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Sources of hematopoietic stem cells

Sources of hematopoietic stem cells
Author:
Robert S Negrin, MD
Section Editor:
Nelson J Chao, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Jun 03, 2022.

INTRODUCTION — Hematopoietic cell transplantation (HCT) is an important and potentially curative treatment option for a wide variety of malignant and nonmalignant diseases. The multipotent hematopoietic stem cells (HSCs) required for this procedure are usually obtained from the bone marrow or peripheral blood of a related or unrelated donor. Umbilical cord blood, the blood remaining in the umbilical cord and placenta following the birth of an infant, has emerged as an established alternative source of hematopoietic stem cells in allogeneic HCT.

This topic review will discuss the HSC model of hematopoiesis followed by a discussion of the sources of hematopoietic cells suitable for transplantation. The selection of an appropriate HCT donor, the evaluation of a potential HCT donor, and the collection of umbilical cord blood are discussed separately.

●(See "Donor selection for hematopoietic cell transplantation".)

●(See "Evaluation of the hematopoietic cell transplantation donor".)

●(See "Collection and storage of umbilical cord blood for hematopoietic cell transplantation".)

●(See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation".)

The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor/hematopoietic stem cells from any source (eg, bone marrow, peripheral blood, cord blood). Otherwise, the source of such cells will be specified (eg, autologous peripheral blood progenitor cell transplantation). (See 'Sources of hematopoietic stem cells' below.)

STEM CELL MODEL

Discovery of HSCs — Hematopoiesis is sustained throughout the lifespan of an individual by a small number of multipotent hematopoietic stem cells (HSC) that slowly cycle from a larger quiescent pool. Circulating blood cells are immediate descendants of maturing precursors that arise from a smaller pool of progenitors. The progenitors in turn arise from an even smaller pool of HSCs. HSCs are multipotent and have the capacity to differentiate into the cells of all blood lineages: erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes, T and B lymphocytes, natural killer cells, and dendritic cells (figure 1).

The identification and role of HSCs in protecting animals from lethal irradiation emerged from studies that began in the 1950s in which it was observed that animals treated with irradiation could be protected by either lead shielding over the spleen or later infusion of splenocytes from a normal donor. With the development of in vitro and in vivo assay systems (eg, Till-McCulloch spleen-colony assay) it became clear that there were clonotypic precursor cells capable of giving rise to both erythroid and myeloid lineages of cells [1]. HSCs were defined functionally as populations of cells capable of rescuing lethally irradiated animals, a definition that is accurate conceptually, although difficult to apply in different systems, especially in humans. Nevertheless, it became possible to define a population of cells capable of multilineage repopulation and rescuing animals from lethal irradiation. These HSCs could be re-isolated and used to rescue other lethally irradiated animals. (See "Overview of hematopoietic stem cells".)

Monoclonal antibodies were subsequently developed that recognized proteins on the surface of both immature and mature populations of bone-marrow-derived cells. With the refinement of cell sorting technologies, it has been possible to separate populations of cells with hematopoietic stem cell activity. Using this approach, a population of highly purified murine bone-marrow-derived HSCs was isolated that was capable of rescuing more than 95 percent of lethally irradiated animals when as few as 100 cells were injected intravenously [2].

Markers on human HSCs — While the exact phenotype remains controversial, in vitro and surrogate in vivo assays have been used to isolate a population of human putative HSCs capable of multilineage growth. Cells with these functions express the HSC antigen CD34 and are Lin-; they are also described as being Thy-1lo, Dr-, or CD38- [3,4]. (See "Overview of hematopoietic stem cells".)

Clinical trials using highly purified populations of CD34+, Thy-1+ cells have demonstrated that this cell population alone is capable of rapid and sustained hematopoietic engraftment [5]. Furthermore, these cells alone are capable of supporting long-term hematopoiesis following autologous hematopoietic cell transplantation (HCT) [6]. The clinical applications of purified HSCs in HCT and gene therapy are quite broad. Using current technology of magnetic bead separation, it is possible to isolate and purify CD34+ cells with high efficiency. Further purification of subpopulations of CD34+ cells (eg, isolating Thy-1+ cells by high speed fluorescence activated cell sorting) is possible, but challenging to perform on a clinical scale.

A population of CD34-negative HSCs has also been described [7,8], which is capable of reconstituting lethally irradiated animals [7]. Despite this observation, there is a large volume of clinical data that support the concept that CD34 expression and the number of CD34+ cells infused correlate closely with the pace of hematopoietic reconstitution both in animals and in humans. (See 'PBPC mobilization' below.)

SOURCES OF HEMATOPOIETIC STEM CELLS — Hematopoietic stem cells (HSCs) can be found in several different human tissues: bone marrow; peripheral blood, especially following mobilization; and umbilical vein cord blood obtained at the time of delivery.

Bone marrow

Bone marrow harvest — The technique of bone marrow harvesting has become routine. Bone marrow is generally aspirated from the posterior iliac crests under either regional or general anesthesia. Additional bone marrow can be obtained from the anterior iliac crest; however, the amounts available are relatively limited and this site is generally used only for diagnostic purposes. In patients who have received prior irradiation to the pelvis, it may not be possible to isolate sufficient bone marrow from these sites, and alternative approaches to collect or alternative sources of HSCs are required. (See "Bone marrow aspiration and biopsy: Indications and technique".)

Multiple aspirations are performed with the collection of approximately 5 to 10 mL of marrow from each puncture, with a goal of collecting up to 2 x 108 cells of marrow per kilogram of recipient body weight (between 700 and 1500 mL of bone marrow for an adult recipient). Guidelines established by the National Marrow Donor Program (NMDP) limit the volume of bone marrow removed to 20 mL/kg of donor weight. Either heparin or acid-citrate-dextran-A can be used to anticoagulate bone marrow products. If the product is to be cryopreserved, red cells are washed off prior to freezing. (See "Evaluation of the hematopoietic cell transplantation donor", section on 'Bone marrow collection'.)

Mobilized bone marrow — An alternative to collection of unstimulated bone marrow is to prime with granulocyte colony-stimulating factor (G-CSF) prior to bone marrow harvest (10 to 16 mcg/kg subcutaneously per day for three days). This has resulted in effective hematopoietic recovery in a study of heavily pretreated patients with poor peripheral blood stem cell mobilization [9,10]. There have been some suggestions that this approach may result in decreased incidence and severity of graft-versus-host disease (GVHD). A relatively small randomized study has suggested that the use of G-CSF-primed bone marrow may result in such benefits [11,12]. However, this is rarely used and will require validation in larger numbers of patients [11].

