In and out of the niche: perspectives in mobilization of hematopoietic stem cells

In and out of the niche: perspectives in mobilization of hematopoietic stem cells

Experimental Hematology 2011;39:723–729 In and out of the niche: perspectives in mobilization of hematopoietic stem cells Mohamad Mohtya,b,c,d and An...

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Experimental Hematology 2011;39:723–729

In and out of the niche: perspectives in mobilization of hematopoietic stem cells Mohamad Mohtya,b,c,d and Anthony D. Hoe a

Centre Hospitalier et Universitaire (CHU) de Nantes, Hematologie Clinique, Nantes, France; bINSERM CRCNA, UMR 892, Nantes, France; cCentre d’Investigation Clinique en Cancerologie (CI2C), CHU de Nantes, Nantes, France; dUniversite de Nantes, Nantes, France; eDepartment of Medicine V, Ruprecht-Karls-University, Heidelberg, Germany (Received 25 March 2011; revised 23 April 2011; accepted 2 May 2011)

Several stem cell mobilization strategies have been employed in the past 2 decades, including chemotherapy, hematopoietic growth factors, and chemotherapy plus growth factors. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF are standard agents approved for peripheral blood stem cell mobilization since the early 1990s. Between 5% and 20% of patients, however, fail to mobilize a sufficient numbers of peripheral blood stem cells in response to G-CSF with or without chemotherapy. Recent advances in defining the basic mechanisms regulating the interactions between hematopoietic stem cells and their marrow niche had led to the discovery that CXCR4 and stromal-cellLderived factor 1a axis play a significant role. Plerixafor, an antagonist of the CXCR4-stromal-cellLderived factor 1a axis has been shown to result in a significant mobilization of hematopoietic stem cells. Numerous clinical trials have demonstrated that the combination of G-CSF and AMD3100 (G+A) resulted in a significant increase in CD34+ cell yield as compared to the administration of G-CSF alone. In particular, the progenitors mobilized have been shown to comprise a significantly higher proportion of primitive and possibly more potent CD34+/CD38- subpopulation. Transplantation of PBSC mobilized by G+A administration have led to a rapid and sustained neutrophil and platelet engraftment. Another prospective role of this new class of agents might lie in the mobilization of dormant leukemia stem cells that are well protected by the niche. The future role of CXCR4 antagonists in treatment of hematologic malignancies includes mobilization of hematopoietic stem cells for transplantation and mobilization of leukemia-initiating cells for long-term cure. Ó 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

Peripheral blood stem cells (PBSCs) have largely replaced bone marrow (BM)derived cells in autologous transplants and have become the source of stem cells in the majority of allogeneic transplants. In the mid-1980s, several institutions demonstrated that PBSCs could represent viable alternatives to BM cells as source of hematopoietic stem and progenitor cells for autologous transplantation [1–5]. Use of PBSCs offers several advantages, such as harvest of cells without general anesthesia, elimination of pain resulting from multiple aspirations from the BM, and it is associated with more rapid engraftment [6–8]. The main challenge of

Offprint requests to: Mohamad Mohty, M.D., Ph.D., Service d’Hematologie Clinique, CHU de Nantes, 1 Place Ricordeau, 44093 Nantes Cedex, France; E-mail: [email protected] or Anthony D. Ho, M.D., Department of Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany; E-mail: [email protected]

PBSCs is that they exist in the circulation in very small numbers. Hematopoietic progenitor and stem cells (HSCs) reside in the BM and have to be mobilized into the circulation before being collected by apheresis. The number of apheresis procedures needed and the success of transplantation are determined by the efficiency of stem cell mobilization [9,10] (reviewed in reference [11]). Stem cells adhere to their BM niche by interactions between stromalcellderived factor 1a (SDF-1a), which is produced by BM stromal cells, and CXCR4, which is expressed on CD34þ cells [12,13]. Granulocyte colony-stimulating factor (G-CSF), the standard and most widely used agent for this purpose during the past 20 years, mobilizes stem cells from the marrow niche by secretion of neutrophilassociated extracellular proteases, such as matrix metalloproteinase-9, which subsequently releases HSCs from their niche [14]. On the other hand, Plerixafor, a novel mobilization agent, can directly inhibit the CXCR4SDF1-a

