Mobilization of hematopoietic stem/progenitor cells to the circulation

Between 1986 and 1991, autologous peripheral blood stem cell graft products were collected either in steady state or after chemotherapy-induced mobilization (Table 2). As expected, fewer apheresis procedures were needed to collect mobilized vs steady-state stem cells, but mobilized cells provided an unanticipated benefit; faster hemato-poietic recovery after transplantation.²² This still in-completely understood phenomenon was responsible for the eventual shift from bone marrow to blood as the preferred source of autologous hematopoietic stem cells for transplantation.

Table 2 - Advances in mobilization of stem/progenitor cells.

Full table

In 1988, two hematopoietic cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF)²⁰ and granulocyte colony-stimulating factor (G-CSF)²¹ were shown to mobilize hematopoietic stem/progenitor cells to the blood stream. When the cytokines were administered after myelosuppressive chemotherapy, the mobilization effect was even greater.²⁰ Thus, in current clinical practice, chemotherapy is no longer used alone as a mobilizing agent but is combined with a hematopoietic cytokine, most often G-CSF. The mobilizing chemotherapy is either cyclophosphamide in doses of 1.5–7 g/m² or chemotherapy specific for the underlying malignancy. In those situations where administration of chemotherapeutic agent(s) is not appropriate, for example, allogeneic donors and some autologous donors in complete remission, cytokines alone are used to induce mobilization (Table 2).²³

Usefulness of specific mobilization therapies

Chemotherapy plus cytokine(s)

Prospective and retrospective inquiries have shown that chemotherapy, especially when given as part of the specific therapy of the underlying malignancy, followed by a cytokine or cytokine combination yields higher numbers of autologous CD34+ cells than cytokines alone.^23,24,25,26 One randomized trial that supports these observations was designed to limit as much as possible the variables associated with mobilization efficacy.²⁷ Patients each received two different mobilization regimens, which were alternately administered first or second. Cyclophosphamide plus G-CSF mobilized CD34+ cells more effectively than GM-CSF plus G-CSF regardless of whether that therapy was given as the first or second mobilizing strategy.

Several randomized studies have approached the issues of which cytokine or cytokine combination and at what doses given after chemotherapy provide the best mobilization. A higher (16 g/kg) rather than a lower (8 g/kg) dose of G-CSF was more effective in patients with a variety of malignancies.²⁸ G-CSF or GM-CSF followed by G-CSF was more effective in patients with solid and hematologic malignancies than GM-CSF.²⁹ In contrast, for patients with non-Hodgkin's lymphoma (NHL), GM-CSF followed by G-CSF permitted more efficient collection of a target number of CD34+ cells than did GM-CSF, while G-CSF was the least efficient of the three cytokine strategies.³⁰ However, cyclophosphamide plus either G-CSF, GM-CSF or GM-CSF plus interleukin 3 (IL-3) mobilized equally well in another trial.³¹ Studies including erythropoietin (EPO) have found that it did³² and that it did not³³ increase mobilization when added to G-CSF after chemotherapy . When added to GM-CSF followed by G-CSF, EPO provided more mobilization than when added to G-CSF.³⁴ The sometimes conflicting outcomes of these prospective studies (Table 3) are confounded by known and unknown variables in the populations studied (for example, different mobilizing chemotherapy regimens, different underlying diseases, previous treatment with different antitumor agents for different lengths of time) and suggest that a single regimen will not prove optimal for every autologous donor.

Table 3 - Randomized trials of cytokine plus chemotherapy mobilization.

