Autologous hematopoietic SCT (auto-HSCT) provides hematopoietic support after high-dose chemotherapy and is the standard of care for patients with multiple myeloma (MM) or chemosensitive relapsed high- or intermediate-grade non-Hodgkin's lymphoma (NHL). However, yields of hematopoietic stem cells vary greatly between patients, and the optimal strategy to mobilize hematopoietic stem cells into peripheral blood for collection has not been defined. Current mobilization strategies consist of cytokines alone or in combination with chemotherapeutic agents. Cytokine-only mobilization regimens are well tolerated, but their utility is limited by suboptimal PBSC yields. When a myelosuppressive chemotherapeutic agent is added to a cytokine mobilization regimen, PBSC collections improve two- to five-fold. This benefit is tempered by increased toxicity, morbidity and resource utilization. All current regimens fail to mobilize sufficient hematopoietic stem cells to proceed to transplantation in 5–30% of patients, necessitating additional mobilization attempts or precluding transplantation, which may negatively affect patient outcomes and survival. Improved strategies to mobilize stem cells would increase the availability of auto-HSCT and optimize engraftment and outcomes in patients with MM or NHL. Novel agents used in conjunction with cytokines have the potential to increase PBSC collections without introducing additional morbidity, thereby improving patient outcomes.
Autologous hematopoietic SCT (auto-HSCT) is the standard of care for patients with multiple myeloma (MM) or chemosensitive relapsed high- or intermediate-grade non-Hodgkin's lymphoma (NHL), providing essential hematopoietic support after the administration of high-dose therapy (HDT).1, 2, 3, 4, 5 Although MM is an incurable malignancy, auto-HSCT used in conjunction with HDT has been shown to prolong survival.5, 6 The rates of complete response to conventional therapy without auto-HSCT in patients with MM are ∼5–15%.5, 6, 7 Auto-HSCT in combination with HDT can increase the rates of complete response to ∼20–44% and is associated with a very low incidence of treatment-related mortality.5, 7, 8, 9 The most common NHL, diffuse large B-cell lymphoma, has a cure rate of ∼40–50% with conventional chemotherapy, but patients who relapse have a worse prognosis.1, 2 Auto-HSCT combined with HDT administered after relapse has been shown to prolong the duration of remission in patients with diffuse large B-cell lymphoma and provides these patients with approximately a 45% probability of long-term disease-free survival.3 Auto-HSCT is also used in conjunction with high-dose myeloablative therapy as a salvage treatment for follicular lymphoma. Although controversial, recent data suggest that more than 10-year disease-free survival is possible after salvage auto-HSCT for patients with follicular lymphoma.10 In addition, auto-HSCT may improve the prognosis in patients with mantle cell lymphoma, specifically when it is used as part of first-line treatment.2
The success of auto-HSCT is influenced by a number of factors, with the dose of reinfused stem cells being a key factor.11 Higher stem cell doses are associated with faster plt engraftment (generally defined as plt count >20 × 109/l), faster neutrophil engraftment (generally defined as ANC >0.5 × 109/l)11, 12, 13, 14, 15, 16 and reduction in the need for supportive measures such as transfusions of packed RBCs and plts and administration of prophylactic antibiotics.12, 15 In some studies, higher stem cell doses have been associated with higher rates of survival for patients.17, 18 Other factors that affect collection efficiency and, therefore, the success of auto-HSCT include patient age, gender, exposure to previous irradiation and chemotherapy, previous mobilization attempts and disease characteristics such as the involvement of BM.19, 20, 21 Unsuccessful initial stem cell mobilization leads to costly additional mobilization attempts and may prohibit auto-HSCT altogether.14, 22, 23, 24
Current regimens to mobilize PBSC for auto-HSCT have differing stem cell yields, safety considerations, resource utilization, and levels of contamination of the apheresis product with tumor cells.20, 25, 26, 27, 28, 29, 30 The two most common mobilization strategies today use cytokines alone or cytokines after chemotherapy (chemomobilization). Table 1 lists the agents that are approved by the United States (US) Food and Drug Administration (FDA) for stem cell mobilization and the agents that are in development or used off-label for this purpose. Mobilization using FDA-approved cytokines alone is generally well tolerated;34, 35 however, yields are often suboptimal, and collection of sufficient numbers of stem cells to support transplantation can be difficult, particularly in patients who have previously been treated with multiple rounds of intensive chemotherapy.22, 36 The addition of a myelosuppressive chemotherapeutic agent to a cytokine mobilization regimen improves collections by a factor of ∼2.5 (Bensinger et al.25) and can reduce the number of apheresis sessions needed for cell collection.37, 38 Although national trends in mobilization practices have not been studied to a large extent, in our experience, chemomobilization is the standard of care in many transplant centers in Europe and the United States. Although treatment-related mortality is rare, the use of chemotherapy agents in a mobilization regimen is associated with variable rates of treatment-related complications and can increase morbidity, particularly from neutropenia and infections.29, 39 As a result, this mobilization strategy requires increased resource use, hospitalizations, transfusions and the use of antibiotic therapy.29, 39, 40, 41, 42 Furthermore, variation among individual responses to chemomobilization can result in irregular collection schedules that can increase resource utilization and potentially delay transplantation.43, 44 The utility of all current mobilization regimens is limited by their high failure rates, which are estimated to be from 5 to 30%, regardless of the approach.26, 45, 46, 47 The question of whether failure rates after chemomobilization are lower than failure rates after cytokine-only mobilization has not been adequately studied. There remains a significant controversy over the question of which method of PBSC mobilization is the safest and most predictable.
This paper reviews current strategies for stem cell mobilization for auto-HSCT in patients with MM or relapsed NHL and focuses on peripheral blood as a source of stem cells. The benefits of mobilization either with cytokines alone or with chemomobilization are compared, and the limitations of each approach are described. Lastly, alternative approaches to mobilization that could improve the outcomes of autologous stem cell collection and transplantation are examined.
