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New agents for mobilizing peripheral blood stem cells
Transfusion and Apheresis Science 41 (2009) 67–71
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Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
New agents for mobilizing peripheral blood stem cells Hildegard T. Greinix *, Nina Worel Medical University of Vienna, Department of Internal Medicine I, Bone Marrow Transplant Unit, Department of Blood Group Serology and Transfusion Medicine, Waehringer Guertel 18-20, Vienna A-1090, Austria
a r t i c l e Article history:
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a b s t r a c t Transplantation with bone marrow (BM) hematopoietic stem cells (HSC) has been used for curative therapy of hematologic diseases and inborn errors of metabolism for decades. More recently, alternative sources of HSC, particularly those induced to exit marrow and traffic to peripheral blood in response to external stimuli, have become the most widely used hematopoietic graft and show significant superiority to marrow HSC. Although a variety of agents can mobilize stem cells with different kinetics and efficiencies and these agents can be additive or synergistic when used in combination, currently G-CSF is the predominant stem cell mobilizer used clinically based upon potency, predictability and safety. Recent studies have demonstrated that the interaction between the chemokine stromalderived factor 1 (SDF-1/CXCL12) and its receptor CXCR4 serves as a key regulator of HSC trafficking. AMD3100, a novel bicyclam CXCR4 antagonist, induces the rapid mobilization of HSC with both short- and long-term repopulation capacity. Mobilization with G-CSF and AMD3100 in clinical trials resulted in more patients achieving sufficient PBSC for transplantation than with G-CSF alone. Thus, chemokine axis-mobilization could allow rapid PBSC harvests with increased cell yields in difficult-to mobilize patients. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts demonstrated prompt and stable engraftment. Enhanced homing properties of chemokine axis-mobilized PBSC suggest that these cells may have greater therapeutic utility in other areas including tissue repair and regeneration. Ó 2009 Published by Elsevier Ltd.
1. Introduction Hematopoietic stem cell transplantation (HCT) has evolved into a curative therapeutic modality for a variety of life-threatening hematologic, oncologic, immunologic, and genetic diseases. Achievement of successful HCT depends on a complex series of biologic interactions between stem cells, hematopoietic growth factors, histocompatibility genes, immune cells, chemokines and chemokine receptors and many other elements that still need to be identified. Since hematopoietic stem cells (HSC) reside in the bone marrow (BM), they have been collected by needle aspirations from iliac crests since the 1970s for use in HCT. In * Corresponding author. E-mail address: [email protected] (H.T. Greinix). 1473-0502/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.transci.2009.05.015
the 1960s it was already recognized that a small number of HSCs circulated in the peripheral blood (PB) during steady-state homeostasis [1]. In the following years an increase in circulating HSC was observed after chemotherapy. In the early 1980s the first autologous HCT using mobilized peripheral blood stem cells (PBSC) were reported [2]. After discovery and clinical development of human granulocyte colony-stimulating factor (G-CSF) cytokine mobilization has become the standard of care for autologous HCT [3]. Since the late 1990s an increasing number of allogeneic HCT with mobilized PBSC instead of BM have been performed worldwide. Multiple randomized trials demonstrated the advantages of mobilized PBSC over BM as the stem cell source for autologous HCT [4–6]. Shorter duration of cytopenias, enhanced immune reconstitution and reduced morbidity supported the current use of PBSC as primary source of stem cells for autologous HCT worldwide
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[7]. In the allogeneic transplant setting use of PBSC compared to BM was associated with more rapid engraftment, reduction of infectious complications and lower transplant-related mortality in patients with advanced hematologic malignancies [8–10]. Whereas the incidence of acute graft-versus-host disease (GVHD) was similar, recipients of PBSC experienced significantly more chronic GVHD in some clinical studies [11–13]. In many transplant centers, PBSC are now the preferred stem cell source for HLA-identical sibling HCT and volunteer unrelated donors decide increasingly to preferentially donate mobilized peripheral blood instead of marrow. Besides G-CSF other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-7, interleukin-3, interleukin-12, stem cell factor, and flt-3 ligand and chemokines like interleukin-8 and others have reportedly been able to mobilize HSC clinically or experimentally in animal models [14]. These molecules differ in their time to achieve efficient mobilization, the type of cells mobilized into PB, and their side effects. Whereas cytokines induce HSC mobilization with delayed kinetics, mobilization with chemokines peaks within hours of administration. Cytokine-mobilized HSC have characteristic phenotypic features that are distinct from HSC residing in marrow under steady-state conditions [15]. Currently, G-CSF is most frequently used administered daily for 4–5 days at a dose of 5–10 lg/kg in the allogeneic setting and given for 5–10 days in the autologous donation process. PBSC mobilization and collection have been optimized in different clinical trials. Nevertheless, 14% of patients receiving chemotherapy and G-CSF for the purpose of autologous donation and 4% of allogeneic donors given G-CSF alone still fail to mobilize a sufficient number of HSC [16]. In this article new agents for mobilization of HSC for both autologous and allogeneic HCT will be discussed focussing on potential areas for improvement. Besides efficiency novel pharmacologic approaches for PBSC mobilization have to be safe which is of critical importance especially in allogeneic HCT.