0301-472X/$ - see front matter. Copyright Ó 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. doi: 10.1016/j.exphem.2011.05.004

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cell-to-cell interaction [15,16]. This agent has, in the meantime, been demonstrated to mobilize quantitatively a larger amount of CD34þ cells in patients who have failed to yield an adequate amount upon mobilization attempts with G-CSF with or without chemotherapy. Thus, Plerixafor has been approved both in North America and in Europe and represents a milestone in the development of PBSC transplantations. This article will review the history and physiology of HSC mobilization and will provide recommendations on the use of Plerixafor in daily clinical practice.

BM vs peripheral blood as the source of stem cells Until the mid-1980s, BM was the only source of HSCs for allogeneic or autologous transplantations. In the second half of the 1980s, several groups had shown that stem cells could be harvested from the peripheral blood after chemotherapy. Myelosuppressive drugs induced a significant increase in the number of PBSCs during the recovery phase [1–5]. The yield was, however, unpredictable and most patients had to undergo up to six leukapheresis procedures before an adequate amount was collected. The availability of granulocyte macrophage (GM)-CSF and G-CSF has revolutionized the mobilization of PBSCs for transplantation. In the meantime, PBSCs have largely replaced BM in autologous stem cell transplants (autoSCT). The latter has been used successfully to induce long-term cure in patients with refractory or recurrent non-Hodgkin’s lymphoma (NHL) [17,18]. Treatment-related mortality rate for autoSCT is !5%. The low rate of early transplantationassociated mortality must, however, be balanced with potential contamination of the autologous stem cell graft with tumor cells. Risk of myelodysplasia/acute myeloid leukemia associated with the conditioning regimens must also be considered. AutoSCT has also become the standard of care after induction chemotherapy for younger and more fit patients (younger than 65 to 70 years old) with multiple myeloma (MM) [19]. Several clinical trials comparing conventional chemotherapy with high-dose chemotherapy/ autoSCT have shown improved outcomes in patients who received autoSCT as primary treatment [19,20]. PBSCs have also become the source of stem cells in a large number of allogeneic transplantations. Use of PBSCs offers several advantages, such as harvest of cells without general anesthesia, elimination of pain after multiple aspirations from the BM, and most important, it is associated with more rapid engraftment [21–23]. The main disadvantage of PBSCs is that they exist in the circulation in very small numbers. Fewer than 0.05% of white blood cells are CD34(þ), which is a cell surface protein that is expressed on hematopoietic stem and progenitor cells and represents a reliable surrogate marker for the presence of progenitor cells responsible for reconstitution after transplantation [24]. As mentioned here, HSCs are mainly found in the BM and have to be mobilized into

the circulation before collection. The number of apheresis procedures needed and the success of transplantations are determined by the efficiency of stem cell mobilization.

Challenges in mobilization of PBSCs In the early days of autoSCT, stem cell mobilization was achieved with chemotherapeutic drugs, as chemotherapy induces a significant increase in the number of HSCs in circulating blood at the time of recovery [1,3,5]. However, many patients also failed to mobilize sufficient PBSCs for transplantation in response to chemotherapy. The availability of GM-CSF and G-CSF has significantly changed the spectrum of PBSCs mobilization (for a detailed review, see reference [11]). Indeed, in the late 1980s, GM-CSF and G-CSF were made available [25–28]. G-CSF and GM-CSF were approved for use as HSC-mobilizing agents, but GCSF (in combination with chemotherapy or alone) has become the standard. Unfortunately, some patients, especially those who have been heavily pretreated with chemotherapy or irradiation, still fail to mobilize sufficient numbers of PBSCs for transplantation in response to GCSF with or without chemotherapy [29–33].