The biology of stem cell mobilization
Recent advances in stem cell mobilization techniques have exploited the interactions between stem cells and the BM microenvironment. Composed of stromal cells, endothelial cells, osteoblasts and other matrix components (for example, collagens, fibronectins and proteoglycans), the BM microenvironment anchors hematopoietic stem cells through a wide range of adhesive interactions.21 Hematopoietic stem cells express a broad array of cell surface receptors, namely the adhesion molecules lymphocyte function-associated Ag-1, very late Ag-4 and Mac-1; the chemokine receptors CXCR4 and CXCR2; the cell surface glycoproteins CD44 and CD62L; and the tyrosine kinase receptor c-kit.21, 31, 48 The BM stroma contains stromal cell-derived factor-1 (SDF-1), CXC chemokine GRO-β, vascular cell adhesion molecule-1, kit ligand, P-selectin glycoprotein ligand-1 and hyaluronic acid, all of which are cognate ligands for the stem cell adhesion molecules.21, 31, 48 Data from a number of preclinical models showed that inhibition of these receptor–ligand interactions resulted in enhanced progenitor cell mobilization.49, 50, 51
Although hematopoietic cells mobilized to peripheral blood for collection contain distinct populations of true stem cells and differentiated progenitor cells, they are often referred to collectively as stem cells.52 In the BM and peripheral blood, stem cells are characterized by Ags specific to various lineages of hematopoietic cell differentiation.53 Many human hematopoietic progenitor cells and their precursors, including the majority of true stem cells, express the CD34 Ag. As such, the CD34 surface marker is commonly used as a marker for mobilization efficiency, despite indications that CD34− cells may also exhibit multilineage reconstitution capacity.52, 53, 54
The ultimate goal of SCT is to repopulate the BM niche with a complete lineage of hematopoietic stem cells,21, 55 with minimal burden to the patient. Although a small number of hematopoietic stem cells circulate in the peripheral blood at all times, mobilization is necessary to drive sufficient numbers of hematopoietic stem cells from the BM to the peripheral circulation, where they can be harvested by apheresis. Peripheral blood has been shown to be superior to BM as a source of hematopoietic stem cells for autologous transplantation34, 56 because collection is easier, morbidity is reduced and the tempo of engraftment is quicker.34, 56, 57
The target dose of infused CD34+ cells varies from a minimum of 2.0 × 106 CD34+ cells/kg31, 58, 59 to an optimal level of 5.0 × 106 CD34+ cells/kg.24, 26, 55 Within this range, higher doses of infused CD34+ cells are more beneficial for patients with MM and NHL.8, 18, 60, 61 The quantity of CD34+ cells infused is positively correlated with the tempo of plt and neutrophil engraftment after PBSC transplantation.13, 14, 24 Toor et al.18 and O'Shea et al.8 reported improved OS in myeloma patients who received transplants of higher doses of CD34+ cells. Univariate and multivariate analyses of patients with MM who underwent chemomobilization with CY and G-CSF revealed that patients with higher CD34+ cell harvest yields had higher OS rates, independent of the cell dose transplanted.62 Several studies have also reported a positive association between CD34+ cell count and survival in lymphoma patients.60, 61 For patients with MM or NHL, the number of CD34+ cells collected is heavily influenced by the mobilization regimen employed.25, 28, 29, 63
The hematopoietic growth factors GM-CSF (sargramostim, Leukine, Bayer Healthcare Pharmaceuticals, Seattle, WA, USA) and G-CSF (filgrastim, Neupogen, Amgen Inc., Thousand Oaks, CA, USA) are the only agents currently approved by the FDA for the mobilization of stem cells for auto-HSCT.64, 65 These agents were developed concurrently 20 years ago.66, 67
GM-CSF induces mobilization by stimulating proliferation and differentiation of hematopoietic progenitor cells, particularly CD14+ monocytes and CD80+ DCs, in patients with NHL.35, 68.Although historically approved for mobilization, GM-CSF is little used for that purpose today. An early analysis of GM-CSF activity69 in 13 patients with sarcoma showed that 3–7 days of treatment administered at a wide range of doses (4–64 μg/kg daily by continuous infusion) elevated WBC counts by a factor of 4.3 and increased the numbers of blood mononuclear cells by a factor of 9.2. However, in subsequent analyses, mobilization with GM-CSF alone has been reported to lead to relatively low yields of CD34+ cells.35 Administration of GM-CSF with chemotherapy has been reported to mobilize fewer or a similar number of CD34+ cells than has been reported with administration of G-CSF with chemotherapy.68, 70, 71 In addition, a higher incidence of both mild and serious adverse events (AEs) is associated with GM-CSF than with G-CSF.64, 65, 68, 70, 71 Mild AEs reported in healthy donors who receive GM-CSF include skin-associated events, arthralgia, bone pain, myalgia and fever with chills.35, 64 Severe AEs include supraventricular arrhythmia, immune hypersensitivity reactions, hypotension, tachycardia, dyspnea and renal or hepatic dysfunction in predisposed patients.35, 64 Consequently, the use of GM-CSF as a single agent for mobilization is comparatively rare.72