2. New mobilizing agents Lapidot and colleagues described in steady-state hematopoiesis the localization of HSC in close proximity to stromal cells in the marrow [14]. Homing and retention of HSC in BM is supposedly mediated by adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1)/very late antigen-4 (VLA-4) and through stromal derived factor-1 (SDF-1)/CXCR4 interactions. SDF-1 degradation and inactivation within the BM by proteolytic enzymes such as elastase, cathepsin G, and various metalloproteinases (MMP) are essential for optimal HSC mobilization. G-CSF induces both cell proliferation, release of neutrophil proteases and upregulation of CXCR4 on marrow cells [14]. SDF-1, a member of the CXC chemokine family, is constitutively expressed on marrow stromal cells [17,18]. The cognate receptor for SDF-1 is CXCR4, a 7-transmembrane G-protein-coupled receptor expressed on many cell types including CD34-positive hematopoietic stem cells [18–20].
AMD3100 is a bicyclam molecule that specifically and reversibly blocks SDF-1 binding to CXCR4 [21,22]. It was initially developed as an antagonist of the CXCR4 HIV coreceptor on CD4-positive T cells, thus blocking HIV cell entry [21,22]. 2.1. AMD3100 in healthy volunteers Single-dose administration of AMD3100 (40–240 lg/ kg) caused rapid, generalized, reversible leukocytosis associated with an increase in PB CD34+ cells in 26 healthy human volunteers with the peak effect observed after 6–9 h after drug administration [23]. Dose-response studies showed a peak 10-fold increase in circulating CD34+ cells from 2.6 ± 0.3/lL to 40.4 ± 3.4/lL at 9 h after 240 lg/kg AMD3100 injected subcutaneously. Reported adverse effects were mild and transient consisting of erythema, headache, perioral paresthesia and nausea that all resolved within 24 h [23]. In a phase I study in healthy volunteers a single-dose of AMD3100 at 240 lg/kg alone was as effective as a 5-day regimen of G-CSF in mobilizing HSC [24]. AMD3100 given at 160 lg/kg on day 5 significantly increased both G-CSF-stimulated mobilization of CD34+ cells 3.8-fold and leukapheresis yield of CD34+ cells. In addition, AMD3100-mobilized leukapheresis products contained significantly greater numbers of T and B cells compared to G-CSF-stimulated leukapheresis products [24]. 2.2. AMD3100 in PBSC mobilization for autologous HCT Devine and colleagues performed a phase I study in 13 patients with non-Hodgkin’s lymphoma (NHL) and myeloma (MM) administering a single dose of AMD3100 (160 or 240 lg/kg s.c.) [25]. CD34+ cell counts increased 5.1-and 6.2-fold from the baseline at 4 and 6 h and were higher in the 240 lg/kg group compared with the 160 lg/kg group. In a randomized phase II study in patients with MM (n = 10) and NHL (n = 15) Flomenberg and colleagues demonstrated superior HSC mobilization with the combination of AMD3100 and G-CSF compared to G-CSF alone [26]. Patients were randomly assigned to an initial mobilization with G-CSF versus G-CSF and AMD3100 (160 or 240 lg/kg) on day 4 (10 h prior to leukapheresis). After collection of >2 106 CD34+ cells/kg and a 2-week washout period remobilization with the alternate regimen was performed. The number of CD34+ cells in PB increased a median of 2.9-fold (range, 1.1 to 13-fold) 6 h after the first subcutaneous injection of AMD3100. In every patient more HSCs were collected per day of leukapheresis after AMD3100 plus G-CSF mobilization than after G-CSF alone, irrespective of which regimen was used first. Patients with MM and NHL mobilized a median of 3- to 3.5-fold (range, 1.3- to 10-fold) and 4.4-fold (range, 1.1- to 54.4-fold) more CD34+ cells per day of leukapheresis with AMD3100 plus G-CSF. Twelve of 25 patients (48%) required fewer leukapheresis procedures with AMD3100 plus G-CSF mobilization to reach the ideal transplantation cell dose of at least 5 106 CD34+ cells/kg. Using G-CSF alone, only 5 of 25 patients (20%) reached the minimum cell dose (2 106 CD34+/kg) after a single leukapheresis, whereas with AMD3100 plus G-CSF 14 of 25 patients
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(56%) did so. In nine patients who did not mobilize at least 2 106 CD34+/kg after G-CSF alone, the combination of G-CSF plus AMD3100 mobilized 5- to 102-fold (median, 21-fold) more CD34+ cells. Nineteen of 24 patients received AMD3100 plus G-CSF-mobilized CD34+ cell grafts for autologous HCT and had durable engraftment of neutrophils and platelets after a median of 10–11 and 16 days, respectively [26]. Recently, Calandra and colleagues reported results on 115 data-audited poor mobilizing patients with MM, NHL and Hodgkin’s disease (HD) given AMD3100 plus G-CSF on a compassionate use basis [27]. Successful collection of >2 106 CD34+ cells/kg was achieved in 60.3% of NHL, 71.4% of MM, and 76.5% of HD patients. Following autologous HCT, median times to durable neutrophil and platelet engraftment were 11 and 18 days, respectively. The most common AMD3100-related adverse events were gastrointestinal effects, injection site reactions and paresthesias. Besides 2 (1.6%) consisting of one patient with headache and one with nightmares all adverse events were mild or moderate. In a phase III multicenter randomized double-blind placebo controlled study of AMD3100 (240 lg/kg) plus G-CSF (10 lg/kg) vs placebo plus G-CSF (10 lg/kg) in 298 NHL patients the primary endpoint was the collection of >5 106 CD34+/kg in four or fewer leukaphereses [28]. AMD3100 plus G-CSF resulted in a 3-fold higher rate of patients (59% vs 20%, p < 0.0001) achieving >5 106 CD34+/kg compared to G-CSF plus placebo [28]. In addition, significantly more patients in the AMD3100 plus G-CSF group (87% vs 47%, p < 0.0001) compared to G-CSF plus placebo achieved >2 106 CD34+/kg. The most common adverse events associated with use of AMD3100 were mild gastrointestinal effects and injection site erythema. Ninety percent of patients in the AMD3100 plus G-CSF group and 55% of patients in the G-CSF plus placebo group underwent autologous HCT. Median time to neutrophil and platelet engraftment was 10 and 20 days in both groups. Recently, DiPersio and colleagues reported results on another phase III multicenter randomized double-blind placebo controlled study of AMD3100 (240 lg/kg) plus G-CSF (10 lg/kg) vs placebo plus G-CSF (10 lg/kg) in 302 MM patients [29]. Significantly more patients in the AMD3100 plus G-CSF arm (72% vs 34%, p < 0.001) compared to the G-CSF plus placebo arm achieved the primary endpoint defined as mobilization of >6 106 CD34+/kg in 2 or less days of leukapheresis. Whereas 54.2% of patients given AMD3100 plus G-CSF reached the target cell dose after 1 day of leukapheresis, only 17.3% of patients given G-CSF plus placebo did so. In addition, in the AMD3100 plus G-CSF arm significantly more patients reached both the target CD34+ cell dose and the minimal transplantable cell dose in 4 days of leukapheresis. The vast majority of patients (96% and 88%) underwent autologous HCT resulting in neutrophil and platelet engraftment after a median of 11 and 18 days in both groups [29]. 2.3. AMD3100 in PBSC mobilization for allogeneic HCT Currently, G-CSF is used at a dose of 10 lg/kg/day subcutaneously as standard mobilizing agent for PBSC donors.
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Leukapheresis is typically commenced on day 4 or 5 of G-CSF treatment when CD34+ cells peak in the PB and is repeated until a target number of CD34+ cells is collected (usually >4 106 CD34+/kg). In an IBMTR/EBMT analysis, 60% of donors required more than one leukapheresis procedure to collect the target number of CD34+ cells, and 15% required three or more [30]. Donor age, steady-state CD34 level, and both the total dose and schedule of G-CSF may impact CD34+ cell mobilization [7]. PBSC mobilization by G-CSF is generally well tolerated but can be associated with moderate, transient morbidity related to G-CSF administration [7,31]. Due to the required multiday dosing regimen donors may experience significant inconvenience, including absence from work during the mobilization process. While no long-term sequelae have been confirmed with short-term use of G-CSF, there are reports of serious acute toxicities related to its administration as well as concerns that it could induce genetic and epigenetic modifications in hematopoietic cells [31,32]. Transplant approaches involving selective depletion or manipulation of the graft may require additional or larger volume apheresis procedures to compensate for cell losses during cell processing. A small percentage of healthy donors have a poor mobilization response to G-CSF resulting in the need for additional apheresis collections or repeat mobilization cycles to collect adequate PBSC dose for engraftment and immune reconstitution [16,33]. Thus, donors may benefit from new mobilization strategies, such as use of CXCR4 antagonists, that minimize exposure to G-CSF injections, reduce the number of leukapheresis procedures and maximize the cell yields by leukapheresis. In addition, patient outcomes could be improved with grafts that provide faster hematologic and immunologic reconstitution or that reduce the incidence of graft-versus-host disease. Preclinical work in murine, canine and non-human primate models have demonstrated that AMD3100 alone can rapidly mobilize hematopoietic cells with both short-term and long-term repopulating capacity [7,34]. Hess and colleagues reported that the marrow repopulation was threefold greater with AMD3100-mobilized mononuclear cells compared to G-CSF mobilized ones [34]. Recently, Devine and colleagues investigated AMD3100 alone at a dose of 240 lg/kg in 25 HLA-identical sibling donors [35]. At 4 h after subcutaneous injection the CD34 count rose to a median of 16/lL (range, 4–54/ lL), representing a median 8-fold increase. In 16 of 24 donors (67%) the minimum required CD34+ cell dose defined as 2 106 CD34+/kg was collected during the first leukapheresis. Only 2 of 24 donors (8.3%) did not achieve the minimum CD34+ cell dose after 2 days of leukapheresis. It is likely that the allografts would have contained a greater quantity of CD34+ cells if leukapheresis was begun 6–9 h after AMD3100 administration which was closer to the peak of mobilization in donors as demonstrated by Liles and colleagues [24]. Compared to G-CSF significantly fewer CD34+ cells/kg (2.9 106 vs 4.2 106, p = 0.006), but greater numbers of CD3+ cells/kg (4.7 108 vs 1.5 108, p = 0.006) and CD4+ cells/kg (3.1 108 vs 1.1 108, p = 0.002) were observed in the AMD3100-mobilized grafts [35]. The differences in CD8+, CD19+, and CD56+ cell content were not significant. Except one donor who
