Systematic Review of Randomized Controlled Trials of Hematopoietic Stem Cell Mobilization Strategies for Autologous Transplantat

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CLINICAL RESEARCH

Systematic Review of Randomized Controlled Trials of Hematopoietic Stem Cell Mobilization Strategies for Autologous Transplantation for Hematologic Malignancies Dawn Sheppard, Christopher Bredeson, David Allan, Jason Tay

Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation; however, a proportion of patients fail to collect the minimum number of cells required. We summarized the efficacy and safety of HSC mobilization strategies. We performed a systematic review of randomized controlled trials comparing HSC mobilization strategies before autologous transplantation for hematologic malignancies. The primary outcome was CD341 cell yield. Secondary outcomes included number of aphereses, proportion of failures, rate of count recovery, and adverse events. We identified 28 articles within 3 broad strategies. Using a cyclophosphamide with growth factor strategy (10 articles), CD341 cell yield is improved by addition of molgramostim to cyclophosphamide (1.4 vs 0.5 Â 106/kg; P 5 .0165), addition of cyclophosphamide to filgrastim (7.2 vs 2.5 Â 106/kg; P 5.004), and addition of ancestim to cyclophosphamide and filgrastim (12.4 vs 8.3 Â 106/kg; P 5.007). Within a growth factor-based strategy (6 articles), addition of plerixafor improves CD341 cell yield over filgrastim alone in multiple myeloma (MM; 11.0 vs 6.2 Â 106/kg; P \ .001) and non-Hodgkin lymphoma (5.69 vs 1.98 Â 106/kg; P \ .01). With combination or noncyclophosphamide-based chemotherapy (12 articles), higher-dose filgrastim (8.2 vs 4.7 Â 106/kg for 16 vs 8/mcg/kg daily of filgrastim, respectively; P \.0001) and addition of rituximab to etoposide and filgrastim (9.9 vs 5.6 Â 106/kg; P 5.021) improve CD341 cell yield. Growth factor alone after chemotherapy, ancestim, or plerixafor provide adequate autologous HSC grafts for the majority of patients. Although some strategies result in higher CD341 cell yield, this potentially comes at the expense of increased toxicity. As all strategies are reasonable, programmatic, and patient-specific considerations must inform the approach to autologous graft mobilization. Biol Blood Marrow Transplant 18: 1191-1203 (2012) Ó 2012 American Society for Blood and Marrow Transplantation KEY WORDS: Hematopoietic stem cell transplantation, Stem cell mobilization, Mobilization strategy, Plerixafor

INTRODUCTION 5% to 40% of patients do not meet the minimum threshold of 2 Â 106 CD341 cells/kg that is associated High-dose chemotherapy, supported by autologous with timely engraftment [5-9]. Although mobilized hematopoietic stem cell transplantation (HSCT), is an peripheral blood is preferred over bone marrow as the effective treatment strategy for a variety of hemato- cell source for autologous transplantation [10], the opti- logic malignancies [1-4]. The collection of adequate mal mobilization regimen for procurement of autolo- numbers of HSCs is a prerequisite for proceeding to gous HSCs remains unknown. autologous transplantation; however, approximately A variety of mobilization strategies are currently used, including growth factors alone or in combination with chemotherapy and, more recently, the partial From the Ottawa Hospital Research Institute, Ottawa Hospital CXC chemokine receptor-4 (CXCR-4) agonist, Blood and Marrow Program, Ottawa, Canada. Financial disclosure: See Acknowledgments on page 1201. plerixafor. Of the available growth factors, the most com- Correspondence and reprint requests: Jason Tay, MD, Ottawa Hos- monly used is the recombinant granulocyte-colony stim- pital Research Institute, Ottawa Hospital Blood and Marrow ulating factor (G-CSF) analog, ﬁlgrastim [11].Other Program, 501 Smyth Road, Ottawa, Ontario, Canada K1H growth factors include pegﬁlgrastim, a polyethylene 8L6 (e-mail: [email protected]). glycol conjugate of G-CSF; lenograstim, glycosylated Received August 8, 2011; accepted January 11, 2012 Ó 2012 American Society for Blood and Marrow Transplantation recombinant G-CSF; molgramostim, recombinant 1083-8791/$36.00 granulocyte macrophage colony-stimulating factor; doi:10.1016/j.bbmt.2012.01.008 sargramostim, glycosylated granulocyte macrophage