Administration of G-CSF induces functional changes within the BM microenvironment, as enzymes released from myeloid cells cleave adhesion molecules and disrupt the interactions between chemokines, their receptors and the extracellular matrix.73, 74.In the presence of G-CSF, the number of myeloid cells committed to the granulocytic lineage increases, which causes the release of active neutrophil serine proteases cathepsin G and neutrophil elastase, along with matrix metalloproteinase-9, into the extracellular fluid of the BM.75, 76 This results in enhanced cleavage of the adhesion molecules vascular cell adhesion molecule-1, c-kit, CXCR4 and SDF-1.74, 76, 77, 78 Several studies have shown that G-CSF and other cytokines can mobilize stem cells in protease-deficient mice, suggesting a more complex model in which both protease-dependent and protease-independent pathways contribute to G-CSF-induced mobilization of stem cells.77, 79, 80 Recent data show that G-CSF reduces osteoblast activity and decreases SDF-1α mRNA expression, suggesting a protease-independent mechanism through which G-CSF could regulate stem cell mobilization.81 Thus, the biological mechanisms through which cytokines induce PBSC mobilization are complex and not completely understood.77 However, it is known that CD34+ cell levels peak on the 5th day after administration of G-CSF.65 Temporally, the initial neutropenia is brief and occurs soon after administration, whereas the ensuing neutrophilic state takes several days to achieve. Subsequent degranulation of neutrophils and release of elastase and cathepsin D into the BM microenvironment occur quickly, resulting in adhesion molecule degradation and release of CD34+ cells.35
G-CSF is the most frequently used stem cell mobilizing agent.72, 82 When G-CSF alone is used for stem cell mobilization, it is administered at doses ranging from 10 μg/kg s.c. daily to 32 μg/kg s.c. daily, beginning at least 4 days before the first apheresis session and continued until the last apheresis session.65, 83 After transplantation, the median time to granulocyte engraftment has been reported to be 11 days, and plt engraftment has been reported to be ∼11–14 days.27, 28 Mobilization with G-CSF is generally well tolerated; common AEs are bone pain, headache, anemia and decreased plt counts.65 Other AEs reported by healthy donors include fatigue, muscle aches, nausea, vomiting and stomach pain.65 In addition, rare but serious AEs have been reported. Myocardial infarction and cerebral ischemia have occurred in high-risk patients with cancer who received G-CSF for a variety of indications.65 Splenic rupture, sickle cell disease with crisis and acute respiratory distress syndrome have also been described.65
The efficacy of G-CSF alone for mobilization of PBSCs for auto-HSCT was established in a phase 3 trial conducted by Schmitz et al.,34 in which 58 patients with NHL or Hodgkin's disease (HD) received either PBSCs mobilized with G-CSF 10 μg/kg s.c. daily for 6 consecutive days (n=27) or BM (n=31) for hematopoietic reconstitution after HDT. A median value of 2.8 × 106 CD34+ cells/kg was collected after G-CSF mobilization. Furthermore, when compared with BMT, reinfusion of G-CSF-mobilized PBSCs was found to reduce the number of plt infusions needed (6 vs 10, P<0.001) and the time to plt and neutrophil engraftment (16 days vs 23 days, P=0.02; 11 days vs 14 days, P=0.005, respectively). Nademanee et al.84 harvested stem cells in 95 patients with lymphoma after the s.c. or i.v. administration of regimens of G-CSF 10 μg/kg daily for a median of 12 days (range: 4–23; n=39), G-CSF 5 μg/kg daily for a median of 12 days (range: 8–27; n=26) or no mobilizing therapy (n=30). The authors reported median CD34+ cell yields of 6.2 × 106 cells/kg, 3.4 × 106 cells/kg and 1.2 × 106 cells/kg in the respective treatment groups.84 Narayanasami et al.28 mobilized stem cells in 22 patients with NHL or HD by using G-CSF 10 μg/kg s.c. daily for 4 days before the start of apheresis and reported a median CD34+ cell collection of 2.5 × 106/kg; approximately 50% of these patients required only one apheresis session, whereas 4% of patients required three sessions.
In many patients with MM or NHL, mobilization with G-CSF as a single agent results in suboptimal CD34+ cell yields (Table 2). These studies show that CD34+ cell yields are generally lower when a cytokine-only mobilization regimen is used than when cytokine mobilization is used with chemotherapy. In addition, mobilization ‘failures’ (defined as CD34+ cell yields of <2.0 × 106/kg) were highly variable throughout these studies, ranging from 0 to 23%. In a study of 58 patients with NHL or HD, Moskowitz et al.88 reported that mobilization with G-CSF alone (10 μg/kg daily) yielded significantly fewer CD34+ cells and was inferior to mobilization with chemotherapeutic agents plus G-CSF (1.5 × 106/kg vs 6.7 × 106/kg, P=0.0002). Previous cycles of chemotherapy increased the risk of poor mobilization.88 In a study of 52 patients with NHL, Micallef et al.89 reported that mobilization with G-CSF alone (16 μg/kg s.c. daily for 4–6 days) failed to yield adequate numbers of CD34+ cells in 35% of patients. The authors identified previous treatment with fludarabine and BM involvement as risk factors for poor mobilization. Sugrue et al.22 followed the outcome of PBSC collection in 21 patients who were termed ‘poor mobilizers’ because an initial mobilization attempt yielded <1 × 106 CD34+ cells/kg in two consecutive large-volume leukaphereses. Protocols for initial mobilization consisted of G-CSF alone in 20 of these patients (10 μg/kg s.c. daily for 4 days before the start of apheresis and continuing throughout the apheresis period) and G-CSF (5 μg/kg daily) with CY and etoposide in 1 patient. Of these 21 patients, 11 did not reach the target dose of 2.5 × 106 CD34+ cells/kg and required a second mobilization, BM harvesting or both. Of the 21 patients, 19 proceeded to transplantation. Engraftment of plts took much longer in this group (median, 31 days) than in a group of 23 similar patients who had been termed ‘good mobilizers’ (median, 13 days). All five patients who received transplants of <1 × 106 CD34+ cells/kg relapsed.
After an initial mobilization attempt, if too few CD34+ cells are collected to ensure prompt engraftment, patients often undergo additional mobilization attempts, which increase the risks associated with treatment.83 Several salvage regimens have been developed to improve mobilization in patients in whom a first mobilization attempt with G-CSF alone fails to result in collection of an adequate cell dose. These salvage regimens include high-dose G-CSF and combinations of G-CSF with other cytokines, such as GM-CSF.