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experienced grade 2 pain at the injection site all other adverse effects were mild consisting of lightheadedness (44%), gastrointestinal symptoms (36%), injection site discomfort (28%), perioral paresthesias, loose stools, or diaphoresis (20%), and headaches (16%). Twenty patients received allografts and had rapid neutrophil and platelet engraftment after a median of 10 (range, 8–13) and 12 (range, 8–32) days, respectively. Acute GVHD grades II–IV occurred in 35% of patients and overall survival at 1 year was 73% [35]. Thus, despite the infusion of higher T cell doses, there was no appreciable increase in GVHD in comparison to G-CSF-mobilized grafts. However, studies including larger patient numbers with longer follow-up are warranted to ultimately answer the issue of GVHD incidence. 2.4. Open questions in use of AMD3100 for PBSC mobilization AMD3100 has been effective in mobilizing CD34+ cells for autologous HCT in a number of diseases, including NHL, MM and HD [25–29]. Clinical studies show that acute myeloid leukaemia (AML) cells may be mobilized by AMD3100 via CXCR4 inhibition, and preclinical studies suggest the same for chronic lymphatic leukaemia (CLL) cells [36–38]. Therefore, AML, CLL and plasma cell leukaemia patients were excluded from AMD3100 trials due to concerns about mobilization of leukaemia cells and autologous graft contamination. However, innovative studies investigating the ability of AMD3100 to mobilize leukaemia cells from the marrow microenvironment and to sensitize them to chemotherapy are currently underway with the aim to improve results of induction chemotherapy. In the limited clinical experience with the SDF-1/CXCR4 inhibitor AMD3100 for mobilization of donor PBSCs, single-agent AMD3100 produced a lower CD34+ cell yield than G-CSF [35]. However, the yield may improve if the interval between dosing and leukapheresis is optimized to take advantage of the period of maximum circulating CD34+ cells. In addition, the improved repopulating capacity of the AMD3100-mobilized graft or clinically important alterations in the graft content may compensate for the lower CD34+ cell dose. Since long-term follow-up after allogeneic HCT is not available, it is currently unknown whether blocking of SDF-1/CXCR4 will inhibit the normal homing and migration of stem and progenitor cells after HCT or whether homing of these cells might be more effective. In addition, other outcome parameters such as relapse and risk of GVHD could be affected by treatment with AMD3100 and its effect on the quality and quantity of other cell subsets in an allograft including T cells and natural killer cells. Further studies on long-term safety of AMD3100 in healthy donors are also necessary to be able to compare toxicity profiles between the current standard of PBSC mobilization, G-CSF, with new agents such as AMD3100.
3. Conclusions The increased use of mobilized PB as the stem cell source for related and unrelated donor transplants has
challenged the transplant community to find better agents for stem cell mobilization. Regulation of hematopoietic stem cell release, migration and homing to the BM involve a complex interaction between chemokines, adhesion molecules, cytokines, proteolytic enzymes, hematopoietic cells and stromal cells. The interaction between the chemokine SDF-1/CXCL12 and its known receptor, CXCR4, serves as a key regulator of hematopoietic stem cell trafficking. Currently, G-CSF that is known to disrupt the SDF-1/CXCR4 interaction is widely used to induce mobilization of HSCs for reconstitution of hematopoiesis following myelosuppressive therapy. A novel bicyclam CXCR4 antagonist, AMD3100, appears capable of mobilizing a fully functional hematopoietic graft within just hours following a single injection. Further studies are needed to answer questions on clinical patient outcome after use of PBSC mobilized by this novel agent and long-term donor safety issues. References [1] Goodman JW, Hodgson GS. Evidence for stem cells in the peripheral blood of mice. Blood 1962;19:702–14. [2] Kessinger A, Armitage JO, Landmark JD, Weisenburger DD. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol 1986;14:192–6. [3] Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, et al. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci USA 1985;82:1526–30. [4] Hartmann O, Corroller AGL, Blaise D, Michon J, Philip I, Norol F, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs: a randomized, controlled trial. Ann Intern Med 1997;126:600–7. [5] Schmitz N, Dreger P, Linch DC, Goldstone AH, Boogaerts MA, Demuynick HMS, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 1996;347:353–7. [6] Beyer J, Schwella N, Zingsem J, Strohscheer I, Schwaner I, Oettle H, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol 1995;13:1328–35. [7] Cashen AF, Lazarus HM, Devine SM. Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF? Bone Marrow Transpl 2007;39:577–88. [8] Korbling M, Anderlini P. Peripheral blood stem cells vs bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001;98:2900–8. [9] Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001;344:175–81. [10] Champlin RE, Schmitz N, Horowitz MM, Chapius B, Chopra R, Cornelissen JJ, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000;95:3702–9. [11] Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem cell and bone-marrow transplantation: a meta-analysis. J Clin Oncol 2001;19:3685–91. [12] Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, HowsonJan K, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 2002;100:1525–31. [13] Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 2002;100:3128–34. [14] Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 2002;30:973–81. [15] Nervi B, Link DC, DiPersio JF. Cytokines and hematopoietic stem cell mobilization. J Cell Biochem 2006;99:690–705.
