Peripheral blood stem cell collection is an effective approach to obtain a hematopoietic graft for stem cell transplantation. Developing hematopoietic stem/progenitor cell (HSPC) mobilization methods and collection algorithms have improved efficiency, clinical outcomes, and cost effectiveness. Differences in mobilization mechanisms may change the HSPC content harvested and result in different engraftment kinetics and complications. Patient-specific factors can affect mobilization. Incorporating these factors in collection algorithms and improving assays for evaluating mobilization further extend the ability to obtain sufficient HSPCs for hematopoietic repopulation. Technological advance and innovations in leukapheresis have improved collection efficiency and reduced adverse effects.
Key points
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The clinical use of mobilization agents is effective to achieve peripheral collection of stem cells.
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Stem cell sources, mobilization strategies, and collection methods may impact graft quality and transplantation outcomes.
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Monitoring and predicting mobilization are critical to coordinate between the various clinical services involved in stem cell transplantation.
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Apheresis-based peripheral blood stem cell collection is safe but requires many periprocedural preparations.
Introduction
Autologous stem cell transplant can be a curative therapy to restore normal hematopoiesis after myeloablative treatments in patients with lymphocytic malignancies, such as multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and other malignancies. Mobilized hematopoietic stem/progenitor cells (HSPCs) collected by apheresis are the predominant source of stem cells for autologous and allogeneic transplant because of their higher yield and the decreased procedural risk compared with bone marrow (BM) harvest. Patients who have had many cycles of high-dose chemotherapy and/or radiation may have a significantly reduced BM reserve and a poor autologous yield after attempted stem cell mobilization and collection. Owing to the toxicity of prolonged chemotherapy exposure, alternative mobilization agents, and algorithms have been explored continuously for improvement.
The clinical practice of HSPC mobilization and collection requires real-time and frequent communication between the clinical transplant team, the apheresis service, and the cellular therapy/stem cell laboratory. These optimized interactions are essential to the success of graft collection for patients who await hematopoietic rescue. There have been several published review articles addressing various aspects of HSPC mobilization. However, very few integrate solutions to the logistical and communication issues between the different services that allow for optimal patient management.
In this article, we review the safety, efficacy, and cost, as well as recent improvements in HSPC mobilization and collection. Finally, we address some of the practical concerns during the coordination of care between the clinical transplant team, the apheresis service and the cellular therapy laboratory. Although the practice continues to evolve, HSPC mobilization for allogeneic donors tends to have less mobilization failure given the allogeneic donor’s healthier status and BM reserve compared with diseased autologous donors. There have been several reviews published on the topic of allogeneic mobilization, and this review focuses on adult autologous donors, with an occasional reference to allogeneic donors when appropriate.
Introduction
Autologous stem cell transplant can be a curative therapy to restore normal hematopoiesis after myeloablative treatments in patients with lymphocytic malignancies, such as multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and other malignancies. Mobilized hematopoietic stem/progenitor cells (HSPCs) collected by apheresis are the predominant source of stem cells for autologous and allogeneic transplant because of their higher yield and the decreased procedural risk compared with bone marrow (BM) harvest. Patients who have had many cycles of high-dose chemotherapy and/or radiation may have a significantly reduced BM reserve and a poor autologous yield after attempted stem cell mobilization and collection. Owing to the toxicity of prolonged chemotherapy exposure, alternative mobilization agents, and algorithms have been explored continuously for improvement.
The clinical practice of HSPC mobilization and collection requires real-time and frequent communication between the clinical transplant team, the apheresis service, and the cellular therapy/stem cell laboratory. These optimized interactions are essential to the success of graft collection for patients who await hematopoietic rescue. There have been several published review articles addressing various aspects of HSPC mobilization. However, very few integrate solutions to the logistical and communication issues between the different services that allow for optimal patient management.