1191 1192 D. Sheppard et al. Biol Blood Marrow Transplant 18:1191-1203, 2012 colony-stimulating factor; and ancestim, recombinant Table 1. MEDLINE Search Strategy human stem cell factor. Lenograstim is widely used for 1. Hematopoietic Stem Cell Mobilization/(2615) HSC mobilization in Europe; sargramostim, molgra- 2. (stem cell$ adj3 mobil$).tw. (1732) 3. (hsc$ adj3 mobil$).tw. (135) mostim, and ancestim are rarely used for mobilization to- 4. (bone marrow adj3 mobil$).tw. (579) day. 5. (Hematopoietic adj3 Mobil$).tw. (557) A combination of chemotherapy along with growth 6. (progenitor cell$ adj3 mobil$).tw. (1024) 7. (mobilisation or mobilization).tw. (34442) factor is a commonly used strategy for mobilization. 8. or/1-7 (36567) Chemotherapy is added to improve CD341 cell yield 9. (plerixafor or amd3100 or amd 3100 or jm 3100 or jm3100).af. [12,13], for in vivo purging of mobilized tumor cells (536) 10. mozobil.af. (11) to reduce tumor burden (although there are limited 11. exp Granulocyte Colony-Stimulating Factor/(11370) supportive data), and to show chemosensitivity before 12. exp Granulocyte-Macrophage Colony-Stimulating Factor/(12702) transplantation. However, approximately 30% of 13. (GCSF or G-CSF or GMCSF or G-MCSF).tw. (10430) 14. hematopoietic cell growth factors/or stem cell factor/(4837) patients undergoing a mobilization strategy that 15. Cyclophosphamide/(39369) includes chemotherapy will develop neutropenic fever 16. exp Antineoplastic Agents/(683920) [14], and many of those will require hospitalization. 17. Antineoplastic Combined Chemotherapy Protocols/(83778) 18. chemotherap$.tw. (209311) The most commonly used chemotherapy regimens 19. Receptors, CXCR4/ai [Antagonists & Inhibitors] (535) include cyclophosphamide at a variety of doses, particu- 20. (CXCR4 antagonist$ or CXCR4 inhibitor$).tw. (414) larly in patients with multiple myeloma (MM) [15,16]. 21. or/9-20 (821399) 22. 8 and 21 (4996) Mobilization regimens for patients with lymphoma 23. Bone Marrow Transplantation/(37961) are varied and include ifosphamide, carboplatin, and 24. exp Stem Cell Transplantation/(36650) etoposide, dexamethasone, doxorubicin, cytarabine, 25. (HSCT or bmt or pbpct or sct).tw. (15427) 26. transplant$.tw. (272768) and cisplatin (DHAP), etoposide, methyl prednisolone, 27. exp Neoplasms, Plasma Cell/(35525) cytarabine, and cisplatin and others [17,18]. 28. (leukemia$ or myeloma$).tw. (169031) Plerixafor belongs to a new class of small molecules 29. or/23-28 (460564) 30. randomized controlled trial.pt. (294851) that reversibly bind to CXCR-4, inhibiting chemokine 31. controlled clinical trial.pt. (81941) stromal cell-derived factor-1a [19-21]. In phase 1 and 32. randomized.ab. (249657) 2 studies, plerixafor either alone or in combination 33. placebo.ab. (123384) 34. clinical trials as topic.sh. (149493) with G-CSF, significantly increased the number of 35. randomly.ab. (154634) CD341 cells collected [22,23]. In a phase 2 study of 36. trial.ti. (89994) patients with MM and non-Hodgkin lymphoma 37. or/30-36 (714333) 38. 22 and 29 and 37 (421) (NHL), the addition of plerixafor to G-CSF increased the likelihood of collection of at least 5 Â 106 CD341 cells/kg and allowed collection to be completed in fewer aphereses [22]. In these studies, plerixafor was Our primary outcome was median CD341 cell well tolerated. yield. Secondary efficacy outcomes included median The optimal type and dose of growth factor-based number of aphereses required to collect the minimum mobilization is not well defined. Similarly, it is unknown HSC yield, proportion of patients going on to trans- whether the potential benefits of chemotherapy-based plantation, proportion of patients in whom there was mobilization may be offset by an increased risk of infec- failure to collect the minimum CD341 cell yield as de- tious complications. Finally, the role of plerixafor has fined by the study, and for those proceeding to HSCT, not been clearly delineated. Herein, we summarize, time to neutrophil recovery, and platelet recovery. within the context of a systematic review of randomized Secondary safety outcomes included a measure of the controlled trials (RCTs), the relative efficacy and safety extent of febrile neutropenia and hospital or intensive of different HSC mobilization strategies in patients care unit admissions. undergoing autologous HSCT for hematologic malig- Using an explicit statement of questions with re- nancies. Considerations for programs when selecting spect to participants, interventions, comparisons, out- a mobilization strategy are also discussed. comes, and study design [24], studies that met the following inclusion criteria were included in our review: (1) included patients .18 years undergoing METHODS peripheral blood HSC collection for autologous transplantation, (2) compared at least 2 mobilization strate- A systematic literature search was performed gies using a randomized controlled study design, and using Ovid MEDLINE (1950 to week 42 of 2010), (3) measured at least 1 of our study outcomes. Pub- EMBASE (1980 to week 42 of 2010), and all EBM re- lished studies in all languages were included. We views (1950 to the fourth quarter of 2010) using the excluded unpublished studies, studies published in ab- search strategy detailed in Table 1. Further, references stract form only, nonrandomized, quasi randomized, were reviewed to identify any additional studies. or crossover studies, studies involving animals, and Biol Blood Marrow Transplant 18:1191-1203, 2012 Hematopoietic Stem Cell Mobilization Strategies 1193

