Mobilization of Hematopoietic Stem Cells for Use in Autologous Transplantation

Hollie Devine, MSN, RN, CNP, D. Kathryn Tierney, RN, PhD, Kim Schmit-Pokorny, RN, MSN, OCN®, and Kathleen McDermott, RN, BSN, OCN®

Autologous hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic approach for various malignant hematologic and lymphoid diseases. Hematopoietic stem cells (HSCs) may be collected from the blood or the bone marrow. HSCs are capable of self-renewal and give rise to progenitor cells, multipotent cells that differentiate and proliferate into the mature cells of the blood and immune system. HSCs and progenitor cells are released from the bone marrow into the peripheral blood through a process called mobilization. HSCs then are collected from the blood in a process called apheresis and cryopreserved for administration following the high-dose preparative regimen. This article reviews stem cell biology, current mobilization strategies, use of novel mobilization agents, and nursing care of patients during the mobilization phase of autologous HSCT. Understanding the biology and process of HSC mobilization is critical for transplantation nurses to deliver and coordinate care during this complex phase of autologous HSCT.

utologous hematopoietic stem cell transplantation (HSCT) is a therapeutic approach that is potentially At a Glance curative for a number of malignant hematologic  Mobilization of hematopoietic stem cells (HSCs) from the bone and lymphoid diseases. The three types of HSCT marrow into the peripheral blood is a multistep process involv- are allogeneic, autologous, and syngeneic. In allo- ing the interplay among chemokines, cytokines, cell adhesion geneicA transplantation, the hematopoietic stem cells (HSCs) molecules, and the bone marrow microenvironment. are obtained from a human leukocyte antigen–matched sibling,  The goal of stem cell collection is to mobilize a sufficient an unrelated volunteer donor, or cyropreserved umbilical cord number of HSCs that are capable of regenerating the full blood. In autologous HSCT, the HSCs are collected from the hematopoietic lineages and to achieve adequate engraftment bone marrow or the blood of the patient when the cancer is following autologous HSC transplantation. in remission or a state of minimal residual disease. The third type of HCT is a syngeneic transplantation, where the source  Nurses need to understand stem cell biology and the mecha- of the graft is an identical twin. Peripheral blood HSCs have nisms of action of current mobilization strategies. largely replaced the use of bone marrow as the graft source for autologous HSCT. The benefits of using HSCs collected from mobilization techniques will be reviewed, including the use the blood compared to HSCs collected from the bone marrow of novel mobilization agents. The collection, processing, and include a shorter period of neutropenia, which translates into cryopreservation of HSCs will be outlined. reduced use of antibiotics, decreased risk of infection, shorter hospitalization, and reduced costs (Schmitz et al., 1996; Smith et al., 1997). Hollie Devine, MSN, RN, CNP, is an adult nurse practitioner and educator The focus of this article is the mobilization of HSCs for use for advanced practice nurses and physician assistants in the James Can- in autologous HSCT. The term mobilization is used to describe cer Hospital at the Ohio State University Medical Center in Columbus; the process by which HSCs are released from the bone marrow D. Kathryn Tierney, RN, PhD, is an oncology clinical nurse specialist at into the blood. The biology of HSCs and the mechanisms by Stanford University Medical Center in California; Kim Schmit-Pokorny, which HSCs remain in the bone marrow microenvironment or RN, MSN, OCN®, is a transplant manager at the University of Nebraska are released into the blood will be reviewed. To date, the two Medical Center in Omaha; and Kathleen McDermott, RN, BSN, OCN®, is principle means of mobilization are the use of cytokines alone a clinical research nurse at the Dana-Farber Cancer Institute in Boston, or the use of cytokines in combination with chemotherapy. MA. (First submission August 2009. Revision submitted September 2009. These mobilization strategies will be described. Strategies for Accepted for publication October 8, 2009.) individuals who do not collect a sufficient graft with current Digital Object Identifier: 10.1188/10.CJON.212-222