Cell dose — The cell dose required for stable long-term engraftment has not been determined with precision; however, useful goals have been established. A nucleated cell dose of 2 x 108/kg is generally considered to be adequate, and cell doses of as low as 1 x 108/kg have been used, although three retrospective studies indicated that rates of hematopoietic recovery, transplantation-related mortality, and five-year survival were significantly better when the CD34+ cell dose was ≥3.0 x 106/kg [13,14], while rates of hematopoietic recovery were significantly worse when the CD34+ cell dose was <1.2 x 106/kg [15]. This generally requires between 700 and 1500 mL of bone marrow for an adult recipient, depending on recipient weight. (See 'PBPC mobilization' below.)

While most studies of cell dose focus on the dose of CD34+ cells, transplant outcomes may also be impacted by the number of plasmacytoid dendritic cells (pDCs) and naïve T cells contained within the bone marrow graft. As an example, in an analysis of 161 recipients of bone marrow grafts enrolled on a prospective trial, those with pDCs, naïve CD8+ T cells, invariant natural killer T cells or naïve CD4+ T cells measuring above the median had superior overall survival at three years (56 versus 35 percent) [16]. Grafts with more pDCs were associated with fewer deaths due to GVHD or graft rejection. These associations were not seen among the 147 patients receiving peripheral blood progenitor cell grafts. Although manipulation of the graft for desired cell content is an attractive clinical goal, graft T cell dose and pDC dose are not evaluated in routine practice.

Complications — Bone marrow harvest is frequently complicated by mild back or hip pain, fatigue, and transient changes in peripheral blood cell counts. Serious complications of bone marrow harvest are extremely rare and involve mechanical injury, complications of anesthesia, infection, and bleeding. This is discussed in more detail separately. (See "Evaluation of the hematopoietic cell transplantation donor", section on 'Complications'.)

Peripheral blood — HSCs are present in peripheral blood at extremely low levels [17]. Levels of HSCs can be increased by 1000-fold or more with hematopoietic growth factor administration (eg, granulocyte-macrophage colony-stimulating factor [GM-CSF], G-CSF, or CXCR4 inhibition with plerixafor) or recovery from cytotoxic chemotherapy [18-20]. The collections used at most institutions contain a mixture of HSCs and progenitor cells and will be referred to as peripheral blood progenitor cells (PBPCs) to differentiate them from studies in which only the purified human HSCs were infused.

PBPC products account for virtually all donor HSCs for autologous hematopoietic cell transplantation (HCT). For allogeneic stem cells, transplantation with mobilized PBPCs is more common, but bone marrow continues to be utilized, especially for those with standard-risk disease or bone marrow failure syndromes, such as severe aplastic anemia. The relative efficacy of different HSC sources is described separately. (See 'PBPC versus bone marrow for malignant disease' below.)

Optimal CD34 cell dose — The absolute number of CD34+ cells/kg of recipient weight is the most reliable and practical method for determining the adequacy of a product. In vitro hematopoietic colony assays correlate with CD34+ cell assays, but they are cumbersome to perform, difficult to standardize, and may require 10 or more days for readout [21,22]. As a result, the standard method used in most laboratories is to measure the CD34+ cell content by fluorescence activated cell sorting (FACS). A major effort has been made to standardize and validate this process among different laboratories [23]. Many centers measure CD34+ cell content prior to beginning apheresis to determine the optimal day for PBPC collection.

Following infusion of the mobilized PBPCs, hematopoietic reconstitution is rapid, requiring approximately 10 days for neutrophil recovery and 10 to 12 days for platelet recovery. The CD34+ cell dose/kg has proven to be a useful value, since patients who receive more than 2 x 106 CD34+ cells/kg generally have rapid and sustained hematopoietic recovery [24-26]. Thus, this cell dose defines an adequate collection of PBPCs that generally ensures rapid reconstitution. However, there is no established minimal dose. Many centers have accepted CD34+ cell doses of 106/kg, although such doses have often been associated with prolonged platelet recovery.

The "optimal" CD34+ cell dose has yet to be defined and likely differs depending on the type of transplantation. A dose of 2 x 106 CD34+ cells/kg appears to be adequate for autologous HCT. In contrast, higher doses are likely needed in patients receiving grafts from HLA identical sibling donors (2 to 5 x 106 CD34+ cells/kg) or undergoing an allogeneic non-myeloablative or haploidentical transplantation (10 to 20 x 106 CD34+ cells/kg). Giving larger doses of CD34+ cells/kg may result in slightly faster platelet recovery following HCT, may have a minimal effect on neutrophil recovery, and a possibly favorable effect on overall survival [27-42]:

●In one study, there was a significant inverse correlation between infused CD34+ cell count and the time to recovery of an absolute lymphocyte count ≥500/microL in patients with non-Hodgkin lymphoma following autologous HCT, along with significantly longer event-free and overall survivals [35].

●A randomized trial comparing mobilization with G-CSF, GM-CSF or a combination of both cytokines with chemotherapy has been performed in 156 patients with breast cancer, lymphoma or multiple myeloma [40]. Patients who received G-CSF either alone or in combination with GM-CSF had significantly higher yields of CD34+ cells (median 7.1 versus 2.0 x 106/kg per apheresis). A significantly higher percentage of patients achieved a dose of 2.5 X 106 CD34+ cells/kg (94 percent versus 78 percent). Although engraftment was more rapid with the higher dose of CD34+ cells, there were no major differences in long-term outcome.

●In another study, a CD34+ dose >8 x 106 cells/kg was associated with an increased risk of clinically extensive chronic GVHD following allogeneic transplantation [31]. However, these observations have not been made by other transplant groups [41].

Prospective studies will be required in order to define the optimal dose of CD34+ cells, CD34+ subsets, total nucleated cell dose, and other graft components [43-47]. (See 'T cell manipulation' below.)

PBPC mobilization — Both G-CSF and GM-CSF, administered either alone or in combination with chemotherapy or other stimulating agents (eg, plerixafor), can be used to mobilize PBPCs. G-CSF is much more commonly utilized. Standard approaches are to use G-CSF alone for allogeneic donors and to use G-CSF alone or G-CSF plus either plerixafor or cyclophosphamide for autologous mobilization. Some centers reserve plerixafor for patients who fail to mobilize adequate numbers of CD34+ cells, but other centers include plerixafor more routinely. (See "Evaluation of the hematopoietic cell transplantation donor", section on 'Procedure'.)

Guidelines regarding the use of myeloid growth factors for PBPC mobilization are available from the American Society of Clinical Oncology [48].