Figure 1. Flow diagram summarizing the identification process of relevant clinical trials. studies exclusively involving the following interven- and 1 was a duplicate publication of data already cap- tions: mobilization of donor HSCs before allogeneic tured by our review. One article was identified by transplantation, mobilization before autologous trans- personal communication. Subsequently, 28 articles plantation for solid tumors, and mobilization before met our inclusion criteria and were included in the bone marrow harvest. systematic review (Figure 1). There were no discrep- Two reviewers (D.S. and J.T.) independently ap- ancies between the 2 reviewers with regard to studies plied the inclusion and exclusion criteria to the articles for inclusion. identified by the search strategy and extracted the data using a standardized data abstraction form. Full text Study Demographics articles assessed for inclusion were discussed between The 28 articles reported on a total of 29 studies; 1 the 2 reviewers. Trial quality was assessed using a vali- article reported the results of 2 studies [27]. There dated 5-point system as proposed by Jadad et al. [25].A were 22 single-center and 7 multi center trials, with Jadad score of 3 or higher was considered high quality. 18 trials exclusively including subjects with hemato- Trial quality was further assessed with the use of stan- logic malignancies (Table 2). The most common indi- dardized questions related to methodology, such as al- cation for autologous transplantation was NHL (19 location concealment [26]. Trial quality was judged studies), followed by MM (17 studies), and Hodgkin conservatively such that if an item (eg, the appropriate- lymphoma ([HL] 11 studies). Eleven studies included ness of the randomization method) was not reported, it patients undergoing transplantation for both hemato- was negatively scored. logic malignancies and solid tumors. Most studies included few participants; the largest study involved 302 subjects (mean, 74.9; SD, 70.8; RESULTS range, 15-302). The mean age of study subjects was The systematic search strategy identified a total 46 years (SD, 9.3; range, 24.5-60). of 1,039 articles. Eighty duplicate articles were excluded, and the remaining 959 were screened for rel- Characteristics of HSC Mobilization Strategy evance based on their titles or abstracts. Of these, 34 The HSC mobilization strategies evaluated are were deemed potentially eligible and retrieved for full summarized in Table 3. Two studies exclusively in- review. After detailed review, 7 of these articles were cluded patients with newly diagnosed disease undergo- excluded for the following reasons: 4 utilized cross- ing autologous transplantation as consolidative over designs, 1 was retrospective, 1 did not meet therapy after an initial response [28,29]. Ten studies our study inclusion criteria for outcome measures, included only patients undergoing transplantation for 1194 D. Sheppard et al. Biol Blood Marrow Transplant 18:1191-1203, 2012

