Autologous stem cell transplantation (ASCT) has

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1 HOW DO I...? How do we mobilize and collect autologous peripheral blood stem cells? Shan Yuan and Shirong Wang Autologous stem cell transplantation (ASCT) with mobilized peripheral blood stem cells (PBSCs) has become a widely applied therapeutic approach for many hematologic and nonhematologic diseases. Adequate PBSC mobilization is critical to the success of ASCT. However, many factors can contribute to poor mobilization. Plerixafor is an effective yet costly adjunct agent that has been increasingly used to improve mobilization in a variety of diagnoses and clinical settings. However, to achieve both optimal cell collection yields and cost-effectiveness, the role of plerixafor in PBSC mobilization needs to be well defined in terms of triggers for initiating its use and criteria for monitoring response. As one of the largest hematopoietic transplant centers in the country, we have developed an approach to PBSC mobilization and collection that incorporates patient laboratory assessments, monitoring of the collection yields, and judicious use of plerixafor as well as various patient support and education programs. These measures have resulted in an increase in our collection success rate and a decrease in the mean number of collection days. In this article we describe our approach to autologous PBSC mobilization and collection. Pertinent reports in the literature are also reviewed and discussed. Autologous stem cell transplantation (ASCT) has been shown to improve the clinical outcomes of patients with hematologic malignancies such as multiple myeloma (MM), Hodgkin s disease (HD), and non-hodgkin s lymphoma (NHL), as well as a number of nonhematologic malignancies. 1,2 Currently more than 98% of adult ASCTs are performed with the support of mobilized peripheral blood stem cells (PBSCs). 3 There is a correlation between the number of CD341 hematopoietic cells infused during ASCT and engraftment outcomes. A dose of CD341 cells/kg body weight is generally considered the minimum required to achieve durable engraftment, 4-6 and a higher dose of to CD341 cells/kg has been associated with faster hematopoietic recovery, better survival rates, and lower resource utilization in some studies CD341 cells can be mobilized from the marrow to the peripheral blood (PB) to allow collection by apheresis. Mobilization is currently usually achieved by the administration of cytokines such as granulocyte colony-stimulating factor (G-CSF, filgrastim, lenograstim, pegfilgrastim) or granulocyte-macrophage colony-stimulating factor (GM- ABBREVIATIONS: ASCT 5 autologous stem cell transplantation; CE(s) 5 collection efficiency(ies); CM 5 chemotherapy mobilization; CrCl 5 creatinine clearance; HD 5 Hodgkin s disease; MM 5 multiple myeloma; NHL 5 non-hodgkin s lymphoma; PB 5 peripheral blood; PBSC(s) 5 peripheral blood stem cell(s). From the Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, City of Hope National Medical Center, Duarte, California. Address reprint requests to: Shan Yuan, MD, Division of Transfusion Medicine, Department of Pathology and Laboratory Medicine, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010; syuan@coh.org. Received for publication July 18, 2016; revision received August 24, 2016; and accepted August 24, doi: /trf VC 2016 AABB TRANSFUSION 2017;57;13 23 Volume 57, January 2017 TRANSFUSION 13

2 YUAN AND WANG CSF, sargramostim, with or without preceding chemotherapy. 11,12 However,anumberoffactorsareassociatedwith poor mobilization, including treatment with marrow toxic chemotherapy (especially lenalidomide, purine analogs, and alkylating agents), advanced age, radiation of marrow, and marrow involvement of the underlying disease In addition, requirement for G-CSF during previous chemotherapy and low baseline platelet (PLT) counts have also been associated with poor mobilization. 17,18 Depending on the criteria, failure rates have been reported to range from 5% to 40% with these conventional regimens, affecting approximately 5000 to 10,000 patients each year globally. 3,11,13,19 Poor mobilization often leads to increased number of collection days, remobilization efforts, delayed engraftment, graft failure, marrow harvest, and patient anxiety. Not uncommonly, patients are precluded from ASCT as a treatment option entirely due to inadequate mobilization. In 2008, plerixafor (AMD3100 or Mozobil, Genzyme) received Food and Drug Administration (FDA) approval for clinical use as a mobilization agent used in conjunction with G-CSF. The approval was based on two Phase III prospective randomized trials in NHL and MM patients, which showed that the combination of plerixafor and G- CSF led to significantly higher CD341 cell yields than with G-CSF and placebo. 20,21 In recent years, extensive literature on plerixafor has emerged, documenting its effectiveness in an expanding list of diagnoses and in various clinical settings of PBSC mobilization, including after chemotherapy mobilization (CM), as an immediate rescue agent of poor mobilization, and during remobilization. 