G-CSF stimulation — For most allogeneic donors, we mobilize PBPCs with G-CSF alone. We treat the donor with G-CSF at a dose of 10 to 16 mcg/kg per day, with HSC mobilization usually occurring between days 4 and 5 [24,25,49,50]. Most donors can be collected in a single apheresis session, but occasionally multiple apheresis procedures may be needed to achieve the desired dose of at least 2 x 106 CD34+ cells/kg of recipient body weight. (See 'Optimal CD34 cell dose' above.)

The optimal methodology for mobilizing PBPCs has yet to be defined, and several different approaches have been used [51-53]. In one randomized study, G-CSF was given either in a single daily dose of 10 mcg/kg, or in divided doses of 5 mcg/kg twice per day to normal donors undergoing collection for allogeneic transplantation [54]. The latter strategy led to a higher yield of CD34+ cells and required fewer apheresis procedures, without increasing toxicity or cost. Use of a longer-acting recombinant G-CSF (pegylated recombinant G-CSF, pegfilgrastim), which requires less frequent dosing, has also resulted in successful mobilization but is not commonly used for this purpose in adults [55-57]. In two other studies, doses between 20 to 50 mcg/kg per day improved the CD34+ cell yield, thereby reducing the number of days of apheresis required to reach the collection goal of more than 2.5 or 5 x 106 CD34+ cells/kg, but this is not used routinely [58,59].

Inadequate G-CSF response — The use of G-CSF alone results in successful mobilization of PBPCs in most patients, but some patients are difficult to adequately mobilize [60]. Why this occurs is not known, but the degree of prior exposure to chemotherapy or irradiation or the underlying diagnosis may be important [58,61]. (See 'PBPC mobilization' above.)

As an example, prior exposure to lenalidomide in patients with multiple myeloma (especially for more than four to six months) was associated with decreased ability to successfully collect PBPCs mobilized with G-CSF alone, which could be overcome with the use of chemotherapy plus G-CSF or the addition of plerixafor [62]. Despite these observations, it has been extremely difficult to predict which patients will be poor mobilizers prior to initiating the mobilization procedure.

Strategies that can increase the PBPC yield and thereby reduce the number of apheresis procedures include:

●A combination of G-CSF with chemotherapy [19]. (See 'Mobilization after chemotherapy' below.)

●A combination of G-CSF with the CXCR4 inhibitor plerixafor. (See 'Plerixafor' below.)

●Stem cell factor (SCF, Steel factor, c-kit ligand) can be used for HSC mobilization [63]. SCF is approved for this use in a number of countries, but not in the United States. SCF also activates mast cells, producing significant but manageable side effects. Although SCF alone has relatively limited activity, combination therapy with G-CSF produces a significant increase in the percentage of patients who were successfully mobilized using the threshold CD34+ cell dose of 5 x 106/kg to define a successful mobilization [27].

Plerixafor — For patients who fail to mobilize adequate numbers of CD34+ cells with either G-CSF alone or G-CSF plus chemotherapy, we suggest the addition of plerixafor.

Plerixafor inhibits the interaction between stromal-cell-derived factor 1 (SDF-1) and its receptor CXCR4, which plays a key role in the "trafficking" of PBPCs [51,52]. Interruption of these and other interactions therefore results in the release (ie, mobilization) of highly functional PBPCs into the circulation [64-66]. Plerixafor is expensive, so it is often reserved for patients who fail to mobilize adequate numbers of CD34+ cells with either G-CSF or G-CSF plus chemotherapy. Plerixafor is begun after the patient has received G-CSF for a minimum of four days. Subcutaneous plerixafor (240 mcg/kg based on actual body weight) and G-CSF (10 mcg/kg) are administered in the evening, followed by collection the next day. Plerixafor can be administered once daily until sufficient cell collection is achieved up to a maximum of four days.

The following studies support the use of plerixafor:

●Initial phase I studies were performed in patients with multiple myeloma and non-Hodgkin lymphoma at doses of 160 and 240 mcg/kg. A rapid rise in peripheral blood CD34+ cells was noted four to six hours after injection [67]. The drug was generally well tolerated with only minimal side effects.

●The combination of G-CSF plus plerixafor has been shown to improve mobilization of CD34+ cells in subjects who had previously failed mobilization with chemotherapy or cytokine-only mobilization [68] and was superior to G-CSF alone in the mobilization of more than 5 x 106 CD34+ cells/kg, requiring fewer apheresis procedures [69,70].

●In a randomized, placebo-controlled study in 298 patients with non-Hodgkin lymphoma requiring autologous HCT, a significantly higher proportion of subjects treated with plerixafor plus G-CSF achieved the optimal CD34+ cell target for HCT in fewer apheresis days, compared with G-CSF alone [71].

●In one study, plerixafor was given to 25 HLA-matched sibling HCT donors (240 mcg/kg subcutaneously) without G-CSF and leukapheresis initiated four hours later. A CD34+ cell dose sufficient for transplantation was achieved in two-thirds of the donors after a single dose of plerixafor [72]. No donor experienced more than grade 1 toxicity, and no unexpected adverse events were observed in any of the recipients. All patients engrafted in a timely fashion following infusion of the mobilized product.

The US Food and Drug Administration has approved plerixafor for use in combination with G-CSF to mobilize HSCs for collection and subsequent autologous transplantation in patients with non-Hodgkin lymphoma and multiple myeloma. For many groups, the routine use of plerixafor is reserved for patients who fail to mobilize adequate numbers of CD34+ cells with either G-CSF or G-CSF plus chemotherapy [73-77]. However, other groups use it more routinely in combination with G-CSF. Both strategies have been effective. (See "Multiple myeloma: Use of autologous hematopoietic cell transplantation", section on 'Collection of stem cells'.)

Mobilization after chemotherapy — Compared with a growth factor alone, mobilization of PBPCs is more effective using G-CSF plus chemotherapy, after recovery from cytotoxic chemotherapy; >10 circulating CD34+ cells/microL during recovery post-chemotherapy has been used to predict successful PBPC mobilization [61]. However, in most centers, G-CSF plus plerixafor is preferred for mobilization of autologous PBPCs. (See 'Plerixafor' above.)

The addition of growth factors, such as G-CSF, results in a synergistic effect [78-82]. While a variety of mobilization strategies have been developed that exploit this phenomenon [80,81,83-87], the standard approach is to use cyclophosphamide (typically 3 to 4 g/m2) along with G-CSF 10 mcg/kg (rounded to the nearest vial size). This approach has been safely and consistently applied to a number of different disease settings with relatively few toxicities and excellent collection of CD34+ cells. While the addition of chemotherapy can provide further cytoreduction for patients with malignancies, it can also result in complications (eg, febrile neutropenia, hemorrhagic cystitis). As such, the combination of chemotherapy with growth factors is only appropriate in the autologous transplant setting.