High-dose G-CSF was investigated as a primary mobilization regimen throughout the 1990s.90, 91, 92.Although seldom used today for primary mobilization, high-dose G-CSF regimens are occasionally used for remobilization.23, 93 Although there is no standard protocol for high-dose G-CSF administration, doses ranging from 16 to 32 μg/kg s.c. daily to 12–16 μg/kg s.c. twice daily have been considered high-dose regimens even though some of the available data apply to patients with aplastic anemia, solid tumors or hematological malignancies other than NHL.23, 83, 91 Early published studies of G-CSF for primary mobilization presented opposing viewpoints.91, 92 Zeller et al.91 reported that compared to a lower dose regimen (G-CSF 10 μg/kg s.c. daily beginning 4 days before apheresis, n=33), high-dose G-CSF (12 μg/kg s.c. twice daily beginning 4 days before apheresis, n=34) resulted in higher CD34+ cell yields per apheresis session (4.82 × 108/kg vs 1.13 × 108/kg and 4.04 × 108/kg vs 0.93 × 108/kg) and fewer mean apheresis sessions (2 vs 3) in patients with NHL, HD or cancer of the testis. Only minor side effects were noted in each group. Conversely, Sheridan et al.92 reported that for patients with NHL, HD or acute lymphoblastic anemia, apheresis yields did not differ significantly between groups who received one of three different regimens of G-CSF (12 μg/kg s.c. daily for 7 days, 24 μg/kg s.c. daily for 6 days or 12 μg/kg s.c. daily for 6 days plus an additional 12 μg/kg i.v. on days 4, 5 and 6).
Positive results historically reported for high-dose G-CSF remobilization regimens83, 90 have not been notably strengthened or refuted by recent research.23, 93 Gazitt et al.83 reported that the administration of G-CSF 32 μg/kg s.c. daily for 4 days before apheresis and continuing until the last day of apheresis resulted in successful remobilization in 88% of 18 patients whose first mobilization attempt was unsuccessful; most of these patients had NHL. However, the use of high-dose G-CSF has been linked to neutrophil toxicity in patients with aplastic anemia.94 Furthermore, mobilization with high-dose G-CSF (12 μg/kg s.c. twice daily, beginning 4 days before apheresis and continuing until the end of apheresis) has been reported to increase the risk for development of engraftment syndrome in children who are undergoing mobilization for auto-HSCT to treat hematological malignancies or solid tumors.95
GM-CSF plus G-CSF
Significant synergism has been reported between GM-CSF and G-CSF in the formation of granulocytic colonies in vitro.96 Mobilization regimens combining GM-CSF with G-CSF have consisted of sequential or concurrent administration of these agents at a range of doses (G-CSF, 5–10 μg/kg; GM-CSF, 5 μg/kg–250 μg/m2), with or without chemotherapeutic agents.35, 71, 97, 98 These combination regimens have not been shown to have substantial benefits over regimens that use G-CSF alone; therefore, GM-CSF and G-CSF are not commonly administered together for primary mobilization. However, the combination of G-CSF and GM-CSF is used as a salvage mobilization regimen when mobilization with G-CSF alone has been unsuccessful.23, 47, 99 Boeve et al.23 remobilized stem cells in 86 patients in whom a previous mobilization attempt with G-CSF alone had failed. Nineteen patients received a daily regimen of G-CSF 10 μg/kg plus GM-CSF 5 μg/kg from 4 days before apheresis until the end of PBSC collection, and the remaining 67 patients received high-dose G-CSF (16 μg/kg twice daily).23 Among the patients who received G-CSF plus GM-CSF, a median yield of 1.6 × 106 CD34+ cells/kg was collected during a median of three apheresis sessions.23 This result was similar to the average CD34+ cell yield obtained in patients who received high-dose G-CSF.23 The authors concluded that, in comparison with remobilization with high-dose G-CSF, remobilization with G-CSF plus GM-CSF was equally efficacious and entailed fewer costs.23 In general, the AEs seen when GM-CSF and G-CSF are combined are similar to those seen with the use of either agent alone.35, 100
EPO, which is commonly used to preserve blood hemoglobin concentrations in patients undergoing chemotherapy, has also been shown to potentiate the mobilization effect of G-CSF or GM-CSF.101 Although the mechanism of this cooperative effect is unknown, it is thought that expression of EPO receptors on CD34+ progenitor cells primed with G-CSF or GM-CSF may promote survival of these cells.102 However, EPO use is generally regarded as inefficient and, as such, has not become a standard of care. Studies evaluating the mobilization efficacy of EPO plus G-CSF or G-CSF alone in various doses have generated mixed results. Perillo et al.103 found that 3–4 daily concomitant doses of EPO 150 IU/kg s.c. plus G-CSF 5 μg/kg (n=5 patients) or 10 μg/kg (n=10 patients) s.c. conferred no mobilization benefit over administration of G-CSF alone (n=10 patients) in patients with advanced gynecological cancers. Olivieri et al.101 noted that CD34+ cell yields obtained from 16 patients with NHL or other malignancies who received daily doses of EPO (50 U/kg s.c.) plus G-CSF (5 μg/kg s.c.) were 2.8 times greater than the yields obtained in 18 similar patients who received daily s.c. doses of 5 μg/kg G-CSF alone. Further investigation is required to ascertain the clinical benefits of EPO combined with G-CSF.104
The c-kit ligand SCF is produced in BM stromal cells and acts as a potent co-mitogen for many hematopoietic growth factors.105 Recombinant methionyl human SCF (ancestim, Stemgen, Amgen Inc.) administered s.c. in combination with G-CSF has been shown to enhance mobilization and may hasten recovery in transplant recipients.105, 106 The combination of SCF and G-CSF exerts a sustained mobilization effect that persists longer than does the effect of G-CSF alone, which persists for up to 7 days, as shown by an increase in the numbers of circulating CD34+ cells for up to 13 days in patients with breast cancer (BC) who received the combination treatment.105 Escalations in doses of SCF (5-30 μg/kg s.c.) used with G-CSF 10 μg/kg s.c. revealed a dose–response relationship in patients with BC105 that was not seen in a similar trial of heavily pretreated lymphoma patients.107 However, subsequent reports indicated that SCF may have a role in the treatment of patients with lymphoma and other malignancies who have undergone multiple rounds of intensive chemotherapy.108, 109 Stiff et al.108 reported that a combination of G-CSF 10 μg/kg s.c. and SCF 20 μg/kg s.c. administered daily for 5–9 days resulted in significantly higher CD34+ cell yields (3.6 × 106/kg) than did treatment with G-CSF alone (2.4 × 106/kg; P=0.05) in a randomized trial of 102 heavily pretreated patients who had NHL or HD.108 Dawson et al.110 studied remobilization after ⩾5 daily doses of SCF 20 μg/kg plus twice daily administration of G-CSF 10 μg/kg, with or without CY, in 48 patients who had been heavily pretreated for a hematological malignancy and in whom a previous mobilization with G-CSF alone or with chemotherapy had failed. The authors reported that the minimum CD34+ cell dose of >2 × 106/kg was achieved in 38% of these patients. Despite the efficacy of SCF, its use is hindered by the infrequent occurrence of severe anaphylactoid reactions and the resultant need to closely monitor patients after SCF administration.111 Although approved for use in Canada and New Zealand, ancestim is not currently available in the United States,21 and it is seldom used in Europe because of the relatively high risk of side effects.