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Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
New agents for mobilizing peripheral blood stem cells Hildegard T. Greinix *, Nina Worel Medical University of Vienna, Department of Internal Medicine I, Bone Marrow Transplant Unit, Department of Blood Group Serology and Transfusion Medicine, Waehringer Guertel 18-20, Vienna A-1090, Austria
a r t i c l e Article history:
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a b s t r a c t Transplantation with bone marrow (BM) hematopoietic stem cells (HSC) has been used for curative therapy of hematologic diseases and inborn errors of metabolism for decades. More recently, alternative sources of HSC, particularly those induced to exit marrow and traffic to peripheral blood in response to external stimuli, have become the most widely used hematopoietic graft and show significant superiority to marrow HSC. Although a variety of agents can mobilize stem cells with different kinetics and efficiencies and these agents can be additive or synergistic when used in combination, currently G-CSF is the predominant stem cell mobilizer used clinically based upon potency, predictability and safety. Recent studies have demonstrated that the interaction between the chemokine stromalderived factor 1 (SDF-1/CXCL12) and its receptor CXCR4 serves as a key regulator of HSC trafficking. AMD3100, a novel bicyclam CXCR4 antagonist, induces the rapid mobilization of HSC with both short- and long-term repopulation capacity. Mobilization with G-CSF and AMD3100 in clinical trials resulted in more patients achieving sufficient PBSC for transplantation than with G-CSF alone. Thus, chemokine axis-mobilization could allow rapid PBSC harvests with increased cell yields in difficult-to mobilize patients. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts demonstrated prompt and stable engraftment. Enhanced homing properties of chemokine axis-mobilized PBSC suggest that these cells may have greater therapeutic utility in other areas including tissue repair and regeneration. Ó 2009 Published by Elsevier Ltd.
1. Introduction Hematopoietic stem cell transplantation (HCT) has evolved into a curative therapeutic modality for a variety of life-threatening hematologic, oncologic, immunologic, and genetic diseases. Achievement of successful HCT depends on a complex series of biologic interactions between stem cells, hematopoietic growth factors, histocompatibility genes, immune cells, chemokines and chemokine receptors and many other elements that still need to be identified. Since hematopoietic stem cells (HSC) reside in the bone marrow (BM), they have been collected by needle aspirations from iliac crests since the 1970s for use in HCT. In * Corresponding author. E-mail address: [email protected] (H.T. Greinix). 1473-0502/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.transci.2009.05.015
the 1960s it was already recognized that a small number of HSCs circulated in the peripheral blood (PB) during steady-state homeostasis [1]. In the following years an increase in circulating HSC was observed after chemotherapy. In the early 1980s the first autologous HCT using mobilized peripheral blood stem cells (PBSC) were reported [2]. After discovery and clinical development of human granulocyte colony-stimulating factor (G-CSF) cytokine mobilization has become the standard of care for autologous HCT [3]. Since the late 1990s an increasing number of allogeneic HCT with mobilized PBSC instead of BM have been performed worldwide. Multiple randomized trials demonstrated the advantages of mobilized PBSC over BM as the stem cell source for autologous HCT [4–6]. Shorter duration of cytopenias, enhanced immune reconstitution and reduced morbidity supported the current use of PBSC as primary source of stem cells for autologous HCT worldwide
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[7]. In the allogeneic transplant setting use of PBSC compared to BM was associated with more rapid engraftment, reduction of infectious complications and lower transplant-related mortality in patients with advanced hematologic malignancies [8–10]. Whereas the incidence of acute graft-versus-host disease (GVHD) was similar, recipients of PBSC experienced significantly more chronic GVHD in some clinical studies [11–13]. In many transplant centers, PBSC are now the preferred stem cell source for HLA-identical sibling HCT and volunteer unrelated donors decide increasingly to preferentially donate mobilized peripheral blood instead of marrow. Besides G-CSF other cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-7, interleukin-3, interleukin-12, stem cell factor, and flt-3 ligand and chemokines like interleukin-8 and others have reportedly been able to mobilize HSC clinically or experimentally in animal models [14]. These molecules differ in their time to achieve efficient mobilization, the type of cells mobilized into PB, and their side effects. Whereas cytokines induce HSC mobilization with delayed kinetics, mobilization with chemokines peaks within hours of administration. Cytokine-mobilized HSC have characteristic phenotypic features that are distinct from HSC residing in marrow under steady-state conditions [15]. Currently, G-CSF is most frequently used administered daily for 4–5 days at a dose of 5–10 lg/kg in the allogeneic setting and given for 5–10 days in the autologous donation process. PBSC mobilization and collection have been optimized in different clinical trials. Nevertheless, 14% of patients receiving chemotherapy and G-CSF for the purpose of autologous donation and 4% of allogeneic donors given G-CSF alone still fail to mobilize a sufficient number of HSC [16]. In this article new agents for mobilization of HSC for both autologous and allogeneic HCT will be discussed focussing on potential areas for improvement. Besides efficiency novel pharmacologic approaches for PBSC mobilization have to be safe which is of critical importance especially in allogeneic HCT.