3,11,26 The main drawback to plerixafor is its cost. It is not uncommon for the contracted price at individual hospitals to exceed $7800 per single-use vial. 26 However, this must be balanced against the greater mobilization success rates, higher cell yields, and the potential savings in costs due to fewer collection days and better engraftment outcomes compared to conventional mobilization regimens. Hence, the advent of plerixafor highlights the importance for stem cell collection facilities to develop strategies that maximize collection success rates, while maintaining cost-effectiveness. The City of Hope National Medical Center is one of the largest hematopoietic stem cell transplant centers in the United States. Approximately 400 ASCTs are performed with the support of PBSCs annually. In 2015, a total of 390 patients underwent autologous PBSC collections at our center. Further review revealed that between 2007 and 2015, while accommodating a more than 50% increase in the volume of patients undergoing autologous PBSC collections, we had increased the collection success rate (defined as collecting > CD341 cells/kg) from 95.1% to 99.2% and, more importantly, decreased the mean number of collection days from 4.5 to 2.8 per patient, which represents significant cost savings and reduced resource utilization. We were able to accomplish this largely by developing and fine-tuning our approach to PBSC collection, which incorporates the close monitoring of PB CD341 cell counts and collection yields, judicious use of plerixafor, and various patient support and education programs, all of which contribute to the positive patient experience and outcomes. PREMOBILIZATION PREPARATIONS: PATIENT CARE COORDINATION AND EDUCATION Stem cell mobilization and the subsequent collection is a complicated process that can be overwhelming to the patient and family. In addition to the anxiety and emotional strain during this trying time, they must be able to manage the daily injections that are part of the mobilization regimen, catheter care, and a busy schedule of multiple laboratory draws and appointments, which may be changed at short notice depending on the patient s progress. These challenges may pose barriers to a successful mobilization for the patient. To help patients navigate this complex process, each patient is assigned a nurse coordinator who coordinates the patient s care by maintaining the appointment schedule, ensuring compliance with the mobilization regimen, addressing various social issues (insurance, transportation, lodging, language interpretation, and so forth), serving as the patient s advocate and liaison with multiple providers, and playing an essential educational role to the patient and family. When provided with adequate support and education, patients are more likely to be compliant with their mobilization regimen and have a positive experience during their mobilization and collection. Each patient undergoes three separate formal education sessions in the weeks leading up to the stem cell collections. The sessions are generally scheduled to coincide with other clinical appointments so additional visits to the hospital are not needed. Satisfactory completion is documented on an interdisciplinary flow sheet and reviewed by the nurse coordinator to ensure that the patient is well informed on all the key aspects of his or her care. The initial session is conducted by the nurse coordinator, who provides an overview of the mobilization, collection, and transplant processes. A detailed schedule for mobilization, laboratory draws, and apheresis collection appointments; a list of important phone numbers; and a map of key locations are given to the patient. The nurse coordinator also provides teaching on G-CSF injections and the necessary injection supplies. If needed, the nurse coordinator can make arrangements for injections to be done by a home health nurse or at a clinic. A semipermanent central line (12 French Hickman or equivalent at our institution) is placed in nearly all patients undergoing autologous PBSC collections, which provides a reliable vascular access for apheresis collections, as well as 14 TRANSFUSION Volume 57, January 2017