212 April 2010 • Volume 14, Number 2 • Clinical Journal of Oncology Nursing Stem Cell Biology As HSCs mature, they expresses specific combinations of cell surface proteins that serve as biochemical markers. These bio- The Hematopoietic System chemical markers identify the evolutionary stage of the blood cell, dictate the next steps in cell maturation, and serve as regulatory Hematopoiesis is a cell-renewal process that leads to the signals (Scholossman et al., 1997; Zola et al., 2005; Zola, Swart, constant manufacturing of functional differentiated blood cells Boumsell, & Mason, 2003; Zola, Swart, Nicholson, & Voss, 2007). from HSCs and progenitor cells (Lataillade, Domenech, & Le Flow cytometry through the use of fluorescent-labeled antibodies Bousse-Kerdiles, 2004). HSCs are cells that can differentiate into is a technique for analyzing multiple markers of individual cells. functional mature blood cells while maintaining an indefinite The cluster of differention or cluster of designation (CD) system capacity for self-renewal. HSCs have three general properties: is the nomenclature used to classify and analyze cell surface mol- they are capable of self-renewing, they are unspecialized, and ecules present on leukocytes. The CD marker is used to associate they give rise to specialized cells. HSCs are vital in that they as- cells with certain immune functions and properties (Scholoss- sist in regenerating cells damaged by disease, injury, and daily man et al., 1997; Zola et al., 2003, 2005, 2007). CD34 is a marker use (Stem Cell Information, 2006). A progenitor cell is a dividing of HSCs and is used clinically to separate HSCs from other types cell with capacity to differentiate. The developmental pathway of leukocytes (see Figure 2). As HSCs differentiate, they lose the of HSCs into functional blood cells involves loss of the poten- CD34 marker and acquire other biochemical markers specific to tial to proliferate, with progressive differentiation into specific a lineage. T cells will acquire CD4 or CD8 surface markers and B blood elements with defined functions. These fully differentiat- cells will acquire surface immunoglobulin markers and antigen- ed blood cells have finite life spans, requiring constant renewal specific receptors (Manz et al., 2004). Table 2 summarizes the from the HSC pool (Manz, Akashi, & Weissman, 2004). biochemical markers of the various blood cells. In the bone marrow microenvironment, stem cells may The biology of HSC mobilization is a complex process. For remain quiescent for long periods of time until they are acti- successful proliferation of later-stage myeloid and lymphoid vated for the purpose of homeostasis or tissue repair (Manz et cells to occur, the hematopoietic system needs several factors: a al., 2004). Inside the bone marrow reside long-term HSCs that consortium of HSCs, hematopoietic growth factors to stimulate have the capacity for self-renewal (see Figure 1). A subset of proliferation, and stromal cell interactions between HSCs and these long-term HSCs will differentiate into short-term HSCs, progenitor cells. which give rise to multipotent progenitors of either the myeloid or lymphoid cell lineages. The common lymphoid progenitor differentiates into precursors of the B and T lymphocyte and Bone Marrow Microenvironment natural killer lineages. The common myeloid progenitor gives Inside the bone marrow is a multifunctional network of cells rise to two types of progenitors; the granulocyte-monocyte and extracellular matrix that maintain HSC proliferation, differ- progenitor and a megakaryocyte-erythrocyte progenitor. The entiation, and survival. This network of cells and extracellular granulocyte-monocyte progenitor produces the granulocyte lin- matrix are known as the bone marrow microenvironment (see eages (which produce neutrophils, basophils, and eosinophils), Figure 3). Stromal cells are the layers of cells that support the the monocyte-macrophage lineages, and the dendritic cell lin- infrastructure of the bone marrow. Stromal cells assist in the eages. The megakaryocyte-erythrocyte progenitor produces the regulation of HSCs and are important cells for providing dif- erythroid-lineage cells and megakaryocytes (Manz et al., 2004). ferentiation signals to HSCs. Additionally, stromal cells direct Table 1 describes the function of each blood cell. the movement of HSCs out of the bone marrow and into the peripheral circulation (Lataillade et al., 2004). Stromal cells produce stromal-cell derived factor- CLP 1a (SDF-1a), a chemokine widely expressed by Pro-T T many tissues such as the ectoderm, endoderm, B Pro-B mesoderm, and mesenchymal cells (McGrath, NK LT-HSC ST-HSC MPP GMP Koniski, Maltby, McGann, & Palis, 1999). SDF-1a Granulocytes is a signaling molecule involved in the prolif- Monocytes eration, homing, and engraftment of HSCs and Dendritic cells CMP MEP leukocytes. Erythrocytes Platelets Mechanisms of Mobilization CLP—common lymphoid progenitor; CMP—common myeloid progenitor; GMP— In addition to HSCs and stromal cells, mobili- granulocyte-monocyte progenitor; LT-HSC—long-term hematopoietic stem cell; MEP— zation of HSCs from the bone marrow into the megakaryocyte-erythrocyte progenitor; MPP—multipotent progenitor; NK—natural killer; peripheral blood is a multistep process involving ST-HSC—short-term hematopoietic stem cell interplay between chemokines, cytokines, and cell adhesion molecules (CAMs). Chemokines Figure 1. The Hematopoietic System are small proteins that regulate cellular move- Note. From “Biology of Hematopoietic Stem and Progenitor Cells” (p. 79), by M. Manz, K. ment (Laing & Secombes, 2004). Chemokines are Akashi, & I. Weissman in F.R. Applebaum, S.J. Forman, R.S. Negrin, & K.G. Blume (Eds.), Thomas’ produced by hematopoietic and non-hematopoi- Hematopoietic Cell Transplantation (3rd ed.), 2004, Malden, MA: Blackwell. Copyright 2004 etic cells, including leukocytes, platelets, stromal by Wiley-Blackwell. Adapted with permission. cells, the gastrointestional tract, ovary, prostate,