●Mobilization following chemotherapy plus growth factors is superior to growth factors alone – In a study of 47 heavily pretreated patients with relapsed or refractory lymphoma who received combination chemotherapy, those with sensitive or stable disease were randomly assigned to receive G-CSF alone or G-CSF plus cyclophosphamide, followed by collection of PBPCs [81]. Subjects initially treated with G-CSF alone received the same dose of cyclophosphamide following PBPC collection; both groups then received identical chemotherapy, involved-field radiation therapy, and preparative regimens, followed by administration of the collected PBPCs. Although PBPC mobilization following the addition of chemotherapy resulted in higher CD34+ cell collection, there were no differences in median time to engraftment of neutrophils or platelets, tumor cell contamination, overall or progression-free survival, resource utilization, or toxicity between the two study arms.

●G-CSF is more effective in this setting than GM-CSF – G-CSF alone or sequential GM-CSF and G-CSF are superior to GM-CSF alone for mobilization of PBPCs and reduction of toxicity after mobilization with chemotherapy. To compare G-CSF (filgrastim) versus GM-CSF (sargramostim) in this setting, 158 patients with breast cancer, lymphoma, or multiple myeloma were given chemotherapy with cyclophosphamide plus either etoposide or paclitaxel [40,88]. Patients were then randomly assigned to receive G-CSF alone (6 mcg/kg per day), GM-CSF alone (250 mcg/m2 per day), or GM-CSF for five days followed by G-CSF, starting on the day after completion of the chemotherapy. Compared with those who received GM-CSF, patients who received G-CSF had the following characteristics:

•Faster recovery of an absolute neutrophil count to ≥500/microL (11 versus 14 days)

•Fewer patients requiring red blood cell transfusions

•Fewer patients with fever (18 versus 52 percent)

•Fewer hospital admissions (20 versus 42 percent)

•Less intravenous antibiotic therapy

•Higher yields of CD34+ cells (7.1 versus 2.0 x 106 CD34+ cells/kg per apheresis procedure) [21-42]

Risk factors for poor mobilization — Some patients require multiple apheresis procedures (ie, more than four) to achieve an adequate cell dose. Attempts have been made to predict the likelihood of collecting an adequate dose with the hopes of limiting more aggressive mobilization procedures to those more likely to fail. Factors that appear to predict a more difficult harvest include low circulating CD34+ cells, older donor age, and decreased total blood volume. These factors have been used to predict the ability of G-CSF alone or the combination of G-CSF plus chemotherapy to mobilize a sufficient number of PBPCs [61,89-100].

●In one study, the minimum steady-state concentration in the peripheral blood required to assure, with 95 percent probability, the successful mobilization and collection of >2.5 x 106 CD34+ cells/kg was 1.4 and 8.9 CD34+ cells/microL for patients with multiple myeloma and non-Hodgkin lymphoma, respectively [89].

●In two studies involving patients with a variety of malignancies, a pre-apheresis concentration of >34 or >40 CD34+ cells/microL assured collection by a single conventional-volume leukapheresis of >2.5 x 106 CD34+ cells/kg in 88 and 100 percent of subjects, respectively [90,91].

●In one study, the administration of G-CSF to donors <18 years of age (range 1 to 17) led to CD34+ mobilization in a pattern similar to that observed in donors ≥18 years of age, although a significantly higher percent of younger patients reached the targeted cell dose with only one apheresis (56 versus 39 percent) [97].

●A phase 2 study found that a single dose of pegylated G-CSF (100 mcg/kg) resulted in adequate mobilization in 83 percent of children <18 years of age undergoing PBPC collection for autologous transplantation [98]. However, there are few studies in adults, and pegylated G-CSF is not commonly used for this purpose.

●In a retrospective analysis of 129 consecutive related adult donors, factors affecting circulating CD34+ cell counts as a surrogate marker for HSC mobilization included donor weight and total G-CSF dose [99]. No difference was found for the 44 donors age ≥55 when compared with the 85 donors <55 years of age.

Complications — The complication rate following mobilization and collection of PBPCs is very low. Potential risks for the donor include those related to the administration of G-CSF and to apheresis. Bone pain occurs in 10 to 20 percent of donors which can be effectively treated with loratadine. Rarely, patients who receive G-CSF can develop splenomegaly with risk of splenic rupture, however, this is extremely rare. In our experience, we can perform most apheresis collections without central venous access. This is discussed in more detail separately. (See "Evaluation of the hematopoietic cell transplantation donor", section on 'Toxicity of PBPC donation'.)

Tumor cell contamination — Tumor cells may be present among the mobilized PBPCs, but the clinical significance of this finding is uncertain. In one study that used quantitative polymerase chain reaction (PCR), the lymphoma cell burden difference between bone marrow and peripheral blood was less than one log [101]. Since the absolute number of cells infused with an unmanipulated PBPC graft is often 1 to 1.5 logs more than with a bone marrow graft, the total number of tumor cells infused in absolute terms may be similar with these two HSC sources.

One strategy to reduce the risk of contamination of the PBPC collection in patients with B cell non-Hodgkin lymphoma has been to add anti-CD20 monoclonal antibodies (MAbs) with the mobilizing strategy.

Umbilical cord blood — Relatively high numbers of HSCs are present in umbilical cord blood (UCB) collected at the time of delivery. These cells can be processed and cryopreserved in cord blood banks. Units can be searched similar to the way that unrelated donors are identified. Following HLA-matching to a recipient, the cord blood unit can be transported to the transplant center with minimal delay and used. (See "Collection and storage of umbilical cord blood for hematopoietic cell transplantation".)

Unrelated UCB offers many practical advantages over unrelated donor bone marrow or mobilized PBPCs as a source of HSCs, including an expanded donor pool, ease of procurement and lack of donor attrition, and decreased GVHD. (See "Selection of an umbilical cord blood graft for hematopoietic cell transplantation", section on 'Features of UCB grafts'.)

Limitations to UCB include an increased risk of graft failure, delayed immune reconstitution, and unavailability of the donor for additional donations (ie, donor lymphocyte infusions). (See "Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens".)