3 HOW DO WE MOBILIZE AUTOLOGOUS PBSCS? for blood draws and infusions that can be used over many months during the patient s transplant course. Patients and interested family members can attend a small group class on catheter care conducted by a hospital nurse and learn how to flush the catheter, change caps, and perform simple dressing changes. Signs and symptoms of potential complications such as infectionand thrombosis are also reviewed. Finally, patients and interested family members attend a one-on-one education session at the apheresis center during the week before PBSC collection, where they are given a tour of the facility and a detailed orientation to the setting of the stem cell collection. The apheresis center staff review the importance of compliance with G-CSF injections and describe the collection process in detail. Potential adverse reactions such as citrate toxicity are also reviewed at this time. MOBILIZATION: AGENTS AND REGIMENS G-CSF (filgrastim, Neuopogen) Mobilization of stem cells is currently most commonly achieved by administrations of cytokines alone or preceded by chemotherapy. G-CSF (or filgrastim, Neupogen, Amgen) is the most commonly used cytokine in this setting. G-CSF stimulates neutrophil production and maturation and induces the release of various proteases into the marrow, which disrupt the adhesion of CD341 stem cells to the marrow stroma, facilitating their subsequent release into the PB. 27,28 Most individuals begin to show adequate PBSC mobilization after 4 to 5 days of cytokine administration or 9 to 10 days if G-CSF is given immediately after chemotherapy. The default dose of G-CSF at our institution is 10 mg/ kg/day. As G-CSF is supplied in 300- and 480-mg vials,the calculated dose of G-CSF may be rounded up or down to an appropriate degree to facilitate ease of administration and minimize wastage. The dose may be given once a day or divided and given twice a day depending on patient preference, as there is no compelling evidence that either approach provides better mobilization. 29 Pegfilgrastim, or pegylated form of G-CSF, allows stem cell mobilization with a single dose due to its long half-life, as opposed to the daily injections necessitated by the short half-life of G-CSF. However, data on its efficacy in mobilization are both limited and mixed. While an unpublished randomized controlled trial comparing 10 mg/kg/day G-CSF, 6 mg of a single dose of pegfilgrastim, and a 12-mg single dose of pegfilgrastim, showed that patients in both of the pegfilgrastim arms mobilized significantly less well than G-CSF mobilized patients, there are also a number of studies supporting the use of pegfilgrastim in conjunction with chemotherapy, with collection results and patient outcomes comparable to chemotherapy and G-CSF mobilized patients. 11 Chemotherapy After the observation that chemotherapy administration resulted in an increase in peripheral blood (PB) CD341 cell level during hematopoietic recovery, early stem cell mobilization techniques relied on chemotherapy alone. 30 It was recognized soon afterward that the combination of chemotherapy and cytokines led to better mobilization. 31,32 Options for chemotherapy include several cyclophosphamide-based regimens used specifically for PBSC mobilization and disease-specific regimens chosen by the clinician for additional anti-tumor effects. Drawbacks to CM include added cost, unpredictable and sometimes prolonged course of mobilization, and increased toxicities. The literature on various CM regimens is extensive (see review by Giralt et al. 11 ). At our institution, the most commonly used chemotherapy for mobilization is cyclophosphamide at 1.5 g/m 2, with vigorous hydration before and after infusion over a total period of 24 hours. In the majority of cases at our center, G-CSF injections are started within 24 hours after completion of the chemotherapy regimen used for mobilization. Plerixafor Overview Plerixafor is a new, but valuable addition to the arsenal of mobilization agents. Plerixafor disrupts the adhesion between CXCR4 on CD341 cells and its ligand CXCL12 (also known as stromal-derived factor-1) expressed by marrow stromal cells, thereby causing the release of marrow CD341 cells into the peripheral circulation. 33 Due to its high cost, plerixafor is rarely used as the firstline mobilization agent in unselected patients. The highest benefit-to-cost ratio is seen in patients who would fail conventional mobilization regimens. 34 Plerixafor is commonly administered in the following three clinical settings: 1. Upfront use as part of the planned mobilization regimen in patients with clinical factors predictive of poor mobilization. 2. Added just-in-time to rescue a failing mobilization after conventional regimen. 3. Remobilization in patients who have failed prior mobilization attempt(s). Upfront plerixafor: who might benefit from planned use of plerixafor? Table 1 shows the guidelines used at our institution for identifying patients who might benefit from upfront use of plerixafor based on age, treatment history, and marrow involvement of underlying disease. Although these risk factors for poor mobilization are well known, identifying appropriate plerixafor candidates solely based on these clinical factors is problematic in practice and can lead to mobilization failures or overtreatment in a significant Volume 57, January 2017 TRANSFUSION 15