Table 2. Study Demographics

Gender, No. of Patients Median Age % Female

Study, Country Disease Sites Centers Gp1 Gp2 Gp1 Gp2 Gp1 Gp2

Cyclophosphamide Plus Growth Factor Ahn et al. [28], South Korea NHL, breast M 12 15 40 44.5 58.3 53.3 Demuynck et al. [33], Belgium MM S 11 11 50 52 36.3 81.8 Facon et al. [43], France, Spain, Belgium MM M 55 47 60 59 35 49 Gazitt et al. [44], USAa NHL S 10/12b 13 52/55b 46 20/9.1b 15.3 Martinez et al. [47], Spain MM S 8 7 48 48 50 42.9 Min et al. [51], South Korea NHL, MM, breast, Ewing’s sarcoma S 15 15 40 39 60 60 Narayanasami et al. [50], USA NHL, HL S 23 24 41 46 48 29 Pavone et al. [18], Italy NHL S 38 34 37a 35a 60.5 52.9 Quittet et al. A [27], France NHL, HL, MM, CLL, breast, testicular, ovarian S 31 29 51 54 47 45 Quittet et al. B [27], France NHL, HL, MM, CLL, breast, testicular, ovarian S 30 30 57 53 33 47 Vela-Ojeda et al. [48], USA MM, NHL, HL S 28 28 32 35.5 28.6 28.6 Growth Factor Ataergin et al. [30], Turkey Heme, solid S 20 20 24.5 33 30 30 DiPersio et al. [41], USA MM M 148 154 58.2 58.4 32.4 30.5 DiPersio et al. [42], USA NHL M 150 148 56 59 33.3 31.1 Spitzer et al. [36], USA NHL, HL, MM, breast, germ cell/testicular, S 24 26 43 48 75 80.8 ovarian Stiff et al. [37], USA NHL, HL S 51 56 42 47.5 31 43 Weisdorf et al. [53], USA NHL, HL S 16 15 47 46 56 46.7 Combination/Non–Cyclophosphamide-Based Chemotherapy with Growth Factor Andre et al. [39], Belgium NHL, HL, MM, breast M 62 66 49 46 75.8 83.3 Arora et al. [40], USA MM S 37 35 52.5 52.4 46 40 Copelan et al. [31], USA NHL S 28 27 54 47 37.3 40.7 Demirer et al. [32], Turkey L, MM, breast, testicular S 25 25 39 40 40 52 Hohaus et al. [34], Germany HL S 14 12 30.5 32 28.6 66.7 Hart et al. [29], Germany MM S 14 12 58a 61a 50 58 Kim et al. [45], South Korea MM, NHL S 20 20 52 55 30 35 Kopf et al. [46], Italya NHL, HL, MM, breast, germ cell, S 36/29b 38 35/36b 43 58.3/51.7b 60.5 osteosarcoma, other Ozcelik et al. [52], Turkey NHL, MM S 23 25 48 40.6 34.8 40 Shi et al. [35], China NHL, HL, germ cell S 15 15 29 21 40 7 Weaver et al. [49], USA NHL M 40 41 50 48 37 39 Weaver et al. [38], USAa L, MM, breast M 52/53b 51 46/48b 50 85/81b 84

Gp1 indicates comparator 1; Gp2, comparator 2; NHL, non-Hodgkin lymphoma; M, multicenter; MM, multiple myeloma; S, single center; HL, Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; Heme, hematologic malignancies; solid, solid malignancies; L, lymphoma. aMean age. bStudies with 3 arms; data for 2 experimental arms separated by forward slash. chemotherapy-sensitive relapsed disease [18,30-38]. Demuynck et al. [33] compared filgrastim and molgra- Eleven studies included both categories of patients mostim, each at 10 mcg/kg/day, in combination with [39-49], 1 study included relapsed or refractory disease cyclophosphamide 4 g/m2, (2) in a 3-arm study, Gazitt [50] and in 5 studies, this was unclear [27,51-53]. et al. [44] compared molgramostim 250 mcg/day, mol- Studies varied with respect to the number of prior gramostim 250 mcg/day for 7 days followed by filgras- treatment regimens patients had received (range, 0-5). tim 10 mcg/kg/day, and filgrastim alone 10 mcg/kg/ Included studies were grouped into 3 broad categories day, each in combination with cyclophosphamide based on the mobilization strategy (Table 4): (1) 3 g/m2, and (3) in a publication, Quittet et al. [27] re- cyclophosphamide with growth factor, (2) growth ported the results of 2 concurrent trials: study A com- factor(s) or (3) combination chemotherapy or non- pared molgramostim 5 mcg/kg/day plus filgrastim cyclophosphamide-based combination chemotherapy 5 mcg/kg/day to filgrastim 5 mcg/kg/day, and study plus growth factor. B compared molgramostim 2.5 mcg/kg/day plus filgrastim 2.5 mcg/kg/day to filgrastim 5 mcg/kg/day, Cyclophosphamide with Growth Factor each with cyclophosphamide. One trial studied the ad- Strategy dition of ancestim 20 mcg/kg/day to a regimen of cy- Eleven studies used cyclophosphamide in combi- clophosphamide 4 g/m2 plus filgrastim 5 mcg/kg/day nation with at least 1 growth factor as a comparator. [43], 1 trial compared cyclophosphamide 4 g/m2 with One study compared high-(4 g/m2) vs low-dose (1.5 and without the addition of molgramostim 5 mcg/ g/m2) cyclophosphamide in combination with lenog- kg/day [47], and 1 examined early (day 2) vs late (day rastim [28]. Three articles (4 studies) reported on com- 8) addition of molgramostim 5 mcg/kg/day to cyclo- parisons between filgrastim and molgramostim: (1) phosphamide [51]. Two studies compared a different Biol Blood Marrow Transplant 18:1191-1203, 2012 Hematopoietic Stem Cell Mobilization Strategies 1195