Full table

Cytokine(s) alone

Chemotherapy cannot be added to cytokines for mobilization purposes in normal donors and cytokines alone are employed. G-CSF is the most commonly used cytokine for this purpose. Higher doses of G-CSF³⁵ and administration of the cytokine twice rather than once daily^36,37 appear to mobilize more allogeneic CD34+ cells. The combination of EPO and G-CSF did not increase CD34+ cell mobilization in normal donors when retrospectively compared with mobilization with G-CSF alone,³⁸ but a combination of G-CSF plus GM-CSF was reported to mobilize allogeneic CD34+ cells more effectively than G-CSF alone.³⁹

The use of cytokines alone for mobilization in autologous donors with malignancies in remission, who might benefit by avoiding the risks of myelosuppressive chemotherapy holds some attraction. In a retrospective comparison, higher doses of G-CSF (32 g/kg/day) mobilized more CD34+ cells than lower doses (10 g/kg/day) in patients with characteristics predicting poor mobilization.⁴⁰ Stem cell factor (SCF), a cytokine that acts on primitive hematopoietic stem cells and is available in most countries as an investigational agent, added to G-CSF may also provide a more vigorous mobilization than G-CSF alone. More patients who had been heavily pre-treated for lymphoma collected insufficient cells for transplant after receiving G-CSF (26%) than after receiving G-CSF plus SCF (15%) in a randomized study.⁴⁰ Another prospective randomized comparison of G-CSF and G-CSF plus SCF for mobilization in patients with breast cancer showed that those receiving the combination required fewer apheresis procedures to collect progenitor cells for transplant.⁴¹ GM-CSF-mobilizes cells adequately,⁴² and is an alternative to G-CSF as a single cytokine mobilizer. Other single cytokines have been explored as autologous mobilizers, including EPO,⁴³ IL-3,⁴⁴ a fusion product of GM-CSF and IL-3,⁴⁵ FLT3 ligand⁴⁶ and IL-6.⁴⁷ They all had modest activity but were not as useful as G-CSF or GM-CSF. These two cytokines, and especially G-CSF, remain the mainstay mobilizing cytokines and no new or novel cytokine seems likely to be adopted for this use in the near future.

Mobilization efficiency and outcome

Approximately 5 10⁶ transplanted autologous CD34+ cells/kg can be relied upon to provide optimal red and white blood cell recovery,⁴⁸ although lower CD34+ doses have performed equally well.⁴⁹ The pace of circulating platelet recovery increases with higher doses of CD34+ cells. A total of 15 10⁶ or more autologous CD34+ cells/kg resulted in a recovery of circulating platelet counts to 50 10⁹/l in a median of 11 days post transplant as compared with 14 days for patients receiving fewer CD34+ cells but at least 2.5 10⁶/kg.⁵⁰ These patients also maintained platelet counts of >20 10⁹/l beginning a median of 10 days post transplant compared to a median of 8 days for those receiving the higher doses. Unless patients are bleeding, platelet transfusions are not usually used for counts >20 10⁹/l. The benefits of recovery of circulating platelet counts earlier than 10 days after transplant may not be outweighed by the increased resources required to collect more than 2.5–5 10⁶ autologous CD34+ cells/kg.²⁸

Whether identifying the most efficient mobilization therapy among the several demonstrated effective strategies is possible, important or even necessary is an intriguing question. If one strategy routinely produces sufficient number of cells in a single apheresis procedure to assure rapid and reliable hematopoietic recovery, is another strategy that provides twice as many cells preferable? The answer would be yes if infusion of higher doses of circulating mobilized stem/progenitor cells provide added benefit beyond rapid durable engraftment without added toxicity.

Some indirect evidence for added benefits of transplantation of higher numbers of allogeneic stem/progenitor cells than needed for rapid hematopoietic recovery came from a randomized prospective study comparing mobilized blood-derived stem cell vs marrow-derived stem cell transplants. Patients transplanted with blood stem cells had better outcomes as regards disease-free survival and overall survival.⁵¹ Whether the improvement was related to the larger number of stem/progenitor cells in a blood stem cell vs a marrow stem cell graft product⁵² was neither discounted nor demonstrated. A second smaller randomized study of allogeneic marrow vs mobilized blood stem cell transplantation found that patients who received fewer than 2 10⁶/kg CD34+ cells, regardless of the cell source, experienced higher mortality and poorer survival.⁵³ Another potential benefit of transplantation of higher stem cell doses in the allogeneic setting is a more complete recovery of circulating lymphocytes.⁵⁴ In the autologous arena, a study of bone marrow transplantation in CML patients revealed that higher numbers of CD34+ cells infused was associated with a decreased risk of death and decreased +100 day transplant-related mortality. Whether this observation translates to the blood stem/progenitor cell arena is unknown.⁵⁵ Thus, added clinical benefits to very high doses of CD34+ cells for transplant in the autologous setting may exist but none have been positively identified.