4 YUAN AND WANG TABLE 1. Upfront use of plerixafor as an adjunct mobilization agent may be considered for patients who are ASCT candidates, with one or more of the following existing clinical factors* years old 2. History of radiation to pelvis or mediastinum 3. Marrow involvement of the underlying disease 4. MM patients who are candidates for tandem ASCT 5. MM patients with exposure to lenalidomide for > 6 months 6. NHL patients who have received more than two cycles of high-dose cytarabine (HiDAC, fludarabine-based chemotherapy regimens or alkylating agents) 7. NHL and HD patients who have received more than two combination chemotherapy regimens 8. NHL and HD patients in remission at the time of mobilization after at least two cycles of salvage chemotherapy *Upfront use of plerixafor is still likely less cost-effective than on-demand use in patients with the above risk factors for mobilization failure. However, it may be justified in patient in whom a high cell yield and limited number of collection days are necessary. number of patients. 35,36 First, dynamic factors such as the interval between the most recent cycles of chemotherapy and mobilization, ongoing progression of disease, and degree of hematopoietic recovery can exert significant impact on mobilization. 18,37 Second, many patients mobilize well without plerixafor despite the presence of risk factors, especially when chemotherapy is also used along with G-CSF for mobilization. 32 Conversely, there are individuals with no apparent risks factors, who do not mobilize well, including up to 5% healthy allogeneic donors. 19 Currently, patients mobilized upfront with plerixafor account for less than 3% of all mobilized patients and less than 10% of plerixafor-mobilized patients at our center. In most cases, the decision to use plerixafor upfront was based in part on existing clinical risk factors, but also influenced by the desire for fewer collection days or higher collection yields. Currently, most patients at our center are mobilized with the combination of chemotherapy and G-CSF. Requests for planned upfront plerixafor mobilization may increase as our clinicians move away from CM regimens in an effort to decrease toxicities while maintaining high cell yields, especially for tandem ASCT candidates, such as MM patients. Compared to cyclophosphamide and G-CSF or G-CSF alone, the combination of upfront plerixafor plus G-CSF in MM patients has been associated with higher collection success rates; similar or reduced financial burdens due to less remobilization, hospitalization, and G-CSF usage; and as expected decreased toxicities when compared to CM. 38,39 However, routine upfront use in all patients is still likely to be less cost-effective than on-demand use of plerixafor in select patients based on real-time PB CD341 cell counts and/or collection yields, 40 provided that the algorithm for ondemand use of plerixafor is designed with appropriate triggers, and plerixafor can be administered promptly based on real-time or near-real-time data to effectively minimize collection days. In patients who are obviously already mobilizing well with conventional regimens and can reach high collection goals within 1 to 2 days, the additional cost of upfront plerixafor is difficult to justify. Just-in-time plerixafor: salvaging failing and suboptimal mobilizations When plerixafor is not part of the initial regimen but added-on to rescue suboptimal mobilization, patient candidates can be identified based on real-time or nearreal-time laboratory assessments and collection data. Precollection PB CD341 remains the single best predictor for collection yield. 41,42 Many algorithms for identifying plerixafor candidates on the day before or the day of the first planned collection have been presented in the literature, taking into consideration the patient s PB CD341 cell count, collection target, and possibly concurrent white blood cell (WBC) and PLT counts as indicators of degree of hematopoietic recovery (see Giralt et al. 11 ). They have been shown to improve mobilization success rate while managing plerixafor utilization in a cost-effective manner. While checking PB CD341 cell count the day before the first collection to trigger plerixafor use may allow early identification of poor mobilizers and ample time for intervention, this requires another precollection visit by the patient for laboratory assessment. At our institution, similar to other published algorithms, plerixafor is triggered by poor PB CD341 cell counts on the first day of the planned collection or by suboptimal ongoing collection yields. When the turnaround times of PB CD341 cell count and collection yield are rapid enough, this approach still allows quick intervention and immediate addition of plerixafor. Figure 1 is the schematic diagram of our center s overall algorithm for mobilization and plerixafor use. We will discuss specific triggers for initiating plerixafor and criteria for assessing response in a later section. It must be emphasized that individual centers should analyze their own data and determine their own criteria and triggers for plerixafor use. Such customized algorithms should take into consideration the center-specific correlation between PB CD341 cell counts and collection yields, turnaround times of these results, resources available, and other institutional requirements for initiating 16 TRANSFUSION Volume 57, January 2017