2. New mobilizing agents Lapidot and colleagues described in steady-state hematopoiesis the localization of HSC in close proximity to stromal cells in the marrow [14]. Homing and retention of HSC in BM is supposedly mediated by adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1)/very late antigen-4 (VLA-4) and through stromal derived factor-1 (SDF-1)/CXCR4 interactions. SDF-1 degradation and inactivation within the BM by proteolytic enzymes such as elastase, cathepsin G, and various metalloproteinases (MMP) are essential for optimal HSC mobilization. G-CSF induces both cell proliferation, release of neutrophil proteases and upregulation of CXCR4 on marrow cells [14]. SDF-1, a member of the CXC chemokine family, is constitutively expressed on marrow stromal cells [17,18]. The cognate receptor for SDF-1 is CXCR4, a 7-transmembrane G-protein-coupled receptor expressed on many cell types including CD34-positive hematopoietic stem cells [18–20].
AMD3100 is a bicyclam molecule that specifically and reversibly blocks SDF-1 binding to CXCR4 [21,22]. It was initially developed as an antagonist of the CXCR4 HIV coreceptor on CD4-positive T cells, thus blocking HIV cell entry [21,22]. 2.1. AMD3100 in healthy volunteers Single-dose administration of AMD3100 (40–240 lg/ kg) caused rapid, generalized, reversible leukocytosis associated with an increase in PB CD34+ cells in 26 healthy human volunteers with the peak effect observed after 6–9 h after drug administration [23]. Dose-response studies showed a peak 10-fold increase in circulating CD34+ cells from 2.6 ± 0.3/lL to 40.4 ± 3.4/lL at 9 h after 240 lg/kg AMD3100 injected subcutaneously. Reported adverse effects were mild and transient consisting of erythema, headache, perioral paresthesia and nausea that all resolved within 24 h [23]. In a phase I study in healthy volunteers a single-dose of AMD3100 at 240 lg/kg alone was as effective as a 5-day regimen of G-CSF in mobilizing HSC [24]. AMD3100 given at 160 lg/kg on day 5 significantly increased both G-CSF-stimulated mobilization of CD34+ cells 3.8-fold and leukapheresis yield of CD34+ cells. In addition, AMD3100-mobilized leukapheresis products contained significantly greater numbers of T and B cells compared to G-CSF-stimulated leukapheresis products [24]. 2.2. AMD3100 in PBSC mobilization for autologous HCT Devine and colleagues performed a phase I study in 13 patients with non-Hodgkin’s lymphoma (NHL) and myeloma (MM) administering a single dose of AMD3100 (160 or 240 lg/kg s.c.) [25]. CD34+ cell counts increased 5.1-and 6.2-fold from the baseline at 4 and 6 h and were higher in the 240 lg/kg group compared with the 160 lg/kg group. In a randomized phase II study in patients with MM (n = 10) and NHL (n = 15) Flomenberg and colleagues demonstrated superior HSC mobilization with the combination of AMD3100 and G-CSF compared to G-CSF alone [26]. Patients were randomly assigned to an initial mobilization with G-CSF versus G-CSF and AMD3100 (160 or 240 lg/kg) on day 4 (10 h prior to leukapheresis). After collection of >2 106 CD34+ cells/kg and a 2-week washout period remobilization with the alternate regimen was performed. The number of CD34+ cells in PB increased a median of 2.9-fold (range, 1.1 to 13-fold) 6 h after the first subcutaneous injection of AMD3100. In every patient more HSCs were collected per day of leukapheresis after AMD3100 plus G-CSF mobilization than after G-CSF alone, irrespective of which regimen was used first. Patients with MM and NHL mobilized a median of 3- to 3.5-fold (range, 1.3- to 10-fold) and 4.4-fold (range, 1.1- to 54.4-fold) more CD34+ cells per day of leukapheresis with AMD3100 plus G-CSF. Twelve of 25 patients (48%) required fewer leukapheresis procedures with AMD3100 plus G-CSF mobilization to reach the ideal transplantation cell dose of at least 5 106 CD34+ cells/kg. Using G-CSF alone, only 5 of 25 patients (20%) reached the minimum cell dose (2 106 CD34+/kg) after a single leukapheresis, whereas with AMD3100 plus G-CSF 14 of 25 patients
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(56%) did so. In nine patients who did not mobilize at least 2 106 CD34+/kg after G-CSF alone, the combination of G-CSF plus AMD3100 mobilized 5- to 102-fold (median, 21-fold) more CD34+ cells. Nineteen of 24 patients received AMD3100 plus G-CSF-mobilized CD34+ cell grafts for autologous HCT and had durable engraftment of neutrophils and platelets after a median of 10–11 and 16 days, respectively [26]. Recently, Calandra and colleagues reported results on 115 data-audited poor mobilizing patients with MM, NHL and Hodgkin’s disease (HD) given AMD3100 plus G-CSF on a compassionate use basis [27]. Successful collection of >2 106 CD34+ cells/kg was achieved in 60.3% of NHL, 71.4% of MM, and 76.5% of HD patients. Following autologous HCT, median times to durable neutrophil and platelet engraftment were 11 and 18 days, respectively. The most common AMD3100-related adverse events were gastrointestinal effects, injection site reactions and paresthesias. Besides 2 (1.6%) consisting of one patient with headache and one with nightmares all adverse events were mild or moderate. In a phase III multicenter randomized double-blind placebo controlled study of AMD3100 (240 lg/kg) plus G-CSF (10 lg/kg) vs placebo plus G-CSF (10 lg/kg) in 298 NHL patients the primary endpoint was the collection of >5 106 CD34+/kg in four or fewer leukaphereses [28]. AMD3100 plus G-CSF resulted in a 3-fold higher rate of patients (59% vs 20%, p < 0.0001) achieving >5 106 CD34+/kg compared to G-CSF plus placebo [28]. In addition, significantly more patients in the AMD3100 plus G-CSF group (87% vs 47%, p < 0.0001) compared to G-CSF plus placebo achieved >2 106 CD34+/kg. The most common adverse events associated with use of AMD3100 were mild gastrointestinal effects and injection site erythema. Ninety percent of patients in the AMD3100 plus G-CSF group and 55% of patients in the G-CSF plus placebo group underwent autologous HCT. Median time to neutrophil and platelet engraftment was 10 and 20 days in both groups. Recently, DiPersio and colleagues reported results on another phase III multicenter randomized double-blind placebo controlled study of AMD3100 (240 lg/kg) plus G-CSF (10 lg/kg) vs placebo plus G-CSF (10 lg/kg) in 302 MM patients [29]. Significantly more patients in the AMD3100 plus G-CSF arm (72% vs 34%, p < 0.001) compared to the G-CSF plus placebo arm achieved the primary endpoint defined as mobilization of >6 106 CD34+/kg in 2 or less days of leukapheresis. Whereas 54.2% of patients given AMD3100 plus G-CSF reached the target cell dose after 1 day of leukapheresis, only 17.3% of patients given G-CSF plus placebo did so. In addition, in the AMD3100 plus G-CSF arm significantly more patients reached both the target CD34+ cell dose and the minimal transplantable cell dose in 4 days of leukapheresis. The vast majority of patients (96% and 88%) underwent autologous HCT resulting in neutrophil and platelet engraftment after a median of 11 and 18 days in both groups [29]. 2.3. AMD3100 in PBSC mobilization for allogeneic HCT Currently, G-CSF is used at a dose of 10 lg/kg/day subcutaneously as standard mobilizing agent for PBSC donors.
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Leukapheresis is typically commenced on day 4 or 5 of G-CSF treatment when CD34+ cells peak in the PB and is repeated until a target number of CD34+ cells is collected (usually >4 106 CD34+/kg). In an IBMTR/EBMT analysis, 60% of donors required more than one leukapheresis procedure to collect the target number of CD34+ cells, and 15% required three or more [30]. Donor age, steady-state CD34 level, and both the total dose and schedule of G-CSF may impact CD34+ cell mobilization [7]. PBSC mobilization by G-CSF is generally well tolerated but can be associated with moderate, transient morbidity related to G-CSF administration [7,31]. Due to the required multiday dosing regimen donors may experience significant inconvenience, including absence from work during the mobilization process. While no long-term sequelae have been confirmed with short-term use of G-CSF, there are reports of serious acute toxicities related to its administration as well as concerns that it could induce genetic and epigenetic modifications in hematopoietic cells [31,32]. Transplant approaches involving selective depletion or manipulation of the graft may require additional or larger volume apheresis procedures to compensate for cell losses during cell processing. A small percentage of healthy donors have a poor mobilization response to G-CSF resulting in the need for additional apheresis collections or repeat mobilization cycles to collect adequate PBSC dose for engraftment and immune reconstitution [16,33]. Thus, donors may benefit from new mobilization strategies, such as use of CXCR4 antagonists, that minimize exposure to G-CSF injections, reduce the number of leukapheresis procedures and maximize the cell yields by leukapheresis. In addition, patient outcomes could be improved with grafts that provide faster hematologic and immunologic reconstitution or that reduce the incidence of graft-versus-host disease. Preclinical work in murine, canine and non-human primate models have demonstrated that AMD3100 alone can rapidly mobilize hematopoietic cells with both short-term and long-term repopulating capacity [7,34]. Hess and colleagues reported that the marrow repopulation was threefold greater with AMD3100-mobilized mononuclear cells compared to G-CSF mobilized ones [34]. Recently, Devine and colleagues investigated AMD3100 alone at a dose of 240 lg/kg in 25 HLA-identical sibling donors [35]. At 4 h after subcutaneous injection the CD34 count rose to a median of 16/lL (range, 4–54/ lL), representing a median 8-fold increase. In 16 of 24 donors (67%) the minimum required CD34+ cell dose defined as 2 106 CD34+/kg was collected during the first leukapheresis. Only 2 of 24 donors (8.3%) did not achieve the minimum CD34+ cell dose after 2 days of leukapheresis. It is likely that the allografts would have contained a greater quantity of CD34+ cells if leukapheresis was begun 6–9 h after AMD3100 administration which was closer to the peak of mobilization in donors as demonstrated by Liles and colleagues [24]. Compared to G-CSF significantly fewer CD34+ cells/kg (2.9 106 vs 4.2 106, p = 0.006), but greater numbers of CD3+ cells/kg (4.7 108 vs 1.5 108, p = 0.006) and CD4+ cells/kg (3.1 108 vs 1.1 108, p = 0.002) were observed in the AMD3100-mobilized grafts [35]. The differences in CD8+, CD19+, and CD56+ cell content were not significant. Except one donor who