As regards any additional toxicities associated with transplantation of more cells than required for rapid hematopoietic recovery, increasing allogeneic CD34+ cell doses correlated with a higher likelihood of clinical extensive chronic graft versus host disease, suggesting that increasing the CD34 cell numbers in mobilized graft products may be counterproductive.⁵⁶ Transplanted allogeneic CD34+ positively selected cell doses of 1–3 10⁶/kg have been associated with increased survival compared with higher doses.⁵⁷ Taken together, these few studies do not establish whether higher doses of hematopoietic stem/progenitor cells are of any additional advantage but may provide a disadvantage in the allogeneic setting. Consequently, the optimal number of infused blood-derived stem/progenitor cells remains uncertain.

Mobilization of malignant cells

In addition to mobilizing hematopoietic stem/progenitor cells, cytokines⁵⁸ and chemotherapy plus cytokines⁵⁹ have also mobilized malignant cells in to the blood stream, although tumor cell mobilization has not been identified in every studied autologous collection.^60,61 Autologous hematopoietic stem cell donors with follicular NHL were more likely to have detectable tumor cells in their apheresis products if they mobilized CD34+ cells poorly (42%) rather than well (17%), regardless of the mobilizing therapy used.⁶² One study found that poor mobilizers were more likely to experience lymphoma relapse post-transplant, but the infused products were not assayed for tumor cells.⁶³ Other investigators, however, found no differences in event-free survival, overall survival or relapse when the outcomes of good mobilizers and poor mobilizers with NHL treated with high-dose therapy and transplantation were compared.⁶⁴ These results support an earlier finding that patients with low-grade NHL who received either mobilized or steady-state blood stem/progenitor cells following high-dose therapy had similar event free and overall survival.⁶⁵ While avoiding increased tumor cell contamination in autologous mobilized blood stem cell collections seems intuitively desirable, no evidence exists to suggest that infusion of mobilized (in contrast to nonmobilized¹¹) tumor cells in the graft product increases the incidence of relapse of NHL,⁶⁵ multiple myeloma⁶⁶ or breast cancer⁶⁷ following transplant.

Poor response to mobilization therapy

Autologous donors

The response of individual donors to mobilizing therapies is variable and incompletely predictable.⁶⁸ A total of 21–48% of patients with NHL have exhibited poor mobilization after administration of chemotherapy and G-CSF.^63,64,69 Of these patients, 16–33% were unable to mobilize enough collectable stem/progenitor cells for transplantation.^63,69 Factors predicting for a higher likelihood of poor mobilization include increasing numbers of cycles of prior antitumor chemotherapy administration,⁷⁰ prior radiation therapy,^70,71 follicular rather than diffuse NHL as the underlying disease,³⁰ and the presence of overt marrow metastases.²⁵ In donors with lymphoma, low numbers of circulating natural killer (NK) CD3^-16⁺56⁺ cells prior to administration of mobilizing therapies have predicted poor mobilization,⁷² as have low platelet counts on the first day of autologous blood stem/progenitor cell collection.⁷³ Older age was associated with poor autologous mobilization in some patient groups,^30,74,75 but not in others.^74,76 Even though some donors with predictors of poor mobilization respond quite well to mobilizing therapies,⁷⁷ poorly mobilizing autologous donors are assumed to have sustained an injury to the hematopoietic stem cell system that is responsible for the poor effect (see Table 4). In support of this premise, autologous donors with breast cancer who had received more chemotherapy and radiation or had tumor metastases in the marrow also had fewer stem/progenitor cells in apheresis products collected during steady state than donors who were less heavily pretreated and had no marrow metastases.⁷⁸ Such damage may not account for all of the poor mobilization encountered in autologous donors. For example, patients who had received rituximab within 6 months of mobilization therapy mobilized less vigorously than rituximab-naive patients.⁷⁹ The use of rituximab during mobilization therapy for in vivo purging has not negatively affected mobilization.⁸⁰

Table 4 - Factors associated with poor mobilization.