G-CSF in conjunction with chemotherapy
Before the development of hematopoietic cytokines as mobilization agents, transient increases in the number of hematopoietic stem cells in peripheral blood had been noted after the administration of myelosuppressive chemotherapy.112, 113 Thus, the earliest protocols to mobilize hematopoietic stem cells into the peripheral blood used chemotherapy alone.114 When G-CSF and GM-CSF became available, daily administration of either agent after administration of a chemotherapeutic agent was found to enhance collection of hematopoietic stem cells.69, 115
The addition of a chemotherapeutic agent to a cytokine mobilization regimen exerts complex effects on the mobilization process that have yet to be fully elucidated.31, 38 Myelosuppressive chemotherapeutic agents, such as CY and paclitaxel, induce aplasia, which stimulates hematopoietic recovery.116 The mobilization effect is highly variable and peaks 10–18 days after administration of chemotherapy and generally correlates with neutrophil count rebound after a chemotherapy-induced nadir.117 Researchers have speculated that mobilization with CY plus G-CSF may have a synergistic effect on protease release in the BM because, when given individually, G-CSF and CY each increase the release of granulocytic proteases that cleave the adhesion molecules SDF-1, CXCR4 and c-kit.38 However, there are conflicting reports on whether a mobilization regimen consisting of sequential administration of chemotherapy followed by G-CSF causes downregulation of these adhesion molecules.38, 118 Increases in matrix metalloproteinase-9 concentrations after mobilization with chemotherapy plus G-CSF have been noted to correlate with mobilization efficiency.38 In addition, the toxicity of chemotherapeutic agents to the BM stroma could prompt the release of hematopoietic stem cells by damaging the functional ability of stromal cells to support stem cells.38
A variety of chemotherapeutic agents are used with G-CSF or GM-CSF to mobilize hematopoietic stem cells for autologous transplantation. Administration of CY with G-CSF is widespread, as this regimen mobilizes hematopoietic stem cells effectively and is highly active against tumor cells.55 Successful chemomobilization regimens used in combination with G-CSF are often disease oriented. Some of the most frequently used chemotherapeutic regimens in lymphoma patients include IEV (ifosfamide, epirubicin and etoposide), DHAP and ESHAP (etoposide, Ara-C, methylprednisolone and cisplatin).85, 119 Patients with other hematologic malignancies are frequently treated with ICE (ifosfamide, carboplatin and etoposide) plus G-CSF for mobilization.120 Mobilization that follows an induction or a salvage regimen can eliminate separate mobilization chemotherapy.119 Pavone et al.85 compared mobilization with CY or the DHAP regimen followed by G-CSF in patients with relapsed NHL. As similar cell yields were collected after each regimen, DHAP, an excellent salvage chemotherapy for NHL, could be scheduled into the treatment for patients proceeding to transplantation. In large studies of patients with lymphoma, MM and other malignancies (including many with BC) who received chemotherapy and growth factors for mobilization, the median time to neutrophil engraftment was 9–11 days, and the median time to plt engraftment was 9–10 days, which was slightly faster than occurred with G-CSF alone.25, 26
Chemomobilization is widely used in clinical practice because the addition of a myelosuppressive chemotherapy agent to a cytokine mobilization regimen results in higher CD34+ cell yields, which may promise better outcomes for patients. In particular, mobilization with CY and G-CSF rather than with G-CSF alone improves CD34+ cell collection significantly in patients with either MM27, 29 or NHL.28, 63 Table 2 compares yields of CD34+ cells achieved with chemomobilization to CD34+ cell yields obtained using G-CSF alone in patients with either MM or NHL. Benefits of the relatively higher CD34+ cell yields that result from chemomobilization include faster engraftment of plts and neutrophils and improved rates of survival.8, 18, 60, 61 Dose-dependent increases in CD34+ cell counts have been noted when regimens containing CY plus G-CSF are used for mobilization.121 However, it has been noted that the use of CY plus G-CSF severely depletes T cells and spares regulatory T cells, which could negatively affect immune reconstitution.122
Mobilization with CY and G-CSF requires fewer apheresis sessions to collect sufficient numbers of hematopoietic stem cells for auto-SCT than does mobilization with G-CSF alone.37, 38 In a recent retrospective analysis, Dingli et al.37 compared the characteristics of 74 patients with MM who received a hematopoietic growth factor alone for mobilization to the characteristics of 127 patients with MM who received a growth factor plus CY. The authors found no difference in the total numbers of cells collected. However, the addition of CY significantly reduced the median number of apheresis sessions, from 4 to 2 (P<0.0001). Owing to the increased CD34+ cell yields per apheresis session, mobilization with chemotherapy plus G-CSF can be useful in tandem autologous transplantation, which is considered to be superior to single autologous transplantation for patients with MM who do not experience CR after a first transplantation.123
As well as increasing stem cell yields, the addition of chemotherapy to a G-CSF mobilization regimen is thought to improve the outcome of SCT by reducing the in vivo tumor load and subsequently reducing tumor cell contamination in the apheresis product.55 Dose-dependent decreases in potentially malignant CD19+ cells have been noted when both CY and G-CSF are used for mobilization.121 Although mobilization regimens that include chemotherapy have been noted to reduce the risk of tumor-contaminated cell collections in patients with MM or lymphoma,20, 30 there is considerable debate as to whether the cytoreductive effects of mobilization with CY and growth factors confer any survival benefit to the patient. Dingli et al.37 showed that the addition of CY to a G-CSF mobilization regimen did not significantly improve response rates or prolong the time to disease progression. In addition, it is thought that patients whose tumor load has already been maximally reduced are not likely to benefit from any additional chemotherapy. Data from the Center for International Bone Marrow Transplant Research (CIBMTR) indicate that disease relapse remains the primary cause of death after SCT in patients with MM or NHL, and relapse has been traditionally thought to be associated with high levels of tumor cell contamination from both the autograft and the presence of minimal residual disease.124 However, results from a recent study by Bourhis et al.125 suggested that reinfused tumor cells may not be the primary cause of relapse in patients with myeloma. The authors found no difference in relapse rates between a group of patients with MM who were reinfused with grafts containing detectable tumor cells and another group reinfused with grafts free of detectable tumor cells.125 Collectively, these data suggest that adding chemotherapy to the mobilization regimen may decrease tumor contamination of the autograft, but that this may not translate into decreased relapse rates or improved patient survival.