Clinical Journal of Oncology Nursing • Volume 14, Number 2 • Mobilization of Stem Cells for Use in Autologous Transplantation 213 toward a local gradient of SDF-1a. The Table 1. Blood Cell Functions final anchoring of HSCs within the Lineage Progenitor Blood Cell Function bone marrow microenvironment is maintained by the continuous produc- Lymphoid Common T lymphocytes Participate in delayed-type hypersensitivity, di- tion of SDF-1a by stromal cells. The lymphoid rectly kill infected cells, and assist with B cell function loss of attachment to the stromal cells along with the loss of SDF-1a activity Lymphoid Common B lymphocytes Synthesize and secrete immunoglobulins and releases HSCs into the peripheral cir- lymphoid become plasma cells culation (Lataillade et al., 2004). Lymphoid Common Natural killer Kill selected tumor cells without having to be acti- Cytokines also have an integral role lymphoid vated or immunized against a tumor cell; partici- in HSC trafficking, including both the pate in early host defenses against intracellular proliferation and expansion of HSCs. organisms and against viral infections Granulocyte–colony-stimulating fac- Myeloid Granulocyte- Granulocytes Produce neutrophils, basophils, and eosinophils tor (G-CSF) allows for the release of monocyte Monocytes Assist in the facilitation of monocytes leaving the HSCs from the bone marrow through blood and entering tissues, thus turning into secondary interactions with stromal macrophages cells, chemokine receptor interac- Dendritic cells Involved in antigen processing and presentation to T cells of the immune system tions, and the degradation of integrins (Lapidot & Petit, 2002). The release Myeloid Megakaryocyte- Megakaryocytes Fragment to form platelets just before release into of proteases cleave vascular cell ad- erythrocyte the circulation, assisting with coagulation hesion molecule-1 and very late anti- Erythrocytes Tissue nourishment, oxygenation, and blood gen-4, which are CAMs expressed on viscosity stromal cells. In steady state, CAMs Note. Based on information from Anderson, 1999; Mamula, 1999. bind to SDF-1a, anchoring HSCs to the stromal cells within the bone marrow. Administration of G-CSF degrades vas- thymus, heart, and spleen (Broxmeyer & Kim, 1999). Chemo- cular cell adhesion molecule-1, resulting in the release of HSCs kines induce the migration of cells to sites of infection or injury, into circulation (Lapidot & Petit, 2002). activate an immune response, stimulate wound healing, and Another mechanism by which stem cell mobilization occurs direct the movement of myeloid progenitor cells (Broxmeyer & is through chemokine antagonists. Chemokine antagonists Kim, 1999; Laing & Secombes, 2004). (AMD3100) block the CXCR4 receptor located on the surface Cytokines are intracellular signaling proteins that have au- of each HSC. By blocking the CXCR4 receptor, inhibition of the tocrine, paracrine, and endocrine functions (Cannon, 2000). binding of SDF-1a occurs, allowing HSCs to be released from the Their role is to facilitate communications among immune bone marrow and into the circulating blood. system cells. Cytokines function locally or at a distance to en- hance immunity; act by binding to their cell-specific receptors, which are located on the cell membrane; and regulate the in- Current Mobilization Strategies nate immune system (i.e., natural killer cells, macrophages, and neutrophils). They also regulate the adaptive immune system As previously described, mobilization is a method of stimu- and T- and B-cell immune responses (Anderson, 1999). Other lating HSCs that originate in the bone marrow to increase cytokine functions include inflammatory reactions, wound heal- in number and move into the peripheral blood. The goals of ing, and formation of blood cells. mobilization are to move a sufficient number of HSCs that are Multiple chemokines may bind to a single receptor whereas capable of regenerating the full hematopoietic lineages and to cytokines are activated by interactions with a unique and achieve adequate engraftment following autologous HSCT. Ad- specific ligand (Lataillade et al., 2004). CXCR4 is a chemokine equate engraftment generally is defined as achieving an absolute receptor that is expressed on dendritic, endothelial, neural cells neutrophil count greater than 0.5 x 109/L in 10–12 days and a and on mature blood cells (Lataillade et al., 2004). HSCs express platelet count greater than 20 x 109/L in 15–30 days. An ideal CXCR4 for a given time in their development. When binding of mobilization regimen results in the collection of sufficient HSCs CXCR4 to SDF-1a occurs, activation of integrins and CAMs direct leading to rapid and durable engraftment, a low toxicity profile, the movement of HSCs along the stromal cell membrane (Latail- and a minimal number of apheresis procedures (Pusic et al., lade et al., 2004). Integrins are receptors for cell adhesion to 2008). The collection goal is based on a predetermined number extracellular matrix proteins and play an important role in cell- of CD34+ cells/kg of body weight. A minimum of 2 x 106 CD34+ to-cell adhesion. Integrins and their ligands are instrumental cells/kg is a collection goal cited often in the literature (Koc et in cell development, immune responses, leukocyte trafficking, al., 2000; Pusic et al., 2008). A higher number of CD34 cells and homeostasis (Hynes, 2002). CAMs are glycoproteins present present in the graft correlates with more rapid engraftment of on the external surface of the cell membrane. They recognize both neutrophils and platelets (Bensinger et al., 1995; Pusic et and interact either with other CAMs on adjacent cells or with al., 2008; Vogel et al., 1998). Current mobilization strategies proteins of the extracellular matrix. The adhesion of CXCR4 to include the use of cytokines alone or cytokines combined with SDF-1a induces the arrest of HSCs, allowing HSCs to migrate myelosuppressive chemotherapy.