Full table

Allogeneic donors

In the mid-1990s, normal donors with no history of cancer therapy began to receive mobilizing cytokines as allogeneic peripheral blood stem cell transplantation became more commonplace.⁸¹ Of these donors, 4–20% were noted to be poor mobilizers.^82,83,84,85 The varying percentages are likely due, in part, to differences in the definition of poor mobilization. Nonetheless, these observations in normal donors established that a stem cell pool compromised by prior therapy, metastases or aging is not the only explanation for poor mobilization.

The causes of poor allogeneic stem cell mobilization are elusive, but some hints have recently come to light. DBA-strain mice exhibit rapid and vigorous mobilization when treated with G-CSF, Balb/c mice demonstrate delayed but vigorous mobilization and C57Bl/6 mice mobilize poorly.⁸⁶ When plasma from C57Bl/6 mice was injected into Balb/c mice just prior to administration of mobilizing cytokines, mobilization was inhibited. Plasma from Balb/c and DBA mice was less inhibitory,⁸⁷ suggesting that a genetically controlled circulating factor in the blood could be responsible for regulating the vigor and timing of mobilization.

A mouse model of poor mobilization was constructed by exposing Balb/c mice to lower-half body irradiation prior to administration of mobilizing cytokines. These mice do not exhibit mobilization following cytokine administration.⁸⁸ When plasma from part-body irradiated mice was injected into intact mice before cytokine administration, no mobilization resulted, suggesting that a circulating factor was responsible for the inhibition. Injection of plasma from poorly mobilizing human donors into mice prior to administration of mobilizing cytokine also inhibited mobilization.⁸⁹ Whether this circulating factor(s) is operative in the clinical situation of poor mobilization in allogeneic and autologous donors is unknown. Since the survival of poorly mobilizing autologous patients with NHL was inferior to that of rapid mobilizers post-transplant⁹⁰ and tumor relapse was more likely for poor mobilizers,⁶³ identification and inactivation of any circulating factor that inhibits mobilization could improve patient outcome (Table 2).

Molecular markers of mobilization

Methods to improve the vigor of mobilization are virtually impossible to design on a rational basis since the mechanisms involved in the process are largely unknown. Stem cells reside in marrow adherent to marrow stromal cells via ₁₄ integrin-mediated adhesion, that is, very late antigen 4 (VLA-4) on the stem cell and vascular cell adhesion molecule-1 (VCAM) on the stromal cell. Interruption of adhesion releases stem cells to the circulation.⁹¹ A higher percentage of CD34+ cells expressing VLA-4 was observed among the mobilized stem/progenitor cells of good mobilizers with NHL than in those of poor mobilizers.⁹² Marrow stromal cells produce a chemokine, stromal-derived factor 1 (SDF1), whose receptor, CXCR4, is present on CD34+ cells.⁹³ Patients with NHL treated with chemotherapy plus cytokine(s) who mobilized well had significantly lower plasma levels of SDF-1 and lower percentages of CD34+ cells in the collections expressing CXCR4 than poor mobilizers.⁹⁴ High plasma levels of flt3-ligand prior to administration of mobilizing therapies predict poor mobilization of autologous,⁹⁵ but not allogeneic⁹⁶ CD 34+ cells. Prospective studies are needed to confirm that molecular markers can accurately identify poor autologous mobilizers prior to administration of mobilizing therapies (Table 5).

Table 5 - Key areas requiring additional investigation.