The benefits of adding chemotherapeutic agents to a G-CSF mobilization regimen may be offset by the increased risk of complications to the patients. Compared with mobilization regimens using G-CSF alone, chemomobilization is associated with increased morbidity, greater risk of infection, more hospital admissions, transfusions, antibiotic therapy and considerably greater cost overall.29, 39, 40, 41, 42 Although treatment-related mortality is rare, significant morbidity related to neutropenia that can often require hospitalization has been described, and many reports point to greater resource utilization with chemomobilization than with cytokine-alone mobilization.29, 37, 39 Koc et al.39 found that although treatment with CY plus G-CSF resulted in greater stem cell yield than did treatment with GM-CSF plus G-CSF, it also caused greater morbidity. In this study, 30% of patients who underwent mobilization with G-CSF plus CY developed febrile neutropenia that required hospitalization. In the same study, transfusion support was required by 39% of patients who underwent mobilization with G-CSF plus CY, but by only 4% of patients who underwent mobilization with GM-CSF plus G-CSF. Desikan et al.29 reported increased hospitalization and transfusions in patients who underwent mobilization with G-CSF plus high-dose CY than with G-CSF alone. In addition, Jantunen et al.41 and Fitoussi et al.40 reported more hospital days, more days of i.v. antibiotics and more blood transfusions in patients who underwent mobilization with higher doses of chemotherapy than in those who received lower doses.
Variable responses to mobilization with chemotherapy plus cytokines25 result in unpredictable collection schedules that could delay transplantation.43, 44 After chemomobilization, the lapse of time before the number of CD34+ cells peaks varies substantially between patients.25, 43, 44 WBC counts and CD34+ cell counts must be monitored over the course of several days to determine when to begin apheresis.44 Algorithms intended to reduce the incidence of unanticipated PBSC collections and to streamline care by predicting the timing of apheresis after chemomobilization have been used with limited success.39 Hence, patients who undergo mobilization with chemotherapy plus cytokines often require unscheduled apheresis sessions on weekends, a practice that necessitates inefficient allocation of hospital resources and staff.43
Toxicity from chemotherapeutic agents is an important limitation of chemomobilization regimens. Serious AEs are pervasive with the use of chemotherapeutic agents and include the development of hemorrhagic cystitis, cardiac toxicity, infections and anaphylactic reactions.126 Patients undergoing auto-HSCT are already at considerable risk of serious chemotherapy-related AEs, and avoidance of additional risk is prudent. Whether an additional course of chemotherapy given solely for mobilization carries sufficient therapeutic benefit to offset the increased risk posed by the use of chemotherapeutic agents is unclear. Exposure to chemotherapy for as less as 6 months has been shown to significantly delay post transplantation plt and, to a lesser extent, neutrophil engraftments.13 One might speculate that chemotherapy may exert long-term detrimental effects on the BM or the marrow microenvironment. Kalaycio et al.127 reported an increased long-term risk of treatment-related myelodysplastic syndrome or AML after auto-HSCT in patients whose marrow had been damaged by prior chemotherapy and radiation. It is possible that minimizing the use of chemotherapy agents for mobilization may leave more options available for future treatment. In a recent study, Holtan et al.128 reported that the length of time between the last administration of chemotherapy and the start of apheresis is predictive of a patient's immune status at the start of apheresis. This result may reflect long-term damage to the BM caused by chemotherapeutic agents in patients with NHL.
Disease-specific factors such as previous treatment with chemotherapeutic agents or disease state can affect the success of a chemomobilization regimen.13, 30, 129 Although mobilization with chemotherapy results in successful stem cell collections in the majority of patients, obtaining adequate CD34+ cells may be more difficult in patients with low-grade lymphoma than in most other patients who are candidates for auto-HSCT.30, 129 In addition, previous courses of chemotherapy and radiotherapy can adversely influence CD34+ cell yields.20, 30, 129 Tricot et al.13 studied 225 patients with MM; of these, 215 patients received GM-CSF 250 μg/m2 daily plus CY for mobilization and 49 patients received G-CSF 5 μg/kg daily plus CY. The authors reported that the target yield of 5 × 106 CD34+ cells/kg was obtained in only 28% of patients with >24 months of previous chemotherapy, whereas 91% of patients with shorter exposures to chemotherapeutic agents achieved this target. Watts et al.119 reported that in 9 of 78 patients with lymphoma who received CY plus G-CSF 10 μg/kg s.c. daily, the regimen failed to generate collections of >1 × 106 CD34+ cells/kg. Patients with MM who receive initial therapy with lenalidomide are also at risk of low CD34+ cell yields.130 Kumar et al.130 noted significant decreases in the total number of CD34+ cells collected (P<0.001), the average number of CD34+ cells collected each day (P<0.001) and the total number of CD34+ cells collected on apheresis day 1 (P<0.001) among 135 patients with MM who underwent initial treatment with lenalidomide–dexamethasone, as compared with 241 similar patients who underwent initial therapy with either dexamethasone, thalidomide–dexamethasone or VAD (vincristine, Adriamycin (doxorubicin), dexamethasone). Furthermore, a trend was noted toward decreased PBSC yield with increased duration of lenalidomide therapy.130 This effect was observed primarily among patients with G-CSF alone mobilization and was not significant when mobilization with CY plus G-CSF was used.