214 April 2010 • Volume 14, Number 2 • Clinical Journal of Oncology Nursing agents used for mobilization include cyclophosphamide, etopo- Stem cells: clonal precursors Progenitor cells: multipotent side, paclitaxel, and cytarabine (Bensinger et al., 2009; Tarella et capable of self-renewal and precursors with no capacity for production of a defined set of self-renewal, which differentiate al., 2002). In some cases, disease-specific chemotherapy, such differentiated progenitors and proliferate according to their as DHAP (etoposide, cytosine arabinoside, methylprednisolone, pre-programmed destiny and cisplatin) in patients with lymphoma, may be combined CD34+ with G-CSF for mobilization. One of the first observations that HSCs increased in the pe- CMP: common myeloid progenitor ripheral blood after chemotherapy administration was reported by Richman, Weiner, and Yankee (1976). Following administra- CLP: common lymphoid progenitor tion of myelosuppressive chemotherapy, a proliferation occurs of both HSCs and progenitor cells in the bone marrow, resulting MEP: megakaryocyte-erythrocyte in some of these cells migrating into the circulation (Ng-Cashin, No expression of progenitor 2004). The number of HSCs and progenitor cells released into differentiation markers the peripheral blood after chemotherapy can be enhanced by the addition of cytokines. Figure 2. Properties of Hematopoietic Stem Cells An early study on the use of cyclophosphamide to mobilize Note. From “Biology of Hematopoietic Stem and Progenitor Cells” (p. 79), HSCs reported a 14-fold increase in CFU-GM about 17 days fol- by M. Manz, K. Akashi, & I. Weissman in F.R. Applebaum, S.J. Forman, R.S. lowing cyclophosphamide administration (To et al., 1990). Since Negrin, & K.G. Blume (Eds.), Thomas’ Hematopoietic Cell Transplanta- the publication of To et al. (1990), numerous studies have ex- tion (3rd ed.), 2004, Malden, MA: Blackwell. Copyright 2004 by Wiley- amined different combinations of chemotherapy and cytokines, Blackwell. Adapted with permission. different doses of either the chemotherapy or the cytokines, and different schedules of chemotherapy and cytokines. Table 3 shows results from several trials. The use of myelosuppressive Cytokines for Mobilization chemotherapy in combination with a cytokine for mobilization Two U.S. Food and Drug Administration (FDA)-approved has been shown to result in improved CD34+ cell yields over cy- cytokines for mobilization are G-CSF (filgrastim) and granulo- tokines alone (Bensinger et al., 1995, 2009; Pusic et al., 2008). cyte macrophage–colony-stimulating factor (GM-CSF) (sargra- Other benefits of the combination of chemotherapy and cy- mostim). To date, G-CSF is the cytokine most commonly used tokines may be a reduced number of apheresis procedures and for mobilization (Bensinger, DiPersio, & McCarty, 2009). One more rapid engraftment related to a higher number of CD34+ of the earliest studies to assess the effect of GM-CSF on the cells collected. In turn, more rapid engraftment can reduce number of HSCs in the peripheral blood was reported by Socin- the length of hospitalization, reduce the risk of infection, and ski et al. (1988). The authors concluded that administration of reduce the number of transfusions. Another potential benefit GM-CSF with or without chemotherapy increased the number of may be a reduced risk of tumor cell contamination of the graft; colony–forming unit-granulocyte macrophage (CFU-GM) in pe- however, whether this translates into a reduced risk of relapse ripheral blood and may facilitate the collection of HSCs for use has been debated (Bensinger et al., 2009). in autologous HSCT. In the time since Socinski et al. (1988) was Several disadvantages exist when chemotherapy is added to published, many studies have explored the use of cytokines for the mobilization regimen. One possible disadvantage is the need HSC mobilization. In aggregate, these studies have shown that for hospitalization to administer the chemotherapy. Secondly, both G-CSF and GM-CSF facilitate adequate collections of HSCs the patient is exposed to the side effects and toxicities associ- for use in autologous HSCT in the majority of patients (Bishop ated with the chemotherapeutic agent. Of significant concern et al., 1994; Nademanee et al., 1994; Weaver et al., 2000). G-CSF is the subsequent period of neutropenia and the associated risk alone as a mobilization agent yields better CD34+ cell collec- of infection. One study reported that 30% of patients mobilized tions than GM-CSF alone (Gazitt, 2002; Weaver et al., 2000). G-CSF is administered as a subcutaneous injection, and patients can be taught self-administration. A typical regimen is to Table 2. Cluster of Designation (CD) Markers administer the G-CSF for four days and begin apheresis on the of Blood Cells fifth day of G-CSF (Pusic et al., 2008). Administration of G-CSF continues until the desired CD34+ cell dose is collected. Type of cell CD Markers Limitations exist to mobilization of HSCs with cytokines. All leukocyte groups CD45+ Common side effects include bone pain, fever, and malaise. Less B lymphocyte CD45+, CD19+ or CD45+, CD20+ commonly noted side effects include chills, headache, nausea, Cytotoxic T cell CD45+, CD3+, CD8+ vomiting, diarrhea, edema, rash, dyspnea, pleural or pericardial Granulocyte CD45+, CD15+ effusion, and nasal congestion (Schmit-Pokorny, 2004). Rare Monocyte CD45+, CD14+ side effects that have been reported include splenic rupture and Natural killer CD16+, CD56+, CD3– Stem cell CD34+, CD31– pneumothorax (Becker et al., 1997). T helper cell CD45+, CD3+, CD4+ T lymphocyte CD45+, CD3+ Chemotherapy and Cytokines Thrombocyte CD45+, CD61+ A second strategy for mobilizing HSCs is to combine myelo- Note. Based on information from Zola et al., 2007. suppressive chemotherapy with a cytokine. Chemotherapy