PBPC VERSUS BONE MARROW FOR MALIGNANT DISEASE

Autologous transplantation — Virtually all transplant centers use peripheral blood progenitor cells (PBPCs) rather than bone marrow (BM) for autologous hematopoietic cell transplantation (HCT). In two studies, patients with relapsed lymphoma were randomly assigned to receive either autologous PBPCs or BM following induction treatment; PBPCs were found to be superior with regard to engraftment [102], supportive care, quality of life, and cost [103,104]. However, there were no differences in disease-free survival between the two groups in either of the two studies.

Allogeneic transplantation — Both PBPCs and BM are acceptable hematopoietic stem cell (HSC) sources for allogeneic transplantation in patients with malignant disease. A choice between these must be made depending on patient and donor preference. PBSCs may be preferred for those at high risk of graft failure or infections in the early post-transplantation period where more rapid hematopoietic recovery could be a particular advantage. Consistent with this, many centers have decided to utilize mobilized PBPCs for advanced stage patients and bone marrow for standard risk patients.

PBPCs have gained wide acceptance in allogeneic transplantation, and the collection of PBPCs for this purpose has largely been accomplished after mobilization with G-CSF [105,106]. Sufficient numbers of CD34+ cells are collected in the majority of patients without difficulty, although the optimal and required number of CD34+ cells for allogeneic transplantation has not been determined. PBPC may be preferred in cases with a high risk of relapse (eg, advanced disease), whereas BM is acceptable for patients with more standard risk. (See 'PBPC mobilization' above.)

A meta-analysis that included data from nine randomized trials involving a total of 1521 patients reported that, among adults with hematologic malignancies, the choice of stem cell source (PBPC or BM) does not appear to impact overall survival, disease-free survival, or non-relapse or transplant-related mortality [107]. PBPCs are associated with faster engraftment of neutrophils and platelets and a higher rate of overall and extensive chronic graft-versus-host disease (GVHD).

The following studies illustrate the complexity of these effects:

●A large nonrandomized study from the European Cooperative Group for Blood and Marrow Transplantation (EMBT) studied the effect of BM cell dose in 881 adult patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR) using high dose (>2.7 x 108 cells/kg) or low dose (<2.7 x 108 cells/kg) BM or PBPC [108]. There was no difference between PBPC and low dose BM in terms of treatment-related mortality, leukemia-free survival, or overall survival. In contrast, high dose BM compared with PBPC was associated with significantly lower treatment-related mortality and better leukemia-free and overall survival. BM at high or low dose induced less chronic GVHD than did PBPC.

●A retrospective analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) database evaluated the outcomes of patients with AML, myelodysplastic syndrome (MDS), or non-Hodgkin lymphoma undergoing reduced intensity conditioning followed by infusion of PBPC (887 patients) or BM (219 patients) in the United States between 2000 and 2008 [109]. The source of stem cells did not appear to impact survival rates at five years post-transplant or rates of acute and chronic GVHD. Interestingly, survival was higher among those who received GVHD prophylaxis with methotrexate plus a calcineurin inhibitor rather than with mycophenolate mofetil plus a calcineurin inhibitor, a finding that will need confirmation in other studies. (See "Prevention of graft-versus-host disease".)

●A randomized trial involved 350 patients with acute leukemia in first remission or chronic myeloid leukemia (CML) in first chronic phase, and confirmed the more rapid recovery of platelets and neutrophils seen in all prior studies utilizing PBPCs [110]. PBPCs were associated with significant increases in the incidence of grades II-IV acute GVHD (52 versus 39 percent, odds ratio [OR] 1.74, 95% CI 1.1-2.7), and chronic GVHD (67 versus 54 percent, OR 1.7, 95% CI 1.2-2.4). Estimated survival at two years was 65 percent with either source of HSCs.

●In another randomized trial, 228 patients <65 years of age with CML, AML, or MDS were assigned to receive either filgrastim-mobilized PBPCs or BM from an HLA-matched sibling [111]. PBPC transplantation was associated with a significantly shorter time to recovery of a platelet count >20,000/microL (by six days) and an absolute neutrophil count >500/microL (by four days). The two groups had identical rates of grades II-IV acute GVHD (44 percent), and similar rates of extensive chronic GVHD. The probability of overall survival at 30 months was significantly higher for recipients of PBPCs (68 versus 60 percent, hazard ratio [HR] 0.62, 95% CI 0.39-0.97).

●In a phase III trial, 551 adults undergoing allogeneic HCT from HLA-matched unrelated donors were randomly assigned to receive either filgrastim-mobilized PBPCs or BM [112]. At a median follow-up of 36 months, those assigned to PBPCs demonstrated a significantly shorter median time to platelet (by seven days) and neutrophil (by five days) count recovery, a lower incidence of graft failure (3 versus 9 percent), similar rates of acute GVHD, but increased rates of chronic extensive GVHD (48 versus 32 percent), a lower percentage of patients off GVHD therapy by two years (37 versus 57 percent), and a similar overall survival at two years (51 versus 46 percent).

There is not yet compelling evidence for the superiority of PBPCs over BM for allogeneic HCT in the adult, while two retrospective studies found PBPCs to be inferior to bone marrow in children and adolescents with acute leukemia [113] or severe aplastic anemia [114]. While most studies and a meta-analysis have concluded that hematopoietic and early immunohematologic reconstitution is significantly more rapid following use of PBPCs [115-117], acute and chronic (extensive) GVHD may be more common following PBPCs [117-122], although perhaps associated with a beneficial graft-versus-tumor effect and/or improved long-term outcome [111,117,122-124].

In a nine-year follow-up study of a randomized trial, overall and leukemia-free survival were similar in 329 leukemia patients who underwent HCT using PBPCs or BM [119]. While significant differences in the incidence of chronic GVHD and the duration of immunosuppression were noted, survival, general health, and the incidence of late events were not adversely affected.

T CELL MANIPULATION — The majority of studies have focused on the mobilization of human hematopoietic stem and progenitor cells. However, other cell populations may be clinically important, such as conventional CD4+ and CD8+ T cells (including different subsets such as naive and memory T cells), NK cells, invariant NK-T cells, and regulatory T cells, which may modify the graft-versus-tumor effect, the risk of graft-versus-host disease (GVHD), and/or the risk of graft rejection in the allogeneic setting [36,37,125-128]. (See "Prevention of graft-versus-host disease" and "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)' and "Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation", section on 'Graft manipulation and cell dose'.)

GVHD is primarily a T cell mediated disease. As such, one attractive approach to reduce the incidence of GVHD is to eliminate T lymphocytes from the donor inoculum prior to infusion of the bone marrow. Early studies with T cell depletion that reduce GVHD have been associated with an increase in graft failure, delayed immune reconstitution, disease relapse, and post-transplant lymphoproliferative disorder; as a result, there is no significant overall improvement in disease-free survival. Subsequent studies have been more favorable with a reduction in GVHD risk and excellent overall survival [129,130]. T cell depletion using CD34+ cell selection has been evaluated in a multicenter, three arm randomized trial. This is discussed in more detail separately. (See "Prevention of graft-versus-host disease", section on 'In vivo TCD'.)