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experienced grade 2 pain at the injection site all other adverse effects were mild consisting of lightheadedness (44%), gastrointestinal symptoms (36%), injection site discomfort (28%), perioral paresthesias, loose stools, or diaphoresis (20%), and headaches (16%). Twenty patients received allografts and had rapid neutrophil and platelet engraftment after a median of 10 (range, 8–13) and 12 (range, 8–32) days, respectively. Acute GVHD grades II–IV occurred in 35% of patients and overall survival at 1 year was 73% [35]. Thus, despite the infusion of higher T cell doses, there was no appreciable increase in GVHD in comparison to G-CSF-mobilized grafts. However, studies including larger patient numbers with longer follow-up are warranted to ultimately answer the issue of GVHD incidence. 2.4. Open questions in use of AMD3100 for PBSC mobilization AMD3100 has been effective in mobilizing CD34+ cells for autologous HCT in a number of diseases, including NHL, MM and HD [25–29]. Clinical studies show that acute myeloid leukaemia (AML) cells may be mobilized by AMD3100 via CXCR4 inhibition, and preclinical studies suggest the same for chronic lymphatic leukaemia (CLL) cells [36–38]. Therefore, AML, CLL and plasma cell leukaemia patients were excluded from AMD3100 trials due to concerns about mobilization of leukaemia cells and autologous graft contamination. However, innovative studies investigating the ability of AMD3100 to mobilize leukaemia cells from the marrow microenvironment and to sensitize them to chemotherapy are currently underway with the aim to improve results of induction chemotherapy. In the limited clinical experience with the SDF-1/CXCR4 inhibitor AMD3100 for mobilization of donor PBSCs, single-agent AMD3100 produced a lower CD34+ cell yield than G-CSF [35]. However, the yield may improve if the interval between dosing and leukapheresis is optimized to take advantage of the period of maximum circulating CD34+ cells. In addition, the improved repopulating capacity of the AMD3100-mobilized graft or clinically important alterations in the graft content may compensate for the lower CD34+ cell dose. Since long-term follow-up after allogeneic HCT is not available, it is currently unknown whether blocking of SDF-1/CXCR4 will inhibit the normal homing and migration of stem and progenitor cells after HCT or whether homing of these cells might be more effective. In addition, other outcome parameters such as relapse and risk of GVHD could be affected by treatment with AMD3100 and its effect on the quality and quantity of other cell subsets in an allograft including T cells and natural killer cells. Further studies on long-term safety of AMD3100 in healthy donors are also necessary to be able to compare toxicity profiles between the current standard of PBSC mobilization, G-CSF, with new agents such as AMD3100.
3. Conclusions The increased use of mobilized PB as the stem cell source for related and unrelated donor transplants has
challenged the transplant community to find better agents for stem cell mobilization. Regulation of hematopoietic stem cell release, migration and homing to the BM involve a complex interaction between chemokines, adhesion molecules, cytokines, proteolytic enzymes, hematopoietic cells and stromal cells. The interaction between the chemokine SDF-1/CXCL12 and its known receptor, CXCR4, serves as a key regulator of hematopoietic stem cell trafficking. Currently, G-CSF that is known to disrupt the SDF-1/CXCR4 interaction is widely used to induce mobilization of HSCs for reconstitution of hematopoiesis following myelosuppressive therapy. A novel bicyclam CXCR4 antagonist, AMD3100, appears capable of mobilizing a fully functional hematopoietic graft within just hours following a single injection. Further studies are needed to answer questions on clinical patient outcome after use of PBSC mobilized by this novel agent and long-term donor safety issues. References [1] Goodman JW, Hodgson GS. Evidence for stem cells in the peripheral blood of mice. Blood 1962;19:702–14. [2] Kessinger A, Armitage JO, Landmark JD, Weisenburger DD. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol 1986;14:192–6. [3] Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, et al. Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci USA 1985;82:1526–30. [4] Hartmann O, Corroller AGL, Blaise D, Michon J, Philip I, Norol F, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs: a randomized, controlled trial. Ann Intern Med 1997;126:600–7. [5] Schmitz N, Dreger P, Linch DC, Goldstone AH, Boogaerts MA, Demuynick HMS, et al. Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 1996;347:353–7. [6] Beyer J, Schwella N, Zingsem J, Strohscheer I, Schwaner I, Oettle H, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol 1995;13:1328–35. [7] Cashen AF, Lazarus HM, Devine SM. Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF? Bone Marrow Transpl 2007;39:577–88. [8] Korbling M, Anderlini P. Peripheral blood stem cells vs bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001;98:2900–8. [9] Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001;344:175–81. [10] Champlin RE, Schmitz N, Horowitz MM, Chapius B, Chopra R, Cornelissen JJ, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 2000;95:3702–9. [11] Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem cell and bone-marrow transplantation: a meta-analysis. J Clin Oncol 2001;19:3685–91. [12] Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, HowsonJan K, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 2002;100:1525–31. [13] Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 2002;100:3128–34. [14] Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 2002;30:973–81. [15] Nervi B, Link DC, DiPersio JF. Cytokines and hematopoietic stem cell mobilization. J Cell Biochem 2006;99:690–705.
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