5 HOW DO WE MOBILIZE AUTOLOGOUS PBSCS? Fig. 1. Schematic flow chart of mobilization algorithm with optimized use of plerixafor. plerixafor (e.g., pharmacy or transplant physician approval). Furthermore, such algorithms should serve only as a general guideline and be amended as institutional practices change. Decisions regarding stopping or continuing collections with plerixafor still need to be individualized for each patient and should be informed by discussions with the patient and the transplant physician. For example, in patients who respond well to plerixafor, high collection yields can be achieved in a day or two, but in patients who mobilize less robustly, the benefits of sometimes marginally higher total cell yields need to be balanced against the drawbacks of additional collection days and plerixafor doses. Remobilization with plerixafor Finally, plerixafor can be used as a remobilization agent in conjunction with G-CSF. There is abundant evidence of its efficacy in this setting. Historically, when remobilization strategies consisted of higher doses of G-CSF, the addition of GM-CSF, or chemotherapy, success rates have been reported to be in the range of 2%-50% In comparison, in patients who have previously failed conventional regimens, or have even failed just-in-time plerixafor rescue of poor mobilization with conventional regimens, remobilization efforts with plerixafor in combination with G-CSF have success rates in the 64% to 90% range. 26,55,56 Thus, plerixafor in combination with G-CSF should be Volume 57, January 2017 TRANSFUSION 17

6 YUAN AND WANG considered as the remobilization regimen for all patients who have previous mobilization failures. Dosing and administration of plerixafor Dosing of plerixafor is based on body weight and creatinine clearance (CrCl). In general, in patients with CrCl of more than 50 ml/min, plerixafor is administered subcutaneously at a dose of 0.24 mg/kg body weight. Patients with CrCl of 50 ml/min or less should receive a reduced dose of 0.16 mg/kg. The CrCl is calculated with a serum Cr value obtained within the past 72 hours of the first dose. Because plerixafor is provided in 24-mg single-use vials, to minimize wastage, dose is capped for patients weighing between 100 and 125 kg at 24 mg (one vial) at our center, which is the calculated dose for a body weight of 100 kg. For patients who are not collecting adequately while receiving the capped dose, the dose may be increased subsequently to the calculated dose based on weight. The calculated dose is used for those patients who weigh more than 125 kg. Studies in normal donors showed sustained release of PBSCs from 4 to 20 hours after plerixafor administration, with peak observed between 10 and 14 hours. 57 Plerixafor is administered at our center usually in the evening, approximately 11 hours before the next apheresis collection. There is evidence that plerixafor is still effective when given 15 to 18 hours before apheresis due to sustained CD341 cell release; thus late afternoon administration may be possible and more convenient A PB CD341 cell count is routinely obtained the morning after the first dose to monitor response, which is also assessed daily by monitoring the CD34 1 collection yield. Due to the high cost of plerixafor, insurance preauthorization or enrollment in the patient assistance program at our center is required. Whenever possible, the nurse coordinator is notified by 2 PM on the day of the planned first dose, so insurance authorization can be obtained before evening. The nurse coordinator is also responsible for scheduling the evening injection appointment for the patient. COLLECTION OF PBSCs Overview of the collection process PB CD341 cell counts are obtained on the fifth day of G- CSF administration for patients mobilized with G-CSF only and the 10th day for patients mobilized with G-CSF and chemotherapy, approximately 3 hours before the first apheresis collection appointment. PB CD341 cell count is measured by flow cytometry and turnaround time is generally less than 2 hours. Apheresis collection will proceed if the count is /L or greater. When indicated, additional PB CD341 counts may be obtained by the apheresis physician on subsequent days to further assess mobilization. For patients on plerixafor, preapheresis PB CD34 count is not used to qualify patients to proceed to collection. With the current turnaround times, the sample for the preapheresis PB CD341 cell count would have to be obtained between 8 and 9 hours after injection, so the result would be available well before starting the collection at 11 hours. However, serial PB CD341 cell measurements in plerixafor-mobilized patients have shown that in most patients PB CD341 cell counts reach their peak levels between 10 and 18 hours postinjection. 