Poor mobilizersddefinitions and prospective criteria There were numerous reports on patients who failed to mobilize sufficient numbers of PBSCs for transplantation [30–37]. The incidence has been reported to range from 5% to 40% [31–37]. Thus far, there is no consensus on the definition of poor mobilizers. Some reports used a value of 1.0  106 CD34þ cells/kg body weight (BW), whereas others used a threshold of 2.0  106 CD34þ cells/kg BW [32–37], as a measurable parameter for poor mobilization. Most recent studies have adopted the definition of poor mobilization as inability to collect 2.0  106 cells/kg BW CD34þ cells. This can obviously only be estimated retrospectively after leukapheresis has been performed. There was also no clear-cut stipulation on the number of leukapheresis procedures required to achieve this goal as a parameter to distinguish good mobilizers from poor mobilizers. We have previously shown that there is a highly significant correlation between the CD34þ concentration in peripheral blood and the potential to collect an adequate amount of CD34þ cells within one or up to three leukapheresis procedures [38,39]. Given the current advances in development of standards and guidelines for quality control of PBSC products, there is an increasing need for a better definition of poor mobilization. Based on previous reports and a retrospective analysis of 840 patients at the Heidelberg Center who were mobilized with chemotherapy and growth factors with the intent of autologous transplantation, we have confirmed previous observations that

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preapheresis CD34þ count reliably predicts the quality of collection. As reported in the literature, many groups have suggested that a peak level of 20/mL CD34þ cells should be considered as the threshold. Of the 840 patients with MM and NHL scheduled to receive autologous transplants, 129 patients (15.3%) had preapheresis CD34þ counts of !20/mL and were considered to be poor mobilizers. Among them, 38 patients (4.5%) had CD34þ levels between 11 and 19/mL at maximum stimulation, defined as ‘‘borderline’’ poor mobilizers, 49 patients (5.8%) had CD34þ levels between 6 and 10/mL, defined as ‘‘relative’’ poor mobilizers, and 42 patients (5.0%) had levels !5/mL, defined as ‘‘absolute’’ poor mobilizers. Another controversial issue is whether higher concentrations of CD34þ cells transplanted would produce better long-term outcomes. Current evidence indicates that once an adequate amount has been stimulated, CD34þ cell numbers O2.0  106 cells/kg BW CD34þ cells would not necessarily confer more advantage in terms of engraftment of leukocytes and platelets. Our previous observation showed that although higher doses of CD34þ cells (i.e., O6.5  106/ kg BW) might marginally but significantly shorten the time to leukocyte and platelet recovery, stable engraftment was achieved with transplantation of 2.0  106 CD34þ cells/kg BW. Thus, there is no solid evidence that for autologous transplant, levels of O5.0 to 6.0  106/kg BW would improve long-term clinical outcomes.

Plerixafor, a new class of mobilization agent The most primitive CD34þ cells are maintained in the marrow niche by binding to cellular determinants through a number of adhesion molecules. Although multiple adhesive interactions are known that mediate the attachment of HSCs to the extracellular matrix and stromal cells of the BM (for a complete review see reference [40]). Of these, the binding of the SDF-1 chemokine (chemokine [C-X-C motif] ligand 12; CXL-12) located on the surface of BM stromal cells and osteoclasts to its receptor, CXCR4, located on the surface of CD34þ cells, has emerged as an essential signal for HSC trafficking to and from the BM [14]. Experiments with neutralizing antibodies directed against CXCR4 or SDF-1 showed that uncoupling of SDF-1/CXCR4 signaling is a crucial step in G-CSFmediated HSC mobilization. Plerixafor, an inhibitor of CXCR4/SDF-1a signaling, was originally developed to treat HIV, but has since been shown to possess significant stem cellmobilizing activity [16]. Plerixafor reversibly inhibits the binding of SDF-1 to its receptor, CXCR4. This induces the rapid movement of stem cells out of the BM into the peripheral circulation [15]. Compared with G-CSFmobilized cells, a higher proportion of Plerixafor-mobilized CD34þ cells is in the G1 phase of the cell cycle, and belongs to the