Conversely, several small studies have demonstrated that a higher number of regulatory T cells (Tregs) and/or invariant natural killer T (NKT) cells in the graft is associated with improved immune reconstitution and reduced GVHD and cytomegalovirus infection. (See "Pathogenesis of graft-versus-host disease (GVHD)", section on 'Pathophysiology' and "Strategies for immune reconstitution following allogeneic hematopoietic cell transplantation", section on 'Graft manipulation and cell dose'.)

INFUSION OF STEM CELLS — The infusion of either bone marrow or peripheral blood progenitor cells (PBPCs) is a relatively simple process that is performed at the bedside. In the allogeneic setting the bone marrow product is generally used fresh and infused through a central vein over a period of several hours. Autologous products are almost always cryopreserved [131]. They are thawed at the bedside and infused rapidly over a period of several minutes.

The hematopoietic stem cells home to the bone marrow cavity by mechanisms that have not yet been fully elucidated [132]. Vascular cell adhesion molecule-1 (VCAM-1), heparan sulfate, and stromal-cell-derived factor-1 and its receptor (CXCR4) appear to play roles in this process [133-136]. (See 'Plerixafor' above.)

Side effects — Minimal toxicity has been observed in the majority of cases. With bone marrow infusions, there is occasional fever, however, most patients tolerate the infusion similar to a blood transfusion. In those instances in which ABO mismatched bone marrow is infused, hemolytic reactions may occur which are treated in standard fashion by administering fluids and diuretics.

With the infusion of cryopreserved peripheral blood stem cells, minor toxicities such as fever, cough, nausea, vomiting, flushing, headache, and occasional bronchospasm are relatively common and self-limited. Such reactions may be related to the amount of granulocytes or non-mononuclear cells in the apheresis product [137,138]. The cryoprotectant DMSO may contribute to these relatively minor side effects. Most reactions disappear rapidly following the completion of the infusion. The preservative DMSO gives off an odor for one to two days. Significant infusional toxicity such as hypotension, cardiac arrhythmias, and electrolyte disturbances is rare [139].

The risk of infusional toxicities can be reduced by selecting for hematopoietic stem cell populations, such as CD34+ cells [139]. Major and minor ABO incompatibilities can lead to acute hemolytic transfusion reactions; red blood cells need to be depleted from the infusion in patients with major ABO incompatibilities [140]. Plasma depletion can also be performed in the setting of PBPCs where there is a major ABO incompatibility; however, we do not routinely do this and instead use significant hydration to avoid complications of the mild transfusion reaction with hemolysis that will occur in this setting.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

●The rapidly expanding field of hematopoietic stem cell (HSC) biology has resulted in a dramatic improvement in our understanding of the biologic basis of transplantation. With the emergence of peripheral blood progenitor cells (PBPCs) and umbilical cord blood, alternative sources of HSCs are available. The optimal source and composition of the HSC product continues to be an area of active clinical investigation.

●In the autologous setting, most transplant groups use PBPCs in the majority of cases. The optimal HSC dose can be calculated using enumeration of CD34+ cells. As an example, the total number of cells collected as determined by the total nucleated cell count can be multiplied by the percentage of CD34+ cells determined by fluorescence activated cell sorting (FACS) analysis of the product. In this way, the total number of CD34+ cells can be calculated; this is then divided by the recipient weight to arrive at the number of CD34+ cells/kg. A dose of >2 x 106/kg of recipient weight is typically used. (See 'PBPC mobilization' above.)

●In the allogeneic setting, the situation is considerably more complex. The optimal product has yet to be determined with respect to the use of bone marrow versus PBPCs. PBPCs engraft more rapidly than bone marrow, but the increased T cell load may result in higher rates of graft-versus-host disease (GVHD), particularly chronic GVHD. In the setting of malignancy, many centers have decided to utilize mobilized PBPCs for advanced stage patients and bone marrow for standard risk patients. (See 'PBPC versus bone marrow for malignant disease' above.)

●The relative merits of unrelated donor cells versus cord blood versus haploidentical donors remains to be determined, and the choice amongst these different HSC products varies by transplant center. However, both donor sources appear to be acceptable, which improves the likelihood of finding a donor for patients in need. (See "Donor selection for hematopoietic cell transplantation".)

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  112. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367:1487.
  113. Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 2004; 22:4872.
  114. Schrezenmeier H, Passweg JR, Marsh JC, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood 2007; 110:1397.
  115. Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97:3380.
  116. Lapierre V, Oubouzar N, Aupérin A, et al. Influence of the hematopoietic stem cell source on early immunohematologic reconstitution after allogeneic transplantation. Blood 2001; 97:2580.
  117. Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005; 23:5074.
  118. Schmitz N, Eapen M, Horowitz MM, et al. Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. Blood 2006; 108:4288.
  119. Friedrichs B, Tichelli A, Bacigalupo A, et al. Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial. Lancet Oncol 2010; 11:331.
  120. Storek J, Gooley T, Siadak M, et al. Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood 1997; 90:4705.
  121. Remberger M, Beelen DW, Fauser A, et al. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood 2005; 105:548.
  122. Dey BR, Shaffer J, Yee AJ, et al. Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen. Bone Marrow Transplant 2007; 40:19.
  123. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 2001; 344:175.
  124. Brunet S, Urbano-Ispizua A, Ojeda E, et al. Favourable effect of the combination of acute and chronic graft-versus-host disease on the outcome of allogeneic peripheral blood stem cell transplantation for advanced haematological malignancies. Br J Haematol 2001; 114:544.
  125. Bornhäuser M, Platzbecker U, Theuser C, et al. CD34+-enriched peripheral blood progenitor cells from unrelated donors for allografting of adult patients: high risk of graft failure, infection and relapse despite donor lymphocyte add-back. Br J Haematol 2002; 118:1095.
  126. Panse JP, Heimfeld S, Guthrie KA, et al. Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning. Br J Haematol 2005; 128:659.
  127. Cao TM, Shizuru JA, Wong RM, et al. Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose. Blood 2005; 105:2300.
  128. Larghero J, Rocha V, Porcher R, et al. Association of bone marrow natural killer cell dose with neutrophil recovery and chronic graft-versus-host disease after HLA identical sibling bone marrow transplants. Br J Haematol 2007; 138:101.
  129. Devine SM, Carter S, Soiffer RJ, et al. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. Biol Blood Marrow Transplant 2011; 17:1343.
  130. Jakubowski AA, Small TN, Young JW, et al. T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. Blood 2007; 110:4552.
  131. Berz D, McCormack EM, Winer ES, et al. Cryopreservation of hematopoietic stem cells. Am J Hematol 2007; 82:463.
  132. Tavassoli M, Hardy CL. Molecular basis of homing of intravenously transplanted stem cells to the marrow. Blood 1990; 76:1059.
  133. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283:845.
  134. Simmons PJ, Masinovsky B, Longenecker BM, et al. Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells. Blood 1992; 80:388.
  135. Siczkowski M, Clarke D, Gordon MY. Binding of primitive hematopoietic progenitor cells to marrow stromal cells involves heparan sulfate. Blood 1992; 80:912.
  136. Papayannopoulou T, Priestley GV, Nakamoto B, et al. Molecular pathways in bone marrow homing: dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins. Blood 2001; 98:2403.
  137. Calmels B, Lemarié C, Esterni B, et al. Occurrence and severity of adverse events after autologous hematopoietic progenitor cell infusion are related to the amount of granulocytes in the apheresis product. Transfusion 2007; 47:1268.
  138. Milone G, Pinto V, Mercurio S, et al. Adverse events after infusions of cryopreserved hematopoietic stem cells depend on non-mononuclear cell in infused suspention and on patient age (abstract). Blood 2006; 108:402b.
  139. Shpall EJ, LeMaistre CF, Holland K, et al. A prospective randomized trial of buffy coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients receiving high-dose chemotherapy. Blood 1997; 90:4313.
  140. Sniecinski IJ, Oien L, Petz LD, Blume KG. Immunohematologic consequences of major ABO-mismatched bone marrow transplantation. Transplantation 1988; 45:530.
Topic 3537 Version 35.0