60 Therefore, collections should not be held based on low PB CD341 cell count at 8 to 9 hours. In fact, in our experience, even the PB CD341 cell count obtained at the onset of collection or 11 hours postinjection, frequently underestimates the collection yield. Not infrequently patients with PB CD341 cell count between and /L at 11 hours still collect close to CD341 cells/kg in the next 4 hours, contributing substantially to the total cell yield. Presumably, in such patients further mobilization and increase in PB CD341 cell level occur to a significant degree beyond 11 hours postinjection. To minimize weekend collections, the first day of collection is usually scheduled to fall on a Monday or Tuesday. With close monitoring and judicious use of plerixafor, patients rarely need more than 4 days of collection before reaching collection goal or they become candidates for remobilization due to inadequate mobilization. Collections are performed with the MNC protocol on the COBE Spectra (CaridianBCT) and, beginning in 2015, also with the continuous MNC protocol on the Spectra Optia (CaridianBCT) or the MNC protocol on the Amicus (Fenwal) apheresis instruments. Our validation data on the new Optia and Amicus instruments showed that both have similar CD341 cell collection efficiencies (CEs) that compare favorably to the COBE Spectra instruments. Approximately 12 to 14 L of blood are processed over 4 to 5 hours. The CE of apheresis instruments is a qualitative indicator of the separator s potential for collecting PBSCs and can be used to calculate the predicted collection yield based on the patient s PB CD341 cell counts and volume processed. We have not relied on calculated results based on CEs to make clinical decisions for several reasons. First, data on the PB CD341 cell CEs are limited, especially for the newer apheresis instruments increasingly in widespread use. Second, in many cases there are significant discrepancies between the calculated and the actual results, which can be attributed to a variety of factors such as continued mobilization (especially in plerixaformobilized patients), operator issues, interrupted collections, or catheter recirculation. But more practically, the relatively short turnaround times for actual collections yields at our institution make such predictions less useful. 18 TRANSFUSION Volume 57, January 2017

7 HOW DO WE MOBILIZE AUTOLOGOUS PBSCS? Two shifts of collections per day are performed at our center, beginning at 7:30 AM and 11:00 AM, respectively. The preapheresis PB CD341 cell counts qualifying patients for collection are drawn at 5:00 AM at the hospital s 24-hour urgent care clinic for the patients collecting during the early shift and at 8:00 AM at the apheresis collection center for those collecting during the later shift. CD341 cell collection yields are determined via standard flow cytometry analyses and calculations, with results generally available by early afternoon for the early shift of collections, and the following morning for the later shift of collections to allow timely assessment. At our institution, the collection target is CD341 cells/kg for patients undergoing a single ASCT, with CD341 cells/kg as the minimum dose. For double ASCTs candidates (MM or germ cell tumor patients), the collection target and minimum are to and CD341 cells/kg, respectively. After the minimum has been reached, the balance between the potential advantages of reaching the target and the number of additional apheresis sessions required is considered, and collection may be stopped before reaching the target. Larger-volume apheresis collections take up to 6 to 8 hours and process at least 33 instead of the usual approximately 23 to 2.53 the patient s blood volume. They may result in higher CD341 cell yields owing to possible ongoing mobilization of stem cells during apheresis 61 and reduce the number of sessions in some cases. 62 Although currently there are no reports of increased incidence of adverse events associated with larger-volume apheresis collections, the risks of citrate toxicity, electrolyte disturbances, coagulopathy, and possibly thrombocytopenia are theoretically increased. In addition, the longer collection times pose additional challenges to staffing and scheduling, as well as patient tolerance. Thus, largevolume collections are only considered in a small number of cases at our center, such as in patients with poor tolerance for repeated apheresis procedures or time constraints or those with temporary catheters. Monitoring of mobilization and just-in-time rescue by plerixafor The short turnaround times of the PB CD341 cell counts and collection yields allow timely assessment of mobilization and prompt interventions when patients mobilize inadequately. Plerixafor is considered in poorly mobilizing patients who have precollection PB CD341 cell counts below the collection threshold of /L if the collection goal is to CD341 cells/kg or less than /L when the goal is to CD341 