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more primitive subset of CD34þ/CD38 cells. Gene expression profiling also indicated that these cells are of a more primitive type than those mobilized with G-CSF. Animal models showed that Plerixafor-mobilized HSCs have a higher frequency of severe combined immunedeficientrepopulating activity [15]. Therefore, in addition to an absolute increase in overall CD34þ cells upon Plerixafor mobilization, a more primitive and potent progenitor cell population will also be significantly elevated.

Review of clinical data of Plerixafor in autologous stem cell transplantation Plerixafor is a very promising new agent for the mobilization of HSCs in both the autologous and allogeneic settings [41,42]. Large preclinical work in murine, canine, and nonhuman primate systems [15,43,44] suggested fundamental differences in the characteristics of HSCs mobilized by Plerixafor vs G-CSF and set the stage for initial clinical trials to evaluate the effects of transplanting cells mobilized by Plerixafor into humans. Initial clinical trials of Plerixafor in healthy volunteers demonstrated a O10-fold increase in PBSCs beginning 1 hour and peaking 9 hours after subcutaneous injection of Plerixafor [45]. The addition of Plerixafor to G-CSF results in even greater increases in circulating CD34þ cells [46]. Plerixafor can mobilize PBSCs in patients who have received prior chemotherapy as well. In a Phase I study, patients with MM or NHL had a seven-fold increase in circulating CD34þ cells 6 hours after a single dose of Plerixafor (240 mg/kg) [47]. In autologous stem cell collection trials, Plerixafor (160240 mg/kg) has been added to G-CSF on day 4, 6 to 12 hours before apheresis. Flomenberg et al. [48] reported use of this combination in 25 MM and NHL patients who each underwent two mobilizations, one using G-CSF alone and the other with G-CSFþPlerixafor. Given as either the first or second mobilization regimen, G-CSFþPlerixafor mobilized more CD34þ cells per leukapheresis. In addition, patients underwent fewer leukaphereses, and more patients attained the target collection of 5  106 CD34þ cells/kg BW with the combination of G-CSF and Plerixafor. Eighteen of 19 patients undergoing transplantation with the G-CSFþPlerixaformobilized product had early, stable engraftment. In another series, Stiff et al. [49] reported on 49 patients (NHL, n 5 23; MM, n 5 26) who were mobilized with G-CSFþPlerixafor. All completed mobilization and 47 of 49 (96%) underwent transplantation. Circulating CD34þ cells/mL increased by 2.5-fold (range, 1.36.0-fold) after the first Plerixafor dose. Median CD34þ cells/kg collected was 5.9  106 (range, 1.522.5) in 2 (range, 15) days of aphereses. Median days to neutrophil and platelet engraftment were 11 (range, 816) and 14.5 (range, 739) days, respectively. Adverse events were primarily mild nausea and diarrhea. Twenty-eight (57%) were identified as heavily pretreated patients. Their median fold increase in circulating CD34þ