Clinical Journal of Oncology Nursing • Volume 14, Number 2 • Mobilization of Stem Cells for Use in Autologous Transplantation 215 with chemotherapy plus cytokine were hospitalized for neutropenic fever, 39% required transfusions of red blood cells, and CD34+ Peripheral blood 30% required transfusions of platelets (Koc et al., 2000). The variability in the time to CXCR4 receptor the recovery of the white blood cells following myelosuppressive chemotherapy leads Solid bone to challenges in scheduling apheresis. Chemotaxis The current mobilization strategies, cy- and homing Mobilization tokines alone or cytokines combined with myelosuppressive chemotherapy, have ad- vantages and disadvantages. One disad- SDF-1 keeping CD34+ CD34+ vantage of both mobilization strategies cells in the bone Adhesion migration Chemokine is the risk of an insufficient collection of Bone marrow marrow antagonist HSCs to proceed to autologous HSCT. In one retrospective review of 1,040 patients who received either G-CSF alone or G-CSF Solid bone Stromal cell/osteoblast in combination with myelosuppressive chemotherapy, about 19% in each group Stromal-cell derived factor 1 (SDF-1) Chemokine antagonist were unable to collect a sufficient number of CD34+ cells (Pusic et al., 2008). Select- Figure 3. Bone Marrow Microenvironment ing a mobilization strategy will be based on Note. Image courtesy of Jesper Bonde, PhD. Used with permission. multiple variables that may include the research or treatment protocol, institutional practices, and the underlying disease. (Kessinger & Sharp, 1996); and pegfilgrastim (Staber, Holub, Linkesch, Schmidt, & Neumeister, 2005). The results of these clinical trials produced results similar to the results with G-CSF Poor Mobilizers or GM-CSF for mobilization. Plerixafor initially was developed as an inhibitor of HIV en- Poor mobilization often is defined as collection of less than try into T cells. However, during clinical trials in HIV-positive 1–2 x 10 6 CD34+ cells/kg (Goterris et al., 2005; Haas et al., 1994; patients and healthy volunteers, leukocytosis was observed, Kessinger & Sharp, 2003; Stiff, 1999). Various factors have been prompting an investigation into why this occurred and what associated with poor mobilization, including specific types or cells were affected (Hendrix et al., 2004; Liles et al., 2003). It amounts of chemotherapy, patients older than 60 years, and was discovered that the leukocytes were CD34+ cells and plerix- prior pelvic radiation. Patients who do not collect enough HSCs afor’s ability to act as an HSC mobilizer was identified (Burger may not proceed to transplantation; the risks of using a sub- & Peled, 2009). Plerixafor was further explored as a mobilizing optimal HSC collection are delayed, partial, or failed engraft- agent for HSCT. Preclinical and clinical trials demonstrated that ment (Haas et al., 1994). Poor engraftment places the patient at plerixafor alone and in combination with G-CSF mobilizes HSCs increased risk for infections, bleeding, or death. Additionally, an (Broxmeyer et al., 2005; Devine et al., 2004; Liles et al., 2003). increased need for transfusions is likely (Schiller et al., 1995). Plerixafor, a chemokine antagonist, is a reversible inhibitor of Patients who do not mobilize a sufficient number of HSCs need SDF-1a/CXCR4 binding and has been shown to efficiently mo- different mobilization strategies, multiple apheresis collections, bilize HSCs into the peripheral circulation. or possibly a bone marrow harvest. Different remobilization In a phase II study, patients with multiple myeloma (MM) or strategies that have been used include an increased dose of G-CSF non-Hodgkin lymphoma (NHL) were randomized to a crossover or GM-CSF, mobilization with cytokines and chemotherapy, or study in which they received either plerixafor with G-CSF then possible inclusion in clinical studies (Schmit-Pokorny, 2004; Stiff, G-CSF alone or G-CSF alone followed by plerixafor with G-CSF 1999). These remobilization strategies add additional cost, the (Flomenberg et al., 2005). In 84% of patients, the combination of potential for more toxicity, and increased product volume, which plerixafor and G-CSF was found to mobilize 50% or more HSCs may lead to increased toxicities when the graft is infused. compared to G-CSF alone. The most common side effects attributed to plerixafor were gastrointestinal symptoms (e.g., upset Novel Agents for Mobilization stomach, flatulence), injection site erythema, and paresthesias. The authors found that the increase in CD34+ cells was higher Novel strategies for patients who do not collect sufficient in patients with NHL than in patients with MM. In this study, numbers of HSCs with current mobilization strategies are plerixafor was administered at 8 am followed by apheresis six needed. Other cytokines for mobilization have been investi- hours later. This may present some scheduling or logistical issues. gated, including interleukin-3 (Vose et al., 1992); PIXY321, The patients in the study engrafted in a median of 10 days, which a fusion product of GM-CSF and interleukin-3 (Bishop et al., is comparable to other mobilization regimens. 1996); recombinant human stem cell factor (Glaspy et al., 1997); In a compassionate use study, plerixafor was used with G-CSF recombinant human erythropoietin, also known as epoetin alfa as an attempt to mobilize patients who failed previous attempts