In those patients with lymphoma or myeloma for whom initial mobilization with CY and growth factors has failed, regimens combining high-dose etoposide and cytokines have been shown to be effective strategies for remobilization.131 Incorporation of mobilization into the salvage therapy by using G-CSF (10 μg/kg) after the second or third cycle of therapy has been an increasing trend.120 Although the use of G-CSF plus chemotherapy is generally more effective than the use of G-CSF alone for second mobilization attempts, the repeated administration of chemotherapeutic agents for mobilization introduces additional toxicity and may not be the preferred approach for patients in whom chemomobilization has already failed.24 However, no single factor can predict the success of mobilization in a patient.
In recent years, several investigational agents have been developed that may prove useful for amplifying yields of CD34+ cells without introducing additional toxicity. As the understanding of stem cell interactions with the BM microenvironment grows, new mobilizing agents will emerge.
Pegylated G-CSF (pegfilgrastim, Neulasta, Amgen Inc.) is a longer-lasting variant of G-CSF; its plasma half-life of 33 h is substantially longer than the 4- to 6-h half-life of G-CSF.132 A slow rate of renal elimination allows a single dose of pegfilgrastim to result in clinically effective serum levels from administration until neutrophil recovery.132 This agent has been approved by the FDA for prevention of prolonged neutropenia after chemotherapy for non-hematological malignancies.133 Its potential as a mobilizing agent is currently being explored.132, 134 Owing to its pharmacologic efficiency, pegfilgrastim has the potential to reduce resource use by decreasing both the amount of product necessary to induce mobilization and the length of time between the initiation of mobilization and the collection of PBSCs.132 A 12-mg s.c. dose of pegfilgrastim administered after CY mobilized a median of 7.4 × 106 CD34+ cells/kg after a median of one apheresis session in patients with MM.134 In a recent phase 2 study involving 26 patients with MM, pegfilgrastim (12 mg s.c., single dose) administered after CAD (CY, Adriamycin (doxorubicin), dexamethasone) chemotherapy mobilized ⩾7.5 × 106 CD34+ cells/kg in 88% of patients.132 Results from this study indicated that peak CD34+ cell counts were achieved at a median of 13 days (range: 11–22) after pegfilgrastim administration, slightly quicker than the 15 days seen with G-CSF, which may affect the timing of apheresis collections. Pegfilgrastim is well tolerated, with an AE profile similar to that of G-CSF. Thoracic pain and nausea were reported in a study by Fruehauf et al.,132 and a case of splenic rupture that may not have been related to the study drug was reported in another trial.135
Plerixafor (AMD3100, Genzyme Corporation, Cambridge, MA, USA) is a selective and reversible antagonist of CXCR4 and disrupts its interaction with SDF-1, thereby releasing hematopoietic stem cells into the circulation.136, 137, 138 Plerixafor used in conjunction with G-CSF has been shown in a phase 2 study to quickly and predictably enhance the numbers of CD34+ cells circulating in the peripheral blood.139 In this study, patients with NHL mobilized more CD34+ cells per day of apheresis after administration of plerixafor plus G-CSF than after administration of G-CSF alone (median increase of 4.4-fold (range: 1.1- to 54.4-fold)). Similar results were seen in patients with MM (median increase of 3- to 3.5-fold (range: 1.3- to 10-fold)).139 In patients in whom mobilization with G-CSF either alone or in combination with chemotherapy has previously failed, CD34+ cell yields have been noted to increase by 5- to 100-fold in response to administration of plerixafor plus G-CSF.139, 140 A cohort of 115 patients termed poor mobilizers who received plerixafor as part of a compassionate use protocol was assessed by Calandra et al.140 Collections of ⩾2 × 106 CD34+ cells/kg after administration of plerixafor plus G-CSF for mobilization were achieved in 60.3% of patients with NHL, 71.4% of patients with MM and 76.5% of patients with HD; these rates were similar for patients who had previously failed mobilization with chemotherapy plus cytokines or cytokines alone.140
Preliminary results of two phase 3 multicenter randomized placebo-controlled studies indicated that the addition of plerixafor to a G-CSF regimen resulted in greater efficacy than was seen with a regimen of G-CSF alone.141, 142 All patients in both studies received G-CSF 10 μg/kg s.c. daily for 4 days. On the evening of day 4, patients received either placebo or plerixafor (240 μg/kg s.c.). Patients underwent apheresis on day 5 and continued to receive the evening dose of either placebo or plerixafor followed by the morning dose of G-CSF for up to a total of four apheresis sessions or until ⩾5 × 106 CD34+ cells/kg were collected. In one study that examined mobilization with plerixafor in patients with MM, the percentage of patients from whom ⩾6 × 106 CD34+ cells/kg were collected in ⩽2 days of apheresis served as the primary end point.141 In the other study, which evaluated plerixafor for mobilization in patients with NHL, the percentage of patients from whom ⩾5 × 106 CD34+ cells/kg were collected in ⩽4 days of apheresis was the primary end point.142 In the phase 3 study that was conducted in patients with MM, it was reported that ⩾6 × 106 CD34+ cells/kg were collected from 72% of patients in the plerixafor group in ⩽2 days of apheresis, whereas only 34% of patients in the placebo group had reached this goal (P<0.0001). In the phase 3 study conducted in patients with NHL, the target yield of ⩾5 × 106 CD34+ cells/kg collected in ⩽4 apheresis days was reached by 59% of patients in the plerixafor group but by only 20% of patients in the placebo group (P<0.0001). Furthermore, the minimum yield of ⩾2 × 106 CD34+ cells/kg collected in ⩽4 apheresis days was reached by 87% of patients in the plerixafor group but by only 47% of patients in the placebo group (P<0.0001). More patients proceeded to transplantation in the plerixafor group (90%) than in the placebo group (55%). In general, treatment with plerixafor and G-CSF was associated with side effects similar to those seen with treatment with G-CSF alone. Most treatment-related AEs appeared to be mild and transient. The most common AEs were gastrointestinal tract effects, such as diarrhea, nausea and vomiting, and injection-site reactions, such as erythema or edema.141, 142