Table 3. Characteristics of HSC Mobilization Strategy

HSCT for Median No. Interventions Initial/Salvage of Prior Chemo Study Therapy Regimens Gp1 Gp2

Cyclophosphamide with Growth Factor Ahn et al. [28] Yes/no 1 CY 1.5 g/m2 + lenograstim 250 mcg/day CY 4 g/m2 + lenograstim 250 mcg/day Demuynck et al. [33] No/yes NS CY 4 g/m2 + molgramostim 10 mcg/kg/day CY 4 g/m2 + filgrastim 10 mcg/kg/day Facon et al. [43] Yes/yes NS CY 4 g/m2 + filgrastim 5 mcg/kg/day + CY 4 g/m2 + filgrastim 5 mcg/kg/day ancestim 20 mcg/kg/day Gazitt et al. [44]a Yes/yes $1 CY 3 g/m2+ molgramostim 250 mcg/m2 CY 3 g/m2+ filgrastim 10 mcg/kg/day Gp3: CY 3 g/m2+ molgramostim 250 mcg/m2 followed by filgrastim 10 mcg/kg/day Martinez et al. [47] Yes/yes $1 CY 4 g/m2 + molgramostim 5 mcg/kg/day CY 4 g/m2 Min et al. [51] NS/yes NS CY 4 g/m2 + filgrastim 250 mcg/day (late) CY 4 g/m2 + filgrastim 250 mcg/day (early) Narayanasami et al. [50] No/yes NS Filgrastim 10 mcg/kg/day CY 5 g/m2 + filgrastim 10 mcg/kg/day Pavone et al. [18] No/yes NS DHAP + filgrastim 5 mcg/kg/day CY + filgrastim 5 mcg/kg/day Quittet et al. A [27] NS/yes NS CY 4 g/m2 + molgramostim 5 mcg/kg/day + CY 4 g/m2 + filgrastim 5 mcg/kg/day filgrastim 5 mcg/kg/day Quittet et al. B [27] NS/yes NS CY 4 g/m2 + molgramostim 2.5 mcg/kg/day + CY 4 g/m2 + filgrastim 5 mcg/kg/day filgrastim 2.5 mcg/kg/day Vela-Ojeda et al. [48] Yes/yes $1 IFO + molgramostim 5 mcg/kg/day CY 4 g/m2+ molgramostim 5 mcg/kg/day Growth Factor Ataergin et al. [30] No/yes NS Lenograstim 7.5 mcg/kg/day Filgrastim 10 mcg/kg/day DiPersio et al. [41] Yes/yes 1-2 Plerixafor + filgrastim 10 mcg/kg/day Filgrastim 10 mcg/kg/day DiPersio et al. [42] Yes/yes 1-2 Plerixafor + filgrastim 10 mcg/kg/day Filgrastim 10 mcg/kg/day Spitzer et al. [36] No/yes NS Molgramostim 5 mcg/kg/day + filgrastim Filgrastim 10 mcg/kg/day 10 mcg/kg/day Stiff et al. [37] No/yes $1 Filgrastim 10 mcg/kg/day Filgrastim 10 mcg/kg/day + ancestim 20 mcg/kg/day Weisdorf et al. [53] NS/yes NS Molgramostim 250 mcg/m2/day Filgrastim 250 mcg/m2/day Combination/Non–Cyclophosphamide-Based Chemotherapy with Growth Factor Andre et al. [39] Yes/yes 1-2 Chemo + filgrastim 10 mcg/kg/day Chemo + filgrastim 5 mcg/kg/day Arora et al. [40] Yes/yes $1 CMD + molgramostim 250 mcg/m2/day CMD + filgrastim 250 mcg/m2/day Copelan et al. [31] No/yes 2-3 R + VP-16 + filgrastim 10 mcg/kg/day VP-16 + filgrastim 10 mcg/kg/day Demirer et al. [32] No/yes 1-2 Chemo + filgrastim 16 mcg/kg/day Chemo + filgrastim 8 mcg/kg/day Hohaus et al. [34] No/yes 2-3 DexaBEAM + molgramostim 5 mcg/kg/day DexaBEAM + filgrastim 5 mcg/kg/day Hart et al. [29] Yes/no 1 IEE + filgrastim 5 mcg/kg twice a day + EPO IEE + filgrastim 5 mcg/kg twice a day Kim et al. [45] Yes/yes $1 Chemo + lenograstim 5 mcg/kg twice a day Chemo + lenograstim 10 mcg/kg/day Kopf et al. [46]a Yes/yes 1 Chemo + lenograstim 5 mcg/kg/day Chemo + filgrastim 5 mcg/kg/day Exp2: Chemo + molgramostim 5 mcg/kg/day Ozcelik et al. [52] NS/yes 2 CE + filgrastim 10 mcg/kg/day (late) CE + filgrastim 10 mcg/kg/day (early) Shi et al. [35] No/yes 5 VP-16 1,000 mg/m2 + filgrastim 300 mcg/day VP-16 1,500 mg/m2 + filgrastim 300 mcg/day Weaver et al. [49] Yes/yes $1 CIS + CE + filgrastim 6 mcg/kg/day CE + filgrastim 6 mcg/kg/day Weaver et al. [38]a No/yes NS Chemo + sargramostim 250 mcg/m2/day Chemo + filgrastim 6 mcg/kg/day Gp3: chemo + sargramostim 250 mcg/m2/day followed by filgrastim 6 mcg/kg/day