References

1 : The biology of hematopoietic stem cells.

2 : Purification and characterization of mouse hematopoietic stem cells.

3 : Isolation of a candidate human hematopoietic stem-cell population.

4 : Expression of Thy-1 on human hematopoietic progenitor cells.

5 : Transplantation of highly purified CD34+Thy-1+ hematopoietic stem cells in patients with metastatic breast cancer.

6 : Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells.

7 : Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species.

8 : Hematopoietic stem cells: are they CD34-positive or CD34-negative?

9 : Autologous transplantation of granulocyte colony-stimulating factor-primed bone marrow is effective in supporting myeloablative chemotherapy in patients with hematologic malignancies and poor peripheral blood stem cell mobilization.

10 : G-CSF-stimulated BM progenitor cells supplement suboptimal peripheral blood hematopoietic progenitor cell collections for auto transplantation.

11 : Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells.

12 : Pilot study of allogeneic G-CSF-stimulated bone marrow transplantation: harvest, engraftment, and graft-versus-host disease.

13 : CD34+ cell dose predicts relapse and survival after T-cell-depleted HLA-identical haematopoietic stem cell transplantation (HSCT) for haematological malignancies.

14 : Association of CD34 cell dose with hematopoietic recovery, infections, and other outcomes after HLA-identical sibling bone marrow transplantation.

15 : Engraftment of autologous and allogeneic marrow HPCs after myeloablative therapy.

16 : Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.

17 : Cells capable of colony formation in the peripheral blood of man.

18 : Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor.

19 : Granulocyte-macrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man.

20 : Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy.

21 : Stroma-supported progenitor production as a prognostic tool for graft failure following autologous stem cell transplantation.

22 : Prediction of engraftment after autologous peripheral blood progenitor cell transplantation: CD34, colony-forming unit-granulocyte-macrophage, or both?

23 : Toward standardization of CD34+ cell enumeration: an international study. Biomedial Excellence for Safer Transfusion Working Party.

24 : Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.

25 : Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony stimulating factor (rhG-CSF): an analysis of factors correlating with the tempo of engraftment after transplantation.

26 : Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma.

27 : Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients.

28 : High CD34(+) cell counts decrease hematologic toxicity of autologous peripheral blood progenitor cell transplantation.

29 : An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy.

30 : Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy.

31 : CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation.

32 : Efficacy of CD34+ stem cell dose in patients undergoing allogeneic peripheral blood stem cell transplantation after total body irradiation.

33 : Influence of bone marrow nucleated red blood cell dose on outcome after allogeneic haematopoietic stem cell transplantation.

34 : Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose.

35 : Higher infused CD34+ hematopoietic stem cell dose correlates with earlier lymphocyte recovery and better clinical outcome after autologous stem cell transplantation in non-Hodgkin's lymphoma.

36 : Allogeneic transplantation of CD34(+) selected cells from peripheral blood from human leukocyte antigen-identical siblings: detrimental effect of a high number of donor CD34(+) cells?

37 : Transplant dose of CD34(+) and CD3(+) cells predicts outcome in patients with haematological malignancies undergoing T cell-depleted peripheral blood stem cell transplants with delayed donor lymphocyte add-back.

38 : Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD34+ selected blood cells from HLA-identical siblings.

39 : Optimizing the CD34 + cell dose for reduced-intensity allogeneic hematopoietic stem cell transplantation.

40 : Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells.

41 : CD34, CD4, and CD8 cell doses do not influence engraftment, graft-versus-host disease, or survival following myeloablative human leukocyte antigen-identical peripheral blood allografting for hematologic malignancies.

42 : Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses.

43 : Predictive factors for long-term engraftment of autologous blood stem cells.

44 : CD34+/CD90+ cells infused best predict late haematopoietic reconstitution following autologous peripheral blood stem cell transplantation.

45 : Predictive value of circulating immature cell counts in peripheral blood for timing of peripheral blood progenitor cell collection after G-CSF plus chemotherapy-induced mobilization.

46 : Impact of CD34+ cell dose on the outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation.

47 : Transplant-related mortality and long-term graft function are significantly influenced by cell dose in patients undergoing allogeneic marrow transplantation.

48 : Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update.

49 : Granulocyte colony-stimulating factor "mobilized" peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy.

50 : CD34+ cell mobilization for allogeneic progenitor cell transplantation: efficacy of a short course of G-CSF.

51 : It's moving day: factors affecting peripheral blood stem cell mobilization and strategies for improvement [corrected].

52 : Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization.

53 : Current status of stem cell mobilization.

54 : A randomized comparison of once versus twice daily recombinant human granulocyte colony-stimulating factor (filgrastim) for stem cell mobilization in healthy donors for allogeneic transplantation.