In this article, we review the safety, efficacy, and cost, as well as recent improvements in HSPC mobilization and collection. Finally, we address some of the practical concerns during the coordination of care between the clinical transplant team, the apheresis service and the cellular therapy laboratory. Although the practice continues to evolve, HSPC mobilization for allogeneic donors tends to have less mobilization failure given the allogeneic donor’s healthier status and BM reserve compared with diseased autologous donors. There have been several reviews published on the topic of allogeneic mobilization, and this review focuses on adult autologous donors, with an occasional reference to allogeneic donors when appropriate.
Discovery of the hematopoietic stem cell niche and clinical translation
Since hematopoietic transplantation was established in the 1960s, the intricate cellular mechanisms and interactions of HSPCs and their BM microenvironment or “niche” have been investigated extensively. Studies have shown that the BM niche plays an essential role in determining the ultimate fate of the HSPCs, including cellular trafficking, differentiation, and self-renewal. The main cell types comprising the niche are mesenchymal stem cells, osteoblasts, perivascular stromal cells, and endothelial cells. Various ligands expressed on the surface of or secreted from the niche cells dynamically interact with their cognate receptors on the HSPCs. This highly organized, direct cellular engagement is mediated by a sophisticated lipid raft formation that permits the proximity of signaling molecules to transduce intracellular signals ( Fig. 1 ). The formation and disassembly of the lipid raft result in HSPC BM retention and mobilization, respectively. Molecular analyses of these interactions have translated into the rapid development of drugs that are used clinically to mobilize BM HSPCs into peripheral circulation, which allows collections by apheresis.
Clinical hematopoietic stem/progenitor cell mobilization
Quiescent repopulating HSPCs are often tethered to osteoblasts, other stromal cells, and the extracellular matrix in the stem cell niche through a variety of adhesive molecule interactions. Disruption of niche interactions using cytotoxic agents, hematopoietic growth factors, small-molecule chemokine analogs, or even recombinant monoclonal antibodies can lead to release of HSPCs from the BM into the PB. In 2010, Sheppard and colleagues published a systematic review on 28 published randomized, controlled trials evaluating HSPC mobilization/collection strategies. The consensus was that mobilization improvement often comes with increased toxicity; therefore, the selection of a mobilization regimen should be considered and determined based on clinical resources and patient-specific factors. Since 2010, additional published algorithms have addressed some of those considerations ( Table 1 ).
| Published Strategies | Intervention Algorithm | Outcomes |
|---|---|---|
| Jantunen et al, 2012 | Addition of plerixafor when PB CD34 <10/μL and WBC >5000/μL on day 5 (sensitivity 97%; specificity 100%) | Improved success in reaching standard collection goal a |
| Douglas et al, 2012 | The use of plerixafor as single mobilization agent in adults with multiple myeloma and dialysis-dependent renal injury | Improved success in reaching standard collection goal a |
| Lefrere et al, 2013 | Early monitoring of plerixafor-mobilized PB CD34 (3–5 h after infusion), in donors with prior mobilization failure | Increased leukapheresis eligibility and collection success |
| Storch et al, 2015 | Addition of plerixafor for day 4 PB CD34 <10/μL | Reduced leukapheresis operational burden and faster completion of collection |
| Gutensohn et al, 2010 | Initiation of daily PB CD34 monitoring on day 3 of mobilization to determine optimal leukapheresis timing | Reduced G-CSF administration, number of procedures, cost, and time |
| Duong et al, 2011 | Addition of plerixafor when the first collection yield is <0.7 × 10 6 CD34 + cells/kg body weight | Reduced mobilization/collection failure |
| Horwitz et al, 2012 | Use of plerixafor on day 5 for poor G-CSF mobilizers, determined by day-5 PB CD34 of <7/μL | Improved success in reaching standard collection goal a |
a Standard collection goal: 2 to 5 × 10 6 CD34 + cells/kg body weight.