216 April 2010 • Volume 14, Number 2 • Clinical Journal of Oncology Nursing (Calandra et al., 2008). The authors assessed a cohort of 115 were similar across the treatment groups (10–11 days and 18–20 patients who were unable to proceed to apheresis because of days, respectively). The most common adverse events attributed low peripheral blood CD34+ cell counts or who were unable to to plerixafor use were gastrointestinal disorders (e.g., diarrhea, collect the minimum number of CD34+ cells with a reasonable nausea, vomiting) and injection site reactions. The authors con- number of apheresis collections. Side effects were similar to the cluded that plerixafor was well tolerated and allowed patients to phase II study, mostly transient gastrointestinal reactions, injec- collect the optimal target CD34+ cells/kg with fewer apheresis tion site erythema, and paresthesias. Following transplantation, procedures compared to using G-CSF alone (DiPersio, Micallef, patients recovered their neutrophil count in a median of 11 days et al., 2009; DiPersio, Stadmauer, et al., 2009). A summary of and platelet count in a median of 18 days. The authors concluded plerixafor side effects and nursing implications is shown in Tables that plerixafor offers patients who initially mobilize poorly a high 4 and 5 as a summary of the side effects and nursing implications chance to proceed to transplantation. Two multicenter, random- of G-CSF. In December 2008, plerixafor was approved by the FDA ized, double-blind phase III studies (DiPersio, Micallef, et al., for use in combination with G-CSF to mobilize hematopoietic 2009; DiPersio, Stadmauer, et al., 2009) used plerixafor and G-CSF stem cells to the peripheral blood for collection and subsequent versus placebo and G-CSF to mobilize HSC for transplantation in autologous transplantation in patients with NHL and MM. patients with MM and NHL. Results for the 302 patients with MM enrolled showed that significantly more patients collected the optimal target of 6 x 106 CD34+ cells/kg in two or less apheresis Apheresis Process, Goals, and Care sessions with plerixafor and G-CSF (72%) than with G-CSF alone (34%) (DiPersio, Stadmauer, et al., 2009). Results of the 298 Apheresis is the processing of whole blood into its separate patients with NHL demonstrated a yield of 5 x 106 CD34+ cells/ components so that one particular component can be collected kg in four or less apheresis sessions from 59% of patients treated and stored. The criteria to begin apheresis for the collection of with plerixafor and G-CSF compared to 20% of patients who were HSCs vary based on the standards of individual transplantation treated with placebo and G-CSF (DiPersio, Micallef, et al., 2009). centers. Criteria used by transplantation centers include the For patients receiving transplantations in both of these studies, total white blood cell count, the absolute neutrophil count, the times to neutrophil and platelet engraftment and graft durability number of circulating CD34+ cells, or the number of days of

Table 3. Mobilization Regimens and Corresponding CD34 Cell Yieldsa

Median Total Collected Number of Disease CD34 cells x 106/kg Median apheresis mobilization Study State Mobilization Regimen N (range) sessions (range) failures

Alegre et al., 1997 MM G-CSF 22 4.85 (2.1–10.05) 3 (2–6) NR CY 18 6.8 (1.8–34.8) 5 (4–12) NR

Bensinger et al., MM, L, Chemotherapy + G-CSF or 124 10.75 (0.01–178.33) 3 (1–9) 9 1995 BC, O GM-CSF G-CSF 119 5.21 (0.08–65.27) 3 (2–8) 6

Dazzi et al., 2000 NHL G-CSF 12 2.89 (1.7–5.6) 16 totalb NR CY + G-CSF 12 6.41 (2.2–25.9) 15 totalb

Desikan et al., 1998 MM G-CSF 22 5.8 (NR) 5 23%c CY + G-CSF 22 33.4 (NR) 7 18%c

Narayanasami et NHL, HD G-CSF 22 2.5 (0.3–12.4) NR (1–3) 1 al., 2001 CY + G-CSF 24 7.2 (0.3–44/8) NR (1–3) 1

Pavone et al., 2002 NHL DHAP = G-CSF 38 5.9d (NR) 2 (1–3) 5 CY+ G-CSF 34 706d (NR) 2 (1–3) 4

Pusic et al., 2008 NHL, HD, G-CSF 976 3.34 (NR) 2 (1–5) 182 MM Chemotherapy = G-CSF 64 5.43 (NR) 1.5 (1–5) 12

a Reports included in this table were randomized, controlled trials and other studies involving 24 or more patients with MM or NHL that reported CD34 cell yields stratified according to mobilization regimen. b Total number of apheresis sessions for all patients in the group c Percentage is reported instead of n value. d Mean value is reported instead of median. BC—breast cancer; CD—cluster of designation; CY—cyclophosphamide; DHAP—etoposide, cytosine arabinoside, methylprednisolone, and cisplatin; G-CSF—granulocyte–colony-stimulating factor; GM-CSF—granulocyte macrophage–colony-stimulating factor; HD—Hodgkin disease; L—lymphoma; MM—multiple myeloma; NHL—non-Hodgkin lymphoma; NR—not reported; O—other Note. From “Improving Stem Cell Mobilization Strategies: Future Directions,” by W. Bensinger, J.F. DiPersio, and J.M. McCarty, 2009, Bone Marrow Transplantation, 43, p. 4. Copyright 2009 by Macmillan Publishers Ltd. Adapted with permission.