Full table

Harvesting enough cells for transplant from poor mobilizers

Reports of maneuvers to harvest more stem/progenitor cells from donors who responded poorly to initial mobili-zing therapies will be reviewed, but translation of the results to clinical practice is confounded by multiple variables. For example, a graft product anticipated to provide rapid, complete and durable restoration of marrow function at one center could be considered unacceptable at another. Failure to reach targets between 1 10⁶/CD34⁺ cells/kg and 3 10⁶ CD34⁺ cells/kg^68,97,98,99 have defined products unsuitable for transplant at individual institutions. Methods to detect poor mobilization also vary and include sampling peripheral blood¹⁰⁰ rather than determining the number of cell population subsets such as CD34+ cells and/or CFU-GM in an apheresis product. Some centers perform several apheresis procedures if needed to procure the target numbers of cells,⁹⁸ while others do not.⁶⁸ The volume of blood processed by the blood cell separator for each collection has varied from 7¹⁰¹ to 35 l and more.¹⁰² Keeping these differences in mind, maneuvers reported to bolster collection numbers for donors who mobilized poorly following various mobilization therapies are discussed.

Poor autologous mobilization response to myelosuppressive chemotherapy

Chemotherapy alone was used for mobilization before hematopoietic cytokines were available. Remobilization with higher cyclophosphamide doses in a small group of poor mobilizers with a variety of malignancies provided increased numbers of CFU-GM in the apheresis products while remobilization with the same dose of cyclophosphamide did not.¹⁰³ Although chemotherapy without cytokines is no longer used for mobilization purposes, the observation that increasing doses of chemotherapy correlated with increasing vigor of mobilization could be useful when designing remobilization strategies.

Poor autologous mobilization response to myelosuppressive chemotherapy plus cytokines

Autologous donors with lymphoma, myeloma and Ewing's sarcoma who were treated with chemotherapy and G-CSF, and did not amass a suitable graft product with three apheresis procedures were remobilized with essentially the same mobilizing therapies. More CD34+ cells and CFU-GMs were collected during the second mobilization than the first from most donors. When collections from the first and second mobilizations were combined, 70% of the patients had sufficient cells for transplant.⁶⁸ In another instance, a group of autologous donors with a variety of malignancies who mobilized poorly after treatment with disease-specific chemotherapy plus 5 g/kg G-CSF were remobilized with either the same therapy or with 10 g/kg G-CSF alone. Those receiving G-CSF alone yielded significantly higher numbers of CD34+ cells and CFU-GM than during their initial mobilization, while those remobilized with the same therapy yielded similar cell numbers to those with the first mobilization. However, the numbers of cells collected during either of the remobilization strategies were approximately the same.⁹⁷ The value of cytokines alone as remobilizing therapy was also studied in another group of 23 autologous donors with solid tumors and hematologic malignancies who collected insufficient cells for transplant after up to five apheresis procedures. Initial mobilization had been accomplished with chemotherapy, G-CSF or a combination of chemotherapy and G-CSF. Remobilization therapy was initiated within 35 days using a combination of G-CSF and GM-CSF. The median number of CD34+ cells collected during remobilization was significantly higher than during the initial mobilization, although four of the 23 donors studied had poorer collections with remobilization.⁹⁹ The largest study of remobilization in poorly mobilizing autologous donors described 119 patients with a good performance status whose initial mobilization therapy was either G-CSF and chemotherapy or G-CSF alone.⁹⁸ The initial collections contained less than 2.5 10⁶ CD34+ cells/kg. Remobilization was accomplished with either chemotherapy and G-CSF or G-CSF alone. Significantly, more CD34+ cells were collected during the second mobilization attempt than during the first, regardless of which remobilization therapy was used; G-CSF alone was as effective as chemotherapy plus G-CSF in remobilizing CD34+ cells. Thus, for patients who mobilized poorly with chemotherapy and cytokine, remobilization using the same therapy again,^68,98 using cytokine alone at higher doses,^97,98 or a combination of cytokines alone when a single cytokine was originally combined with chemotherapy,⁹⁹ was successful in most but not in all patients.