Chemotherapy Mobilization
It was discovered in the early 1990s that HSPC concentration increased 5- to 15-fold during the postcyclophosphamide (CY) recovery period and that the increase is affected by chemotherapy dosage, longer treatment-free period because prior chemotherapy, and by a higher colony forming unit–granulocyte macrophage level. CY is currently the chemotherapy of choice to mobilize HSPCs in autologous patients. High-dose CY chemotherapy in MM patients showed a significant improvement in clinical outcomes. Although higher CY dosage in combination with granulocyte–colony stimulating factor (G-CSF) results in a higher PB CD34 + concentration, the enhanced mobilization effect plateaus and has more frequent adverse events, such as neutropenic fever, blood transfusion, and longer hospitalization. Owing to the unfavorable toxicity profile, the safety and efficacy of alternative mobilization agents were explored.
Colony-Stimulating Factors
There are two hematopoietic growth factors approved by the US Food and Drug Administration (FDA) for the mobilization of stem cells: G-CSF and granulocyte–macrophage colony-stimulating factor (GM-CSF).
Granulocyte-colony stimulating factor (filgrastim)
G-CSF is the first-line treatment for HSPC mobilization and has been shown to reduce neutropenia-related infection and enhance posttransplant myeloid recovery. The exact mechanism of G-CSF based mobilization has been intensively investigated, but is still not fully understood. At the molecular level, G-CSF is thought to indirectly destabilize the HSPCs retention in BM by disrupting the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif receptor 4 (CXCR4) axis and increasing the release of proteolytic enzymes (neutrophil elastase and cathepsin G). It has been proposed that G-CSF disrupts the BM niche by attenuating endosteal osteoblasts, modulating intramedullary macrophages, and disrupting the local CXCL12 gradient. The usual administration of G-CSF for HSPC mobilization is subcutaneous injection of 10 μg kg −1 day −1 with HSPC collection on day 4 or 5. In the autologous mobilization setting after chemotherapy, the G-CSF is well-tolerated given that these patients are usually pancytopenic at baseline. However, rare severe side effects such as leukostasis and splenic rupture have been reported. An additional concern for G-CSF mobilization in the autologous donor is the contamination of BM tumor cells in the autologous graft product.
Modified filgrastim
Polyethylene glycol-conjugated G-CSF (pegfilgrastim) has captured increasing attention owing to its longer half-life and its ability to achieve a more predictable circulating CD34 concentration. In the setting of autologous transplantation, it only requires a single dose that is independent of donor weight. Therefore, although pegfilgrastim is more expensive than G-CSF per dose, the appropriate use of pegfilgrastim can be more cost effective than G-CSF. However, a comprehensive cost analysis is still required. A recent metaanalysis concluded that pegfilgrastim mobilization is associated with a significantly shorter time to onset of collection and less required leukapheresis procedures. Filgrastim and pegfilgrastim share a similar toxicity profile, and thus pegfilgrastim could be a convenient alternative to G-CSF for mobilizing HSPC. However, it is currently not approved by the FDA for the purpose of HSPC mobilization.
Lenograstim is a glycosylated form of G-CSF that shows comparable mobilization efficacy with reduced dosage compared with the traditional G-CSF. An additional study showed that pegfilgrastim reduced neutropenic fever to a greater extent than filgrastim and lenograstim. Small comparative randomized controlled trials that examined the potency of HSPC mobilization by filgrastim and lenograstim have demonstrated comparable mobilization efficacy to filgrastim.
The efficiency of various forms of G-CSF was directly compared and showed that lenograstim (10 μg kg −1 day −1 ) had significantly higher CD34 + collection yield than filgrastim or pegfilgrastim. However, additional clinical trials evaluating the potency, efficacy, and safety of lenograstim are still needed. Similar to pegfilgrastim, lenograstim has not yet obtained FDA approval for mobilizing HSPC clinically.
Biosimilar granulocyte-colony stimulating factor
To decrease pricing and foster innovative competition, the FDA has created an expedited licensure pathway for the development of biologics that possess similar potency, efficacy, and safety to a reference-approved biologic. However, these biosimilars are not automatically approved for the claimed indication to the reference product. Since the patent expiration of filgrastim (Neupogen) in 2006, several G-CSF biosimilars known as Ratiograstim/Tevagrastim, Nivestim, Zarxio/Filgrastim-sndz, and Grastofil have entered into clinical trials for the purpose of obtaining approvals from the European Medicine Agency and the FDA. One of the major benefits to using these G-CSF biosimilars is the low cost.