HSC indicates hematopoietic stem cell; HSCT, hematopoietic stem cell transplantation; Gp1, comparator 1; Gp2, comparator 2; Gp3, Comparator 3; CY, cyclophosphamide; NS, not stated; Exp2, XXX; DHAP, cisplatin, cytosine arabinoside, dexamethasone; IFO, ifosfamide; CMD, cyclophosphamide, mitoxantrone, dexamethasone; R, rituximab; VP-16, etoposide; DexaBEAM, dexamethasone, carmustine, etoposide, cytarabine, melphalan; IEE, ifosfamide, epirubicin, etoposide; EPO, erythropoietin; CE, cyclophosphamide, etoposide; CIS, cisplatin. aStudies with 3 arms; data for 2 experimental arms separated by forward slash. chemotherapy regimen to cyclophosphamide: (1) day to lenograstim 7.5 mcg/kg/day, (2) Spitzer et al. Pavone et al. [18] compared DHAP for mobilization [36] compared filgrastim 10 mcg/kg/day to molgra- in patients with NHL, and (2) Vela-Ojeda et al. [48] mostim 5 mcg/kg/day in combination with filgrastim used ifosfamide in patients with lymphoma or MM. 10 mcg/kg/day, and (3) Weisdorf et al. [53] compared These studies used chemotherapy in combination filgrastim to molgramostim, both at a dose of 250 mcg/ with filgrastim and molgramostim 5 mcg/kg/day, m2/day. One study investigated the addition of ances- respectively. Finally, 1 study compared filgrastim tim 20 mcg/kg/day to filgrastim [37], and 2 articles 10 mcg/kg/day with and without cyclophosphamide reported on the addition of plerixafor to filgrastim 5g/m2 [50]. [41,42]. Growth Factor or Non–Chemotherapy-Based Combination Chemotherapy or Non– Mobilization Strategy Cyclophosphamide-Based Chemotherapy with Six studies evaluated a mobilization strategy in- Growth Factor Strategy volving one or more growth factors without chemo- Twelve studies compared combination chemotherapy. Three studies compared growth factors: (1) therapy or non–cyclophosphamide-based chemother- Ataergin et al. [30] compared filgrastim 10 mcg/kg/ apy plus one or more growth factors. Of these, 1196 D. Sheppard et al. Biol Blood Marrow Transplant 18:1191-1203, 2012