Clinical Journal of Oncology Nursing • Volume 14, Number 2 • Mobilization of Stem Cells for Use in Autologous Transplantation 217 CD34+ cells correlates with a higher number of CD34+ cells col- Table 4. Common Side Effects of Plerixafor lected and fewer apheresis procedures (Bensinger et al., 2009). and Nursing Interventions An anticoagulant is added to the blood during processing Side Effect Assessment Intervention to prevent clotting of lines and clumping of the product. The most common anticoagulant is citrate dextrose, which can de- Gastrointestinal crease the serum level of ionized calcium, causing symptoms of symptoms hypocalcemia, outlined in Table 6. In a retrospective study of • Diarrhea and Monitor number Instruct patient that diarrhea abdominal of episodes. may occur as early as 1–1.5 540 collections, paresthesias from citrate toxicity was the most distention Monitor fluids. hours after administration. prevalent adverse event (20%) during collection (Moog, 2001). Patients should have antidiar- Untreated low serum calcium may progress to nausea, vomiting, rheal medications readily loss of consciousness, tetany, and seizures (Rowley, 2000). Low • Nausea Monitor fluids. available to use at home. calcium can be prevented or minimized by the administration of Antiemetics oral calcium supplements, IV calcium gluconate, and decreasing Skin reactions at Monitor sites. Notify physician for evaluation the blood flow rate during collection. injection site if not resolving or causing Central catheter–related issues with positioning or clotting can discomfort to patient. interrupt or slow the collection process. Moog (2001) described Headache or flu- Monitor frequency Administer analgesics. catheter-related issues in 7% of patients that included blood flow like symptoms and intensity. Notify physician for persistent alarms (11%) and blockages in the return line (4%). Other side or severe complaints. effects of apheresis (e.g., lightheadedness, dizziness, chills, fever, Orthostatic Baseline pulse, Administer or instruct patient urticaria, hypotension) are generally mild and transient. Antihy- hypotension blood pressure to administer while sitting. pertensive medications can worsen hypotension and should be Monitor after The patient should wait held prior to apheresis. The hematocrit and platelet count can be injection. 5–10 minutes before rising temporarily lowered because of apheresis, and each transplanta- and should rise slowly. tion center has guidelines for red blood cell or platelet transfu- Thrombocytope- Monitor platelet Notify physician if less than sion. Table 6 summarizes potential complications of apheresis. nia counts. 50,000 mm3. Although most patients tolerate apheresis without signifi- Monitor for post-procedure cant incident, all patients should undergo a thorough physical bleeding. examination and medical history prior to beginning apheresis. Administer platelet products. Educate patient about throm- bocytopenic precaution if less than 50,000 mm3. Table 5. Common Side Effects of Filgrastim and Nursing Interventions Note. Based on information from Calandra et al., 2008; Flomenberg et al., 2005; Genzyme Corporation, 2008. Side effect Assessment Intervention

Bone pain Monitor frequency Educate patient that bone cytokine administration. Based on its ability to process large and intensity. pain can be expected. Administer analgesics. volumes, a continuous-flow apheresis device which simultane- Notify physician of persistent ously collects, spins, and returns blood often is used in the col- or severe complaints. lection of HSCs. Some patients have adequate antecubital veins to support a vein-to-vein procedure; however, if they do not, a Gastrointestinal Monitor fluid status. Administer antiemetics. symptoms Encourage fluid intake. large-bore dual-lumen venous access catheter may be surgically • Nausea or Antidiarrheals or laxatives if inserted. Patients who have received previous chemotherapy anorexia indicated and are proceeding to autologous HSCT may have the central • Diarrhea or Notify physician of severe or line placed prior to mobilization so that it can be used for col- constipation unresolving symptoms. lection of HSCs and for the HSCT. Skin reactions or Monitor sites. Notify physician for evaluation Apheresis consists of removing whole blood from the circula- bruising at injec- if not resolving or causing tion and separating the blood into individual components: red tion site discomfort to patient. blood cells, plasma, white blood cells, and platelets based on the component’s density. Red blood cells are the most dense, and the Headache or flu- Monitor frequency Administer analgesics. like symptoms and intensity. Notify physician of persistent plasma and platelets are the least dense. HSCs circulate in the buffy or severe complaints. coat, which lies between the layer of red and white blood cells. The buffy coat layer, including the HSCs, flows into a collection Liver function Monitor LFT, tran- Instruct patient that transient bag; the other blood components are returned to the patient. test (LFT) sient increases in al- increases may occur. kaline phosphatase, Monitor laboratory results Multiple apheresis procedures may be required for a patient to and lactate acid de- for normalization after fil- meet the target collection goal. Typically, the quantity of blood hydrogenase. grastim therapy is discon- processed in a single apheresis session is three to four times the tinued. total blood volume and takes four to six hours. The length of time Note. Based on information from Amgen Inc., 2007; Schmit-Pokorny, is determined by patient size, total blood volume, blood flow 2004. rate, and patient tolerance. The higher the number of circulating

218 April 2010 • Volume 14, Number 2 • Clinical Journal of Oncology Nursing Table 6. Potential Complication of Apheresis

Potential Complication Etiology Assessment Nursing Intervention

Hypocalcemia Sodium citrate used to Baseline serum calcium Notify physician if low. prevent blood from Monitor ionized calcium.a Slow flow rate and offer oral calcium, liquid, or clotting in the aphere- Patient age tablets. sis machine binds ion- Assess for paresthesias of the extremities Increase calcium-containing foods. ized calcium. or circumoral area during the proce- Oral calcium supplements dure. IV calcium gluconate

Hypovolemia Extracorporeal volume Baseline pulse, blood pressure, Hgb/Hct, Notify physician of abnormal or unexpected find- greater than patient and health history ings before proceeding. tolerance Brief physical assessment and vital signs Interrupt the procedure until the patient is stable, every five minutes initially, gradually de- then resume at a slower flow rate and minimal creasing frequency as patient’s tolerance extracorporeal volume. Monitor physical status is established and vital signs closely. Notify physician if symp- Assess for hypotension, tachycardia, toms persist or progress. light-headedness, diaphoresis, and Administer blood products. dysrhythmias. Administer fluid. Hold angiotensin-converting enzyme inhibitor medication.