Poor autologous mobilization response to cytokines

Studies specifically addressing the question of remobilization in autologous donors who mobilized poorly following cytokine administration are sparse. Since chemotherapy plus cytokine has been shown to mobilize more effectively than cytokine alone,^{23,24,25,26,27} this strategy might be tried for remobilization, provided neutropenia is an acceptable risk for the patient. Since good mobilizers have responded better to higher doses of cytokines than lower doses,⁴⁰ and donors who mobilized poorly after chemotherapy plus cytokines have responded better to higher doses of cytokine or cytokine combinations,⁹⁷ these strategies could be viable options for remobilization. For those few patients with obvious disease progression who mobilize poorly with cytokines alone, remobilization with disease-specific chemotherapy plus cytokines has often resulted in a better mobilization response in the experience of the authors.

Autologous bone marrow harvests from poor mobilizers

Marrow has occasionally been harvested from poorly mobilizing autologous donors in an attempt to construct a suitable graft product. A total of 13 patients with a variety of malignancies failed to mobilize target numbers of CD34+ cells prior to initiating apheresis and underwent marrow harvesting rather than blood stem cell collection. Nine were transplanted with the marrow after high-dose therapy and experienced delayed platelet recovery compared to a group of autologous marrow transplant patients that served as a historical control.¹⁰⁰ Whether a suitable graft product could have been collected from the peripheral blood of those patients is unknown, but the marrow-derived graft product was inferior. Autologous bone marrow harvests with good cellularity but unknown numbers of CD34+ cells were harvested from another group of patients who had mobilized poorly. The marrow cells were added to the blood-derived progenitor cells and transplanted to 11 evaluable patients. Delayed hematopoietic recovery and a high (42%) procedure-related mortality resulted, leading to the conclusion that marrow harvested from poor mobilizers is an unreliable product.⁴⁹ The number of publications regarding marrow harvests in poorly mobilizing donors is small, but available data suggest that the transplantation quality of the marrow is poor.

Poor allogeneic mobilization response to cytokines

Little information is available regarding strategies to improve the vigor of mobilization in poorly mobilizing allogeneic donors. However, remobilization in good mobilizers to obtain a second allogeneic graft product has been described. In a single case report, retreatment with a mobilizing cytokine 3 days after completing a successful apheresis collection resulted in a poor CD34+ cell yield,¹⁰⁴ suggesting that a longer time period is needed before retreatment with mobilizing cytokines. This observation was confirmed in a report of 13 allogeneic donors who underwent remobilization at a median of 5 months (range 1–13 months) after the initial mobilization and the number of CD34+ cells harvested during the first and second mobilization were comparable.¹⁰⁵ Another group of 10 donors were mobilized twice with G-CSF for allogeneic blood stem/progenitor cell collection.¹⁰⁶ The median time between the first and second mobilization was 41.5 days (range 16–385 days). Shorter time intervals between the two mobilization events were associated with fewer CD34+ cells collected during the second mobilization period. However, after 60 days, the CD34+ cell content of the first and second collections were similar. The only patient who received twice as much cytokine during the second mobilization than the first had more CD34+ cells in the second collection. Taken together, these reports suggest that if a poorly mobilizing allogeneic donor is considered for remobilization, a time interval of a month or two should be considered between the two collections if possible. If a month's wait is not feasible, then remobilization with a higher dose of growth factor might be helpful.

Transplantation of cells from poorly mobilizing donors

A minimum of 1 10⁶ CD34+ cells/kg is considered essential to assure hematopoietic recovery following transplant, with higher doses providing more rapid platelet recovery.⁴⁰ A total of 18 patients who collected <1 10⁶/kg mobilized CD34+ cells/kg and <1 10⁵ CFU-GM were transplanted with those cells after high-dose therapy. Six patients received only those cells and five experienced delayed engraftment. A cellular marrow harvest was added to the cells for transplant to the remaining 12 patients. Of 11 evaluable patients, four had delayed neutrophil and eight delayed platelet engraftment, suggesting suitable graft products cannot be reliably constructed by adding marrow harvests to inadequate numbers of poorly mobilized blood stem/progenitor cells.⁴⁹