Table 4. Summary of HSC Mobilization Strategy Comparisons

HSC Mobilization Strategy

Combination/Non–CY-based Study Comparison CY + Growth Factor Growth Factor Alone Chemotherapy + Growth Factor

Growth factor type Demuynck et al. [33] Ataergin et al. [30] Arora et al. [40] Gazitt et al. [44] Spitzer et al. [36] Hohaus et al. [34] Quittet et al. [27] Weisdorf et al. [53] Kopf et al. [46] Weaver et al. [38] Growth factor dose Andre et al. [39] Demirer et al. [32] Growth factor timing Min et al. [51] Ozcelik et al. [52] Growth factor single or divided dose Kim et al. [45] Addition of plerixafor DiPersio et al. [41] DiPersio et al. [42] Addition of rituximab Copelan et al. [31] Addition of ancestim Facon et al. [43] Stiff et al. [37] Addition of erythropoietin Hart et al. [29] Chemo +/2growth factor Martinez et al. [47] Growth factor +/2chemo Narayanasami et al. [50] Varied chemo dose Ahn et al. [28] Varied chemo regimen Pavone et al. [18] Shi et al. [35] Vela-Ojeda et al. [48] Weaver et al. [49]

HSC indicates hematopoietic stem cell; CY, cyclophosphamide.

2 studies compared growth factor dose: (1) Andre et al. duration of patient follow-up [40-44,50,53], and in [39] compared filgrastim at 5 and 10 mcg/kg/day, and 3 (11%), it was stated that the analysis was by (2) Demirer et al. [32] compared doses of 8 and 16 intention to treat [41-43]. mcg/kg/day. Four studies compared growth factors: 2 (1) filgrastim vs molgramostim, each at 250 mcg/m / Efficacy of Hematopoietic Stem Cell day [40], (2) filgrastim vs molgramostim, each at 5 Mobilization Strategies mcg/kg/day [34], (3) filgrastim vs molgramostim vs lenograstim, each at 5 mcg/kg/day [46], and (4) filgras- Primary outcome: CD341 cell yield 2 tim 6 mcg/kg/day vs sargramostim 250 mcg/m /day vs Of the studies that evaluated a cyclophosphamide 2 sargramostim 250 mcg/m /day for 5 days followed by with growth factor strategy, 3 used interventions that filgrastim 6 mcg/kg/day [38]. One study investigated resulted in a statistically significant improvement in the addition of rituximab to a combination of etopo- CD341 cell yield (Table 6). In the study by Facon side and filgrastim 10 mcg/kg/day [31], one investi- et al. [43], the addition of ancestim resulted in a median gated the addition of erythropoietin to a strategy of CD341 cell yield of 12.4 Â 106/kg compared with combination chemotherapy plus filgrastim 5 mcg/kg 8.2 Â 106/kg for cyclophosphamide plus filgrastim bid [29], one studied single-dose or divided-dose le- without ancestim (P 5 .007). In the Martinez et al. nograstim (10 mcg/kg/day vs 5 mcg/kg twice a day) [47] study, the addition of growth factor (molgramos- [45], and one studied early (day 4) vs late (day 7) com- tim) to cyclophosphamide resulted in a significant im- mencement of filgrastim [52]. Two studies compared provement in median CD341 cell yield (1.4 vs 0.5 Â chemotherapy regimens: Shi et al. [35] compared 2 dif- 106/kg; P 5 .0165). Narayanasami et al. [50] reported 2 ferent etoposide doses (1,000 vs 1,500 mg/m ) in com- CD341 cell yield was improved with cyclophospha- bination with filgrastim 300 mcg/day, and Weaver mide combined with filgrastim over filgrastim alone et al. [49] studied the addition of cisplatin to a regimen (7.2 vs 2.5 Â 106/kg; P 5 .004). involving cyclophosphamide, etoposide, and filgrastim Of the studies that used a non-chemotherapy 6 mcg/kg/day. mobilization strategy, significant improvement in CD341 cell yield was achieved with plerixafor in com- Quality of Studies bination with G-CSF in patients with MM (11.0 vs Items included in the quality assessment are de- 6.2 Â 106/kg; P \ .001) [41] or NHL (5.69 vs 1.98 Â scribed in Table 5. Three (11%) studies were assigned 106/kg; P \ .01) [42]. a Jadad score of at least 3 [31,41,42], with only 2 studies In the category of non–cyclophosphamide-based clearly describing allocation concealment [42,47] and 2 chemotherapy with growth factor, 2 studies found sig- describing an appropriate method of randomization nificantly improved CD341 cell yield with their inter- [31,46]. Three studies were stated to be double blind ventions. In the Copelan et al. [31] study including [34,41,42], although none described the process of exclusively patients with NHL, rituximab improved blinding. Fourteen articles discussed withdrawals or the yield (9.9 vs 5.6 Â 106/kg; P 5 .021). Doubling dropouts. Seven articles (25%) clearly stated the the dose of filgrastim improved the CD341 cell yield Biol Blood Marrow Transplant 18:1191-1203, 2012 Hematopoietic Stem Cell Mobilization Strategies 1197