Thrombocytopenia Collection of platelets Baseline platelet count Notify physician if less than 50,000 mm3. into product Ascertain whether platelet-rich plasma Monitor for signs of post-procedure bleeding. will be returned at the procedure’s Administer platelet products. completion.

Issues related to the Positional or clotted Pressure alarms from apheresis machine Troubleshoot access lines and apheresis machine. catheter catheter identifying access or return-line issues Reposition patient.

Miscellaneous effects • Chilling Cooling of blood while Observe for chilling. Provide warmth (e.g., blankets, heating pad). circulating in the Use blood warmer return line. apheresis machine • Prolonged Previous chemotherapy Observe for headache. Notify physician. cytopenia regimens Observe daily CBC, Plt, and Diff. Transfuse as indicated. Pediatric patients with Manage symptoms. less developed hematopoietic progenitor pool

a Applies to pediatric patients CBC—complete blood count; Diff—differential; Hct—hematocrit; Hgb—hemoglobin; Plt—platelets Note. Based on information from Hooper & Santos, 1993; Schmit-Pokorny, 2004.

The apheresis session requires a nurse adept at troubleshoot- cells from ice formation and dehydration during freezing. A ing issues with the central or peripheral access as well as the cryoprotectant, such as dimethylsufloxide or hydroxyethyl apheresis device. Patients require close monitoring throughout starch, can be used to accomplish this goal. Reducing the risk of the apheresis procedure to ensure their safety and comfort. cell injury during cyropreservation is the third principle and can be accomplished by adding plasma protein to the graft. Saline or tissue culture media can be used to provide suspension of Cell Processing the cells and serve as a diluent for the cyroprotectants to meet the fourth principle of cryopreservation. The fifth principle is Once the HSCs are collected, the product is taken to the labora- controlled cooling of the hematopoietic cell graft. The rate of tory for processing and cryopreservation. The processing of the freezing for hematopoietic cells when using the cyroprotectant autologous graft includes sterility testing, blood typing, and a dimethylsufloxide is 01 C–30C per minute. The sixth principle reduction in fluid volume (Schmit-Pokorny, 2004). Understanding is related to the storage of the cells. Cells must be stored at a the science of HSC cryopreservation is beyond the scope of this ar- temperature that protects the cells from ice recrystallization ticle, but a review of the basic principles will complement nurses’ and cell damage. HSCs should be stored at temperatures below overall knowledge of transplantation and explain some of the side –120 0C in liquid nitrogen or mechanical freezers. effects that nurses may observe during the infusion of the graft. Reducing the volume of the hematopoietic cell graft leads to Rowley (2004) outlined six principles of HSC cryopreserva- a reduction in the amount of cryoprotectant that is needed dur- tion. The first principle is to reduce the number of mature blood ing freezing. This has a direct impact on the care of the patient cells in the graft because mature blood cells do not tolerate during the infusion of the autologous graft (Schmit-Pokorny, cryopreservation well. The second principle is to protect the 2004). Most of the side effects observed during infusion of the

Clinical Journal of Oncology Nursing • Volume 14, Number 2 • Mobilization of Stem Cells for Use in Autologous Transplantation 219 cyropreserved autologous graft are related to the cryoprotectant to the content of this article have been disclosed by the dimethylsufloxide and include nausea, hypo- or hypertension, independent peer reviewers or editorial staff. an increase or decrease in heart rate, arrhythmias, chest discomfort, facial flushing, and an unpleasant taste (Reed, 1992). Author Contact: Hollie Devine, MSN, RN, CNP, can be reached at hollie Reducing the mature red blood cells in the graft prior to freezing [email protected], with copy to editor at [email protected]. also minimizes the risk of hemoglobinuria that may be noted after the autologous graft is infused (McAdams, 2004). References

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CD antigens 1996: Updated nomen- stromal cell molecules: The CD markers. Hoboken, NJ: John clature for clusters of differentiation on human cells. IUIS/ Wiley and Sons. WHO Subcommittee on CD Nomenclature Bull World Health Organization. Smith, T.J., Hillner, B.E., Schmitz, N., Linch, D.C., Dreger, P., Goldstone, A.H., . . . Erder, M.H. (1997). Economic analysis of Receive free continuing nursing education credit a randomized clinical trial to compare filgrastim-mobilized for reading this article and taking a brief quiz peripheral-blood progenitor-cell transplantation and autologous online. To access the test for this and other ar- bone marrow transplantation in patients with Hodgkin’s and non- ticles, visit http://evaluationcenter.ons.org. After Hodgkin’s lymphoma. Journal of Clinical Oncology, 15, 5–10. entering your Oncology Nursing Society profile Socinski, M.A., Cannistra, S.A., Elias, A., Antman, K.H., Schnipper, username and password, select CNE Listing from L., & Griffin, J.D. (1988). Granulocyte-macrophage colony stimu- the left-hand tabs. Scroll down to Clinical Journal lating factor expands the circulating haemopoietic progenitor of Oncology Nursing and choose the test(s) you cell compartment in man. Lancet, 1, 1194–1198. doi: 10.1016/ would like to take. S0140-6736(88)92012-0

222 April 2010 • Volume 14, Number 2 • Clinical Journal of Oncology Nursing