cells/kg. Plerixafor may also be considered subsequently in patients with low or rapidly declining CD341 cell yields (< / kg/day for single ASCT candidates, < /kg per day for double ASCT candidates, or a >50% decrease in yield compared to the previous day). Because plerixafor primarily enhances the mobilization of stem cells by interrupting the adhesion of CD341 cells to the stromal cells in their marrow niches, 12 efficacy in patients with low hematopoietic activity and low CD341 cell content in the marrow is limited. Plerixafor is generally not considered for patients who are still pancytopenic after chemotherapy, with WBC counts of less than cells/l or in patients with extremely low PB CD341 cell counts (< /L). A satisfactory response in such patients is rarely seen in our experience. In an algorithm for plerixafor rescues validated by Li and colleagues, 50 using the cutoff values of a WBC count of more than cells/l together with PB CD341 count of fewer than cells/l identified appropriate patients who demonstrated improved mobilization after plerixafor administration with a specificity of 91% and a positive predictive value of 78%, indicating that plerixafor works better where there is evidence of hematopoietic recovery and some response to G-CSF injections. Furthermore, heavily pretreated patients may take longer to achieve hematopoietic recovery and reach their peak PB CD341 cell count. 63 In a study of 113 patients mobilized with chemotherapy and G-CSF, 12% to 13% of patients who had previously received more than six cycles of chemotherapy or irradiation reached their peak PB CD341 cell count later than Day 20 versus only 2% to 5% in the patients who had received six or fewer cycles of chemotherapy or those without prior irradiation. Yet, many of the heavily treated patients did achieve high PB CD341 cell counts eventually by simply continuing G-CSF administration. Such data suggest that in some heavily pretreated patients, patience and additional time for hematopoietic recovery may be all that is necessary. For such patients, who usually demonstrate both low PB CD341 cell and WBC counts, a waitand-see approach is appropriate. Complete blood count and PB CD341 cell counts can be repeated in 24 to 72 hours, and plerixafor may be considered if the patient begins to show increasing WBC counts (> to cells/l), but still lagging PB CD341 cell counts. Poor response to plerixafor: now what? The currently FDA-approved prescribing information for plerixafor states that up to four consecutive doses can be given to improve mobilization, and this is also the number of doses most insurance carriers would approve for a given patient at a time. However, four doses should not be automatically given consecutively without daily monitoring the response to plerixafor. Inadequate response to plerixafor must be recognized in a timely manner. If a patient demonstrates inadequate response to plerixafor, as evidenced by minimally improved PB CD341 count and/or persistently low collection yield, the Volume 57, January 2017 TRANSFUSION 19

8 YUAN AND WANG apheresis physician then initiates a discussion with the transplant physician to decide whether to continue the current collection attempt with plerixafor or to pursue remobilization at a later date. Continuing collections despite suboptimal response to plerixafor may be preferred if the patient is likely to demonstrate further hematopoietic recovery and thus improved mobilization or if the patient s cumulative yield thus far is reasonably close to the collection goal, which can be reached within 1 to 2 days based on projected yields. Finally, continued collection may be favored if the transplant physician and the patient wish to avoid the delays, risk of relapse, and inconveniences associated with remobilization and are willing to settle for a lower cell dose for transplant. Remobilization should be considered for most patients demonstrating disappointing response to plerixafor and still wish to pursue ASCT as a treatment option, especially if the minimum collection goal is unlikely to be attained in 1 to 2 days based on the current collection yields. The collection attempt should be stopped to limit unproductive utilization of plerixafor and other valuable resources. Patient is generally given a 2- to 3-week interval to rest, with both G-CSF and plerixafor injections stopped during this time. Patient then begins daily G-CSF injections at 10 mg/kg/day, with plerixafor added on the night of Day 4 of G-CSF and collection resuming on Day 5. Remobilization studies in cytokine-mobilized rhesus monkeys have shown that when the interval between the two mobilization attempts is 2 weeks, half of the monkeys showed increased and the other half showed decreased circulating colony-forming units. However, when remobilized at 4 weeks after the initial mobilization attempt, all animals showed improved mobilization, indicating that less than 2 weeks may not be enough to allow full recovery of the hematopoietic capacity in all subjects. 