55 : Single-dose pegfilgrastim for the mobilization of allogeneic CD34+ peripheral blood progenitor cells in healthy family and unrelated donors.

56 : Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients.

57 : A single dose of Pegfilgrastim versus daily Filgrastim to evaluate the mobilization and the engraftment of autologous peripheral hematopoietic progenitors in malignant lymphoma patients candidate for high-dose chemotherapy.

58 : The role of diagnosis in patients failing peripheral blood progenitor cell mobilization.

59 : Mobilization and harvesting of peripheral blood stem cells: randomized evaluations of different doses of filgrastim.

60 : How I treat patients who mobilize hematopoietic stem cells poorly.

61 : Fludarabine-containing regimens severely impair peripheral blood stem cells mobilization and collection in acute myeloid leukaemia patients.

62 : Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma.

63 : c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities.

64 : Chemokine-mobilized adult stem cells; defining a better hematopoietic graft.

65 : BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells.

66 : Advances in mobilization for the optimization of autologous stem cell transplantation.

67 : Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.

68 : AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.

69 : The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone.

70 : Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.

71 : Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma.

72 : Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction.

73 : International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).

74 : Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilizers, including assessment of tumor cell mobilization.

75 : Plerixafor and granulocyte-colony-stimulating factor (G-CSF) in patients with lymphoma and multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy for autologous hematopoietic stem cell mobilization: the Austrian experience on a named patient program.

76 : Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization.

77 : Evaluation of Dutch guideline for just-in-time addition of plerixafor to stem cell mobilization in patients who fail with granulocyte-colony-stimulating factor.

78 : Factors that influence collection and engraftment of autologous peripheral-blood stem cells.

79 : Mobilization of peripheral-blood progenitor cells with high-dose etoposide and granulocyte colony-stimulating factor in patients with breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease.

80 : Randomized cross-over trial of progenitor-cell mobilization: high-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF.

81 : Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation.

82 : Factors associated with successful mobilization of progenitor hematopoietic stem cells among patients with lymphoid malignancies.

83 : Leukapheresis after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation: a novel approach to harvest a second autograft.

84 : Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors.

85 : Optimizing the timing of chemotherapy for mobilizing autologous blood hematopoietic progenitor cells.

86 : A single dose of 6 or 12 mg of pegfilgrastim for peripheral blood progenitor cell mobilization results in similar yields of CD34+ progenitors in patients with multiple myeloma.

87 : Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma.

88 : Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim.

89 : Peripheral blood progenitor cell (PBPC) counts during steady-state haemopoiesis enable the estimation of the yield of mobilized PBPC after granulocyte colony-stimulating factor supported cytotoxic chemotherapy: an update on 100 patients.

90 : Inverse relationship between patient peripheral blood CD34+ cell counts and collection efficiency for CD34+ cells in two automated leukapheresis systems.

91 : Monitoring of peripheral blood CD34+ cell counts on the first day of apheresis is highly predictive for efficient CD34+ cell yield.

92 : Analysis of PBPC cell yields during large-volume leukapheresis of subjects with a poor mobilization response to filgrastim.

93 : Identification of the CD34 enumeration on the day before stem cell harvest that best predicts poor mobilization.

94 : A cell-kinetic model of CD34+ cell mobilization and harvest: development of a predictive algorithm for CD34+ cell yield in PBPC collections.

95 : Collection of peripheral blood stem cells from normal donors 60 years of age or older.

96 : Peripheral blood stem cell mobilization in elderly (≥70 years) versus younger patients: A study of 984 multiple myeloma patients [abstract]

97 : Donor age-related differences in PBPC mobilization with rHuG-CSF.

98 : A Phase II study on the safety and efficacy of a single dose of pegfilgrastim for mobilization and transplantation of autologous hematopoietic stem cells in pediatric oncohematology patients.

99 : Older age does not influence allogeneic peripheral blood stem cell mobilization in a donor population of mostly white ethnic origin.

100 : Evaluation of an algorithm based on peripheral blood hematopoietic progenitor cell and CD34+ cell concentrations to optimize peripheral blood progenitor cell collection by apheresis.

101 : Lymphoma cell burden in progenitor cell grafts measured by competitive polymerase chain reaction: less than one log difference between bone marrow and peripheral blood sources.

102 : Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow.

103 : Autologous peripheral blood stem cell transplantation in patients with relapsed lymphoma results in accelerated haematopoietic reconstitution, improved quality of life and cost reduction compared with bone marrow transplantation: the Hovon 22 study.

104 : Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease.

105 : Characterization of CD34+ peripheral blood cells from healthy adults mobilized by recombinant human granulocyte colony-stimulating factor.

106 : Allogeneic blood stem cell transplantation: considerations for donors.

107 : Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

108 : Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: influence of dose and stem cell source shows better outcome with rich marrow.

109 : Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation.

110 : Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia.

111 : A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies.

112 : Peripheral-blood stem cells versus bone marrow from unrelated donors.

113 : Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry.

114 : Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.

115 : Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation.

116 : Influence of the hematopoietic stem cell source on early immunohematologic reconstitution after allogeneic transplantation.

117 : Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials.

118 : Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation.

119 : Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial.

120 : Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease.

121 : Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors.

122 : Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen.

123 : Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.

124 : Favourable effect of the combination of acute and chronic graft-versus-host disease on the outcome of allogeneic peripheral blood stem cell transplantation for advanced haematological malignancies.

125 : CD34+-enriched peripheral blood progenitor cells from unrelated donors for allografting of adult patients: high risk of graft failure, infection and relapse despite donor lymphocyte add-back.

126 : Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning.

127 : Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.

128 : Association of bone marrow natural killer cell dose with neutrophil recovery and chronic graft-versus-host disease after HLA identical sibling bone marrow transplants.

129 : Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303.

130 : T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin.

131 : Cryopreservation of hematopoietic stem cells.

132 : Molecular basis of homing of intravenously transplanted stem cells to the marrow.

133 : Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

134 : Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells.

135 : Binding of primitive hematopoietic progenitor cells to marrow stromal cells involves heparan sulfate.

136 : Molecular pathways in bone marrow homing: dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins.

137 : Occurrence and severity of adverse events after autologous hematopoietic progenitor cell infusion are related to the amount of granulocytes in the apheresis product.

138 : Adverse events after infusions of cryopreserved hematopoietic stem cells depend on non-mononuclear cell in infused suspention and on patient age (abstract)

139 : A prospective randomized trial of buffy coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients receiving high-dose chemotherapy.

140 : Immunohematologic consequences of major ABO-mismatched bone marrow transplantation.