Nivestim, one of the G-CSF biosimilars, has recently shown a mild but significant decrease in the number of leukapheresis procedures for autologous donors. In a cohort of 51 patients, Nivestim-induced mobilization shared a similar toxicity profile to the reference filgrastim arm; however, the Nivestim-mobilized graft was associated with a 2-day delay in platelet engraftment. Several completed clinical trials demonstrate that the G-CSF biosimilars have comparable efficacy and safety for HSPC mobilization in both autologous and allogeneic donors. In March 2015, Zarxio became the first G-CSF biosimilar approved by the FDA for the same indications as filgrastim (Neupogen), including mobilization of autologous hematopoietic progenitor cell (HPC) for collection. However, a long-term safety evaluation of the biosimilars is still needed.
Granulocyte-macrophage colony-stimulating factor (sargramostim)
Similar to G-CSF, GM-CSF is a growth factor approved by the FDA to hasten myeloid recovery in patients with treatment-related neutropenia. It was noted that GM-CSF could also mobilize HSPCs into the PB. When directly compared with G-CSF, GM-CSF is less efficacious in mobilizing HSPCs with or without chemotherapy. When compared with G-CSF, GM-CSF mobilized grafts lead to slower neutrophil engraftment but faster platelet recovery. GM-CSF could further enhance G-CSF–mediated HSPC mobilization in autologous donors after chemotherapy. However, the synergism is not significantly better than the mobilization by G-CSF alone. Thus, it is considered a salvage mobilization regimen in patients who have failed G-CSF mobilization.
Small Molecule Chemokine Analogs and Monoclonal Antibodies
Plerixafor
Plerixafor (also known as AMD3100) is a small bicyclam molecule that reversibly antagonizes the CXCR4 receptor, leading to disruption of CXCL12-CXCR4–supported HSPC retention. Before plerixafor’s FDA approval in 2008 as a mobilizing agent, two large phase III randomized controlled trials were conducted by DiPersio and colleagues that showed a significant increase in circulating CD34 + cells and the graft collection yield mobilized by plerixafor versus placebo and concurrent G-CSF. In addition, comparable engraftment outcomes and adverse events were observed during these trials in both NHL and MM patient cohorts. Plerixafor is generally well-tolerated with rare severe side effects, such as hypotension, dizziness, and thrombocytopenia. The most commonly observed adverse reactions were diarrhea, nausea, and skin erythema at the injection site.
The use of plerixafor has been shown to be helpful in facilitating mobilization in autologous donors that have had repetitive intense systemic chemotherapy, lenalidomide treatment, or worsening disease. Although plerixafor with G-CSF is superior to and comparably safer than G-CSF alone, Devine and colleagues have examined mobilization potency and transplantation outcomes using a mobilization regimen with plerixafor alone versus G-CSF alone. Although plerixafor alone led to an eight-fold increase in PB CD34 count, 5-day G-CSF mobilization has a significantly greater increase in PB CD34 mobilization (>15-fold increase from baseline). Interestingly, the plerixafor mobilized graft contained a lower CD34 content with more mobilized lymphocytes, but resulted in similar engraftment outcomes compared with the G-CSF mobilized graft. In addition, plerixafor plus G-CSF was recently reported to increase the mobilization of HSPCs with greater repopulating potential (CD34 + CD133 + CD38 − ) in autologous donors with MM and NHL. These findings collectively support the idea that variable mechanisms for disrupting BM niches could differentially liberate different HSPC populations from their specific niches into the circulation.
