safety and efficacy of clinical trial or a compassionate use program of a novel mobiliza- HSCT. Plerixafor may be used in up-front, preemptive, immediate tion agent before resorting to salvage BM harvest. salvage and remobilization settings, and the most cost-effective protocols are still in development. More accurate predictors of poor mobilization are still sought, and the triggers for immediate salvage Experimental agents for stem cell need to be developed for each site. These measures should be mobilization and their possible role in poor supported by rigorous and validated standard operating procedures of HSC harvesting and processing. Moreover, novel approaches mobilizers that explore HSC expansion, ␤-adrenergic innervation, bone turnover, macrophage function, integrin blockade, and new chemotac- The role of CXCR4/SDF-1 inhibition is being further explored tic modulators may further improve HSC mobilization. with alternative CXCR-4 antagonists such as POL6326 and BTK140 in early phase clinical trials in patients with multiple myeloma, both showing promise as mobilization agents for Acknowledgments HSCs.137,138 Improved understanding of the HSC niche and HSC reserve has raised possibilities for restoring the niche with the use The authors thank Prof John Rasko, Prof David Gottlieb, Dr Ian 103 of agents such as SCF and parathyroid hormone. Other avenues Lewis, Prof Jeff Szer, Dr Julian Cooney, and Dr Anthony Mills for for research include investigation of ways to trigger effector cells helpful discussions. They also thank Dr Tony Cambareri and Ms ␣ and pathways more efficiently such as through TNF- , manipula- Rachel Furno for their assistance with preparation of the manuscript. ␤ tion of the -adrenergic circadian pulse (eg, harvesting HSCs in the This work was supported by the National Health and Medical ␤ afternoon, or pretreatment with 2 agonists), or optimizing macro- Research Council (grants 288701 and 434515, J.-P.L.) and a ␤ phage-mediated pathways (eg, with Gro ). The recent description Cancer Council of Victoria Early Career Clinician Researcher grant 139 of S1P and ceramide-1 phosphate as chemoattractants for HSCs (K.E.H.). also raises possibilities for HSC mobilization. Natalizumab and other ␣4 integrin blockers may be useful in plerixafor failures. Authorship

Conclusion Contribution: L.B.T, K.E.H., and J.-P.L. conceived, wrote, and edited the manuscript. Advances in the understanding of the mechanisms of mobilization Conﬂict-of-interest disclosure: The authors declare no compet- have provided new insights into how poor mobilization can be ing ﬁnancial interests. prevented and managed. The avoidance of HSC and niche damage, Correspondence: Luen Bik To, Haematology, IMVS/SA Pathol- the timing of mobilization, and the remarkable synergism between ogy, PO Box 14 Rundle Mall, Adelaide, South Australia 5000, plerixafor and G-CSF plus chemotherapy are critical in optimizing Australia; e-mail: [email protected]. References

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