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cells/mL was 2.5 (range, 1.45.0) after Plerixafor, similar to minimally pretreated patients, suggesting that this combination may have particular value in heavily pretreated patients [49]. Mobilization with G-CSFþPlerixafor has also been shown to be efficacious in patients with Hodgkin’s disease (HL). Cashen et al. [50] reported on 22 patients with HL who were candidates for autoSCT. Fifteen patients (68%) collected $5  106 CD34þ cells/kg BW, and 21 patients (95%) achieved the minimum collection of $2  106 CD34þ cells/kg BW, in a median of two apheresis procedures. Both the proportion of patients collecting $5  106 CD34þ cells/kg BW and the median CD34þ cells collected in days 1 to 2 of apheresis were significantly improved over historical controls [50]. In order to assess the effect of Plerixafor outside of clinical trials, Calandra et al. [51] examined data from the Single Patient Use protocol, referred to as a ‘‘Compassionate Use Protocol.’’ A cohort of 115 data-audited poor mobilizers in Compassionate Use Protocol was assessed, with the objective being to collect $2  106 CD34þ cells/kg BW following G-CSFþPlerixafor mobilization. The rates of successful CD34þ cell collection were similar for patients who previously failed chemotherapy mobilization or cytokine-only mobilization: NHL 5 60.3%, MM 5 71.4%, and Hodgkin’s disease 5 76.5%. After transplantation, median times to neutrophils and platelets engraftment were 11 and 18 days, respectively. Engraftment was durable. There were no drug-related serious adverse events. Of the adverse events considered related to Plerixafor, two (1.6%) were severe (one patient had headache and another had nightmares). Other Plerixafor-related adverse events were mild (84.8%) or moderate (13.6%). The most common Plerixafor-related adverse events were gastrointestinal reactions, injection-site reactions, and paresthesias. This Compassionate Use Protocol analysis highlights that G-CSFþPlerixafor offers a new treatment to collect CD34þ stem cells for autoSCT from poor mobilizers, with a high success rate [51]. In December 2008, Plerixafor (Mozobil; Genzyme), was approved by the US Food and Drug Administration for use in combination with G-CSF to mobilize HSCs blood for collection and subsequent autoSCT in patients with NHL and MM (US Food and Drug Administration labeling information accessed at http://www.fda.gov/cder/foi/label/ 2008/022311lbl.pdf, 2008). This approval was based on the results of two phase III, multicenter, randomized, placebocontrolled trials of PlerixaforþG-CSF vs G-CSFþplacebo for mobilization and engraftment of NHL and MM patients undergoing autoSCT (trials 3101 and 3102) [52,53]. A total of 298 NHL and 302 MM patients were enrolled and randomized in these trials. Baseline characteristics were similar between the active treatment and placebo groups. In trial 3101, a significantly greater number of NHL patients in the G-CSFþPlerixafor group achieved $5  106 CD34þ

cells/kg BW in 4 or fewer days of apheresis and had successful engraftment compared with the G-CSFþplacebo group (57.3% vs 18.9% of patients, respectively; p ! 0.001). Similarly, in trial 3102, a significantly greater number of patients in the G-CSFþPlerixafor group achieved $6  106 CD34þ cells/kg BW in 2 or fewer days of apheresis and had successful engraftment compared with the G-CSFþplacebo group (70.3% vs 34.4%, respectively; p ! 0.001). Through 12 months follow-up, there were no differences in graft durability and hematology profiles between groups in either study, demonstrating that G-CSFþPlerixafor, compared with G-CSFþplacebo, significantly increased the proportion of NHL and MM patients who were able to mobilize the target number of CD34þ cells needed for autoSCT with equally prompt and durable engraftment [52,53].

Future of Plerixafor in autologous stem cell mobilization Thus far, standard procedure for mobilization of PBSCs has been accomplished by treatment with G-CSF alone or in combination with chemotherapy. With current PBSC mobilization techniques and dependence on the criteria for poor mobilization, a significant proportion of patients might not be able to mobilize a sufficient or target number of cells to proceed to autoSCT. The wide range of reported failure rates stems at least partly from different definitions of what constitutes a failure. Wuchter et al. [54] have recently demonstrated that using a preapheresis CD34þ count of !20/mL as a parameter for failure prediction, 15% of the patients with MM or NHL would be considered to be poor mobilizers [54]. There data showed that these patients might benefit from mobilization with G-CSF and Plerixafor. Optimizing stem cell collection either early or later in the course of the disease will continue to be an integral component of autoSCT treatment planning, and should be incorporated into the design of future prospective trials because the advent of Plerixafor will likely change the current standards for SCT and PBSCs mobilization. Many patients require more than one apheresis session and protracted (i.e., often up to 5 or 6 days) treatment with G-CSF or other mobilization agents. The availability of Plerixafor has broadened the therapeutic options for mobilization of PBSCs for patients in need of high-dose chemotherapy, thereby increasing the pool of patients for whom autoSCT is an option. Currently, PBSC mobilization regimens might differ with respect to PBSC yield, predictability of the time to peak mobilization (especially when G-CSF plus chemotherapy is used), resource utilization, and safety for the patients. Differences in apheresis content such as quantity and quality of CD34þ progenitor cells and tumor cell contamination in the product are probable with different