64 Caution is clearly needed when extrapolating results from healthy nonhuman primates with no apparent mobilization defects to human patients who are known to mobilize poorly. However, the 2- to 3-week interval between mobilizations in our experience allows most patients to successfully remobilize. While a shorter interval (e.g., 1 week) may not be long enough to allow adequate hematopoietic recovery, it may be considered in select patients under time constraints due to medical or personal reasons. Chemotherapy is not needed when the interval between the first and second mobilization attempts is less than 1 month, and thus additional patient morbidities and costs are minimized. When the interval between the initial and the remobilization attempt is longer, we leave the decision regarding whether additional chemotherapy is needed up to the patient s transplant physician, who will take into consideration the patient s risks for disease relapse, comorbidities, and prior response to chemotherapy. In an earlier publication, 56 we reported the remobilization of 18 patients with plerixafor, all of whom had previously mobilized poorly despite the addition of plerixafor to their existing regimen of G-CSF with or without chemotherapy. During the initial trial of plerixafor, they collected only to (median, )CD341 cells/kg after one to four collections, with a median average daily yield of CD341 cells/kg while on plerixafor. Remobilization began after 1 to 4 weeks of rest with G-CSF and plerixafor, preceded by cyclophosphamide in three cases. Each patient collected an additional to (median, ) CD341 cells/kg after one to four doses, and the median daily average increased to CD341 cells/kg. Remobilization contributed 36% to 98% (median, 83%) of the total cell yields and allowed all but three patients to collect more than CD341 cells/kg, representing a success rate of 83.3%. Since the publication of that article, we have accrued more experience with plerixafor remobilization. Given our current practice of routinely salvaging poor mobilizations with plerixafor, almost all remobilized patients have previously failed plerixafor. Our mobilization process has been further standardized in that patients rarely receive more than two doses of plerixafor during the first trial if response is suboptimal, and remobilization generally occurs after a 2-week rest period, so no additional chemotherapy is needed. Furthermore, the majority of remobilized patients collected more than CD341 cells/kg just after one or two additional doses of plerixafor or collection was stopped in a timely manner due to lack of response. Monitoring collection response and limiting the number of doses of plerixafor administered is important to cost containment. According to a recent retrospective study of various remobilization strategies, unless more than two doses of plerixafor are used, the plerixafor plus G-CSF remobilization regimen compares favorably to G-CSF plus chemotherapy or G-CSF with or without GM-CSF in terms of not only collection success rate, but also resource utilization and overall cost. 65 In 2015, of the total of 390 patients undergoing autologous PBSC collections at our center, plerixafor was administered to 125 patients, including nine cases of upfront use, and added on as just-in-time salvage due to poor mobilization in 116. Of the plerixafor-mobilized patients, 27 failed to collect CD341 cells/kg despite plerixafor use during the initial attempt and were remobilized subsequently with G-CSF and plerixafor. Upon remobilization, 24 (88.9%) patients were able to collect enough cells to proceed to ASCT. Thus the overall rate of successful mobilization, defined as collecting more than CD341 cells/kg was 99.2% for all patients. CONCLUDING REMARKS The chief goal of stem cell mobilization and collection is to obtain enough stem cells to permit ASCT and durable 20 TRANSFUSION Volume 57, January 2017

9 HOW DO WE MOBILIZE AUTOLOGOUS PBSCS? engraftment. PBSC mobilization collection can be significantly improved by closely monitoring the patient s mobilization progress and the use of both conventional and newer mobilization agents. However, it is also important to accomplish this in a cost-effective manner. Plerixafor is a costly mobilization agent that, when judiciously used, can lead to both optimized cell yields and reduction in the overall costs associated with stem cell collection and transplant. We have presented our approach to autologous PBSC mobilization and the algorithm for plerixafor use. However, collection centers need to develop algorithms that reflect their own practice environment. Specific criteria and triggers for plerixafor use, for example, should be supported and validated by data and patient outcomes. Finally, collection goals, priorities, and strategies should be individualized for each patient, informed by discussions with the patient and the transplant team. 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