Three reports regarding transfusion of re-mobilized cells are instructive. A group of 23 patients whose mobilized collections contained fewer than 3 10⁶ CD34+ cells/kg were remobilized with G-CSF and GM-CSF.⁹⁹ Cells collected during both mobilization attempts were combined and transplanted following high-dose therapy. In all, 20 patients received at least 2 10⁶ CD 34+ cells/kg and recovered neutrophils at a median of at least 13 days and platelets at a median of at least 27 days. A second report of transplantation using remobilized cells described 27 patients who collected less than 2 10⁶ CD34+ cells/kg and/or less than 10 10⁴ CFU-GM/kg during the first mobilization. Both cell collections were combined and 24 received high-dose therapy and transplantation of 1.03–5.85 10⁶ CD34+ cells. All but one patient recovered hematopoietic function by a median of 26 days (platelets, reticulocytes and neutrophils) after infusion.⁹⁷ A third group of 49 patients who failed to collect 1 10⁶ CD34+ cells after the first mobilization was remobilized and the collected cells were combined. The patients were treated with high-dose therapy and 0.88–6.74 10⁶ autologous CD34+ cells/kg were infused. Recovery of 0.5 10⁹/l granulocytes to the circulation occurred at a median of 11 (9–16) days for 48 evaluable patients and platelet recovery occurred at a median of 14 (6–85) days for 47 evaluable patients.⁹⁸ These three reports suggest that, with remobilization, enough hematopoietic stem/progenitor cells can be collected from most poorly mobilizing autologous donors to construct a transplant product that provides timely hematopoietic recovery.

A mobilization strategy

Taken together, these studies can support more than one evidence-based algorithm for mobilization of hematopoietic progenitor/stem cells. One general approach is to identify donors at high risk for poor mobilization and provide them with therapies opined to provide maximum mobilization vigor,⁴⁰ accepting any increased time, cost, resource utilization and/or donor risk for morbidity that might be associated with the selected therapy. A second general approach is also supportable, recognizing that while groups of autologous donors can be categorized as being at high risk for poor mobilization, individual autologous and allogeneic donors who will mobilize poorly cannot be accurately identified prospectively. Since most donors are good or adequate mobilizers, all donors are treated with therapies known to produce useful mobilization in most cases, saving the more rigorous and/or costly therapies for those who respond poorly.

Cytokine administration produces sufficient mobilization to harvest 1.5–4 10⁶ CD34+ cells/kg in one to four 15 l apheresis procedures for most donors at the University of Nebraska Medical Center. The entire collection process from the time of administration of the first dose of cytokine until the final apheresis procedure is complete in 5–9 days when cytokine administration begins on Thursday and the first apheresis procedure begins the following Monday. If chemotherapy is given specifically for mobilization, the process will require 14–16 days from the date of chemotherapy administration until the graft product is collected. If chemotherapy given as part of disease-specific therapy is also used for mobilization, the time saving is optimal. Remobilization is performed for those patients who do not amass a sufficient number of cells for transplant during the first mobilization attempt (Table 6).

Table 6 - Algorithms of mobilization strategies.

Full table

Conclusion

Cytokines alone or chemotherapy plus cytokines mobilize hematopoietic stem cells to the circulation. Mobilized hematopoietic stem/progenitor cells provide rapid hematopoietic recovery following transplantation. While most donors mobilize well, a percentage of both allogeneic and autologous donors respond poorly to mobilizing therapies. A single solution to poor mobilization is unlikely to exist, since the reasons for the problem are multiple and differ from one donor to the next. Until the causes are accurately defined, solutions are unlikely to be found. The issue is important not only for current transplant needs, but also for future needs if, as early reports suggest, these circulating hematopoietic cells are capable of transdifferentiation and will be used to engineer nonhematopoietic cells and tissues. Hopefully, additional research will optimize mobilization to the extent that a sufficient number of cells for any need can be harvested with a simple phlebotomy.

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