Patients with NHL who did not mobilize the minimum yield of ⩾2 × 106 CD34+ cells/kg in the phase 3 trial of plerixafor were enrolled in a follow-up study in which rescue mobilization therapy with plerixafor plus G-CSF was administered.143 All patients received G-CSF (10 μg/kg) s.c. daily for 4 days; on the evening of the fourth day, patients received plerixafor (240 μg/kg s.c.). Apheresis commenced on day 5, after a morning dose of G-CSF. Patients continued to receive plerixafor in the evening and G-CSF in the morning for up to 4 days of apheresis or until 5 × 106 CD34+ cells/kg had been collected. This rescue therapy resulted in collections of ⩾2 × 106 CD34+ cells/kg in 33 of 52 patients (63%) in whom initial mobilization with placebo and G-CSF had failed and in 4 of 10 patients (40%) in whom initial mobilization with plerixafor and G-CSF had failed.143 The high success rate seen with plerixafor and G-CSF in patients with NHL in whom initial mobilization with G-CSF alone had failed is consistent with results from the compassionate use protocol.140
SB-251353 is another investigational mobilization agent currently in preclinical studies.32, 33 SB-251353 is an analog of GRO-β, a human CXC chemokine involved in directing the movement of stem cells and leukocytes.32, 33 Although human data are lacking, this agent, when combined with G-CSF in rhesus monkeys, was shown to greatly increase mobilization of stem cells and progenitor cells in comparison with G-CSF alone.32 Further research is necessary to determine the efficacy and potential toxicities of this treatment in humans.32, 33
Endogenous TPO is the primary regulator of megakaryocyte development. Recombinant human TPO (rhTPO) has been shown to act synergistically with G-CSF to enhance stem cell mobilization.144 This regimen has not been shown to be more efficacious or safer than existing mobilization regimens; however, a few studies document encouraging results. In one such study of 134 patients undergoing HDT and auto-HSCT, the target yield of ⩾5 × 106 CD34+ cells/kg was reached in 73% of patients when rhTPO was added to G-CSF, whereas the target yield was reached in only 46% of patients whose stem cells were mobilized with G-CSF plus a placebo.145 AEs associated with the use of rhTPO plus G-CSF appear to be similar to those seen with the use of G-CSF alone;144, 145 however, cytopenias owing to neutralizing antibodies to TPO have been reported in a small number of patients who were given rhTPO to treat chemotherapy-induced thrombocytopenia.146, 147 Currently, no TPOs have been approved by the FDA for mobilization.148
Parathyroid hormone (PTH) activates osteoblasts, which produce hematopoietic growth factors in the stem cell niche, thereby increasing the numbers of circulating stem cells.149, 150 The efficacy and safety of PTH have yet to be established. In a recent phase 1 study, 20 patients with MM, NHL, HD or AML, in whom one or two previous mobilization attempts had failed, received escalating doses of 40, 60, 80 and 100 μg of PTH (s.c.) for 14 days; PTH doses were combined with G-CSF 10 μg/kg on the last 4 days of treatment.150 Overall, 47% of patients in whom one previous mobilization attempt had failed reached the mobilization criterion of >5 CD34+ cells/μl in the peripheral blood, and 40% of patients who had previously experienced two failed mobilization attempts reached the mobilization criterion. No dose-limiting toxicity was evident, and PTH was well tolerated; AEs included headache, muscle pain, back pain, fatigue and hypothermia.150
Current stem cell mobilization regimens for auto-HSCT in patients with NHL or MM vary with regard to CD34+ cell yield and toxicity. Mobilization with cytokines alone, most commonly G-CSF, is generally well tolerated; however, this approach is limited by suboptimal yields and the need for repeated apheresis sessions to collect sufficient cells for transplantation. Mobilization regimens that combine a chemotherapeutic agent with a cytokine enhance the collection of CD34+ cells. However, the higher CD34+ cell collection may be offset by increased toxicities and resource utilization. Importantly, the optimal time to collect CD34+ cells after chemotherapy is highly variable and unpredictable, which potentially increases resource utilization.
Although chemomobilization is widely used in Europe and the United States, no strategy for mobilization can be considered standard, and there are no published guidelines regarding PBSC mobilization. For patients with MM who undergo transplantation and who have not received initial therapy with lenalidomide, mobilization with G-CSF alone is often sufficient for a single transplant and should be considered. However, CD34+ cell yields resulting from mobilization with G-CSF alone may not be high enough to support tandem transplantation. Furthermore, G-CSF alone is insufficient up to 23% of the time for mobilization in patients with NHL or HD. For these patients, it may be necessary for mobilization regimens to include chemotherapeutic or novel agents. It is our opinion that effectiveness will be the main driver for the use of any novel mobilization strategy. The addition of plerixafor to a G-CSF regimen has led to substantial improvements in efficacy in clinical trials; this strategy shows great potential for future use in patients with NHL, HD or MM who undergo transplantation.
Collectively, all regimens in current use fail to mobilize adequate numbers of CD34+ cells in 5–30% of patients. High failure rates can adversely affect patient outcomes, because these patients cannot proceed to transplantation without a repeat of mobilization and apheresis, which is associated with increased morbidity and resource utilization. Thus, advances in mobilization strategies are needed to improve patient outcomes. Novel agents used in conjunction with existing therapies have the potential to amplify CD34+ cell yields without introducing additional toxicity, thereby improving the process of PBSC mobilization in patients undergoing auto-HSCT for MM or NHL. The future of mobilization will use promising new agents in the context of a patient-tailored strategy that depends on individual disease characteristics and the nature of previous treatment.
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Bensinger, W., DiPersio, J. & McCarty, J. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 43, 181–195 (2009). https://doi.org/10.1038/bmt.2008.410
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