Stem cell factor (ancestim)
Stem cell factor (SCF), also known as c-kit ligand, is another hematopoietic growth factor produced by perivascular stromal progenitors and endothelial cells. Similar to CXCL12, SCF also has differential splicing protein variants present as soluble or membrane-bound proteins. Upon binding to its cognate receptor, membrane-bound SCF could further upregulate the expression of the very late antigen-4 adhesion molecule that tethers HSPCs to the BM niche. However, the soluble SCF could differentially inhibit this engagement, resulting in the liberation of HSPCs. Ancestim, the recombinant form of human SCF, when used with G-CSF, increases the CD34 + cell yield in poor mobilizers. The most recent published clinical study in 2011 was led by Lapierre and colleagues, which included more than 500 patients with various hematologic malignancies. The administration of ancestim for mobilization has been shown to lead to a 31% success rate in collecting 2 × 10 6 CD34 kg −1 body weight in patients who previously failed mobilization; however, it is also associated with significant reactions, including allergic reactions owing to mast cell degranulation. Johnsen and colleagues have conducted the first randomized, controlled trial comparing the effect of Ancestim with conventional chemotherapy in conjunction with G-CSF. The study showed that although ancestim reduced chemotherapy toxicity, it was also associated with reduced CD34 + HSPC product yield. Currently, ancestim is only approved in Canada and New Zealand. It is not available in the United States.
Recombinant very late antigen-4 (VLA-4) antagonist
Natalizumab is a recombinant humanized anti-VLA-4 monoclonal antibody approved for Crohn’s disease and multiple sclerosis; however, it has also been shown to enhance peripheral HSPC mobilization. No clinical trials have been conducted using this VLA-4 inhibitor antibody for HSPC mobilization.
Clinical approaches in collecting mobilized hematopoietic stem/progenitor cells
An apheresis procedure is used to collect HSPCs. Leukapheresis selectively removes the mononuclear buffy coat layer to harvest the HSPCs. The goal of stem cell collection is to achieve maximum efficiency by reaching the goal for CD34 + cells collected in the minimum number of apheresis procedures. Efficient HSPC collection is critical owing to the high cost of each leukapheresis procedure and the risk to patients during the procedure. Several clinical trials have established that a minimum of 2 × 10 6 CD34 + cells kg −1 body weight is needed for successful engraftment. However, for autologous stem cell transplantation, 5 to 10 × 10 6 CD34 + cells kg −1 body weight is desirable for faster engraftment (neutrophil and platelet) and less resource utilization. To achieve the ideal collection goal in a cost-balanced manner, many groups have proposed various strategies using laboratory data to optimize collection efficiency. Successful collection algorithms depend on optimized mobilization methods, optimal timing of collection using predictive assays, and an efficient leukapheresis procedure. Although many studies have reported successful improvements in collection efficiency, no randomized controlled trials have directly compared the available algorithms.
Predicting Successful Collection
The first challenge during stem cell collection is to determine the ideal time to collect the patient. Certain donor-related variables may impact the ability to achieve the HSPCs collection goal, such as donor age, previous chemotherapy, mobilization regimen, and platelet count at the time of mobilization. Thus each patient needs to be closely monitored to determine the optimal timing for collection. Generally, three approaches have been taken to determine donor readiness for collection: (1) monitoring the white blood cell (WBC) count, (2) PB CD34 count, or (3) HPC enumeration using a Sysmex hematology analyzer. Over time, many comparative studies have been performed to search for the best parameter to predict the success of reaching the collection goal. With the advancement of technology and establishment of assay standardization, preharvest PB CD34 evaluation seems to be the most consistent predictor for yield and successful collection. In addition, the use of PB CD34 can significantly avoid the cost of unnecessary apheresis procedures and product processing. However, different platforms for determining the optimal time for collection all have advantages and disadvantages ( Table 2 ). In general, the optimal timing of apheresis is generally after 5 days of daily G-CSF administration. CD34 + cells tend to begin to increase in the PB by day 4 with a peak on day 5, and generally tend to decrease after day 5. Thus, optimizing the timing of the procedure is critical. The timing of the collection after chemotherapy mobilization depends on the chemotherapy regimen.
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