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mobilization regimens. In addition, clinical practice depends not only on clinical or medical factors, but also on logistical factors, such as the relationship of the apheresis unit to the transplantation team, and distance of the patient’s home from treatment centers. Therefore, the elements that are recognized to be key factors for optimal mobilization of autologous PBSCs are number of PBSCs mobilized and collected, predictability of peak of mobilization, burden on the patient and medical team, and intensity of resource utilization for the society. Considering the side effects associated with chemotherapy plus G-CSF and the lack of predictability of maximum stimulation, this strategy might not be the most efficient. An optimal PBSC mobilization regimen should have high mobilization efficiency that translates into a reliable and optimal yield of PBSCs with as few apheresis procedures as possible. It should have predictable mobilization kinetics so that the day of apheresis can be planned in advance, resulting in optimal resource utilization. The quality of the apheresis product (e.g., number of CD34þ cells in the graft, presence of immune competent cells, and absence of tumor cell contamination), and the possibility of collecting enough PBSCs for tandem, salvage, or back-up autoSCT, are additional factors to be taken into account. Finally, pharmacoeconomic considerations, in relationship to the overall clinical outcomes, are important issues to be analyzed if medical advances should remain affordable. Thus far, G-CSF has been the most essential agent for stem cell mobilization for almost 25 years. The role of Plerixafor in solving some of the aforementioned critical issues will be defined in the next several years. So far it seems that Plerixafor might reduce the risk of mobilization failure, allow improved access to autoSCT, and increase probability of achieving an optimal CD34þ cell yield toward better post-transplantation clinical outcomes. Beyond the field of SCT, recently, the significance of leukemia stem cells responsible for disease relapses in patients with acute myeloid leukemia has been demonstrated extensively. Leukemia stem cells (LSC) share many features of HSCs, such as slow divisional kinetics and adherence to the marrow stem cell riche, and they have the ability to repopulate the whole hematopoietic system (in this case with leukemia cells) upon transplantation. Many authors have shown that LSC, in analogy to their normal counterparts, have the ability to remain dormant, thus allowing LSC to escape conventional chemotherapy that targets rapidly dividing cells. Developing mechanisms to eradicate LSC is therefore crucial to inducing a lasting cure for patients with acute myeloid leukemia: Plerixafor has been shown in animal models to mobilize LSC into the circulating blood as well as normal CD34þ cells. Thus, ‘‘priming’’ or ‘‘mobilizing’’ LSC before consolidation chemotherapy or before allogeneic transplantation might lead to better eradication of not only residual leukemia blasts, but also LSC for lasting cure for patients with acute

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myeloid leukemia. From that perspective, Plerixafor is currently tested for the mobilization of dormant LSCs. In all, the advent of Plerixafor will enrich the therapeutic armamentarium of hematological malignancies because it represents a great opportunity for stem cell collection for autoSCT or allogeneic transplantation and a tool for tumor stem cells mobilization toward eradicating dormant tumor stem cells.

Conflict of interest disclosure Dr. Mohty and Dr. Ho have served on diverse Advisory Boards for Genzyme and Amgen whose products were discussed in this article. They also reported having received honoraria from Genzyme and Amgen for occasional Educational Activities.

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