Table 5. Quality Assessment

Jadad Scoring System Questionsa

Allocation Study 1 2 3 4 5 6 7 Jadad score concealment? ITT analysis?

Cyclophosphamide with Growth Factor Ahn et al. [28] + 222222 1 22 Demuynck et al. [33] + 222222 1 22 Facon et al. [43] + 22222+2 2 + Gazitt et al. [44] + 222222 1 22 Martinez et al. [47] + 222222 1 22 Min et al. [51] + 22222+2 22 Narayanasami et al. [50] + 22222+2 22 Pavone et al. [18] + 222222 1 22 Quittet et al. A [27] + 222222 1 22 Quittet et al. B [27] + 222222 1 22 Vela-Ojeda et al. [48] + 222222 1 22 Growth Factor Alone Ataergin et al. [30] + 22222N/A N/A 2 N/A DiPersio et al. [41] + 22+ 22+3 2 + DiPersio et al. [42] + 22+ 22+3 + + Spitzer et al. [36] + 222222 1 22 Stiff et al. [37] + 22222+2 22 Weisdorf et al. [53] + 22222+2 22 Combination/Non–Cyclophosphamide-Based Chemotherapy with Growth Factor Andre et al. [39] + 22222+2 22 Arora et al. [40] + 22222+2 22 Copelan et al. [31] ++ 2222+3 22 Demirer et al. [32] + 22222N/A N/A 2 N/A Hohaus et al. [34] + 22+ 222 2 22 Hart et al. [29] + 22222+2 22 Kim et al. [45] + 222222 1 22 Kopf et al. [46] ++ 22222 2+2 Ozcelik et al. [52] + 222222 1 22 Shi et al. [35] + 22222+2 22 Weaver et al. [49] + 22222+2 22 Weaver et al. [38] + 22222+2 22

ITT indicates intension to treat; +, yes; 2, no; N/A, not applicable. aJadad scoring system questions: (1) Was the study described as randomized? (2) Was an appropriate randomization sequence described and used? (3) Was an inappropriate method to generate the sequence of randomization used? (4) Was the study described as double blinded? (5) Was an appropriate method for blinding used? (6) Was an inappropriate method for blinding used? (7) Were withdrawals and dropouts described? in the Demirer et al. [32] study in a heterogeneous required to proceed to transplantation as defined group of patients (8.2 vs 4.7 Â 106/kg; P \ .0001). by the study protocol [18,27,29-31,37,38,40,41,43- 45,47,48,52]. Secondary outcomes Four of these reported the proportion that failed out Three studies used interventions that resulted in of the entire study population only [18,27,40,45], and fewer aphereses required to reach the minimal HSC the other 12 reported the proportion for the individual target. In the Facon et al. [43] study, a median of 1 study groups. None of the studies reported statistically apheresis was required to collect a target of 5 Â 106 significant differences between groups, either because CD341 cells/kg in the group that received ancestim, none was found [18,29,31,35,43,44,47,52] or because vs 2 aphereses for the control group that received cyclo- significance testing was not done/reported. phosphamide with filgrastim only (P 5 .008). In the Twelve studies reported on the proportion of pa- Demirer et al. [32] study, patients who received the tients who ultimately proceeded to transplantation higher dose of filgrastim required a median of 1 apher- [28,31,35,37,40-42,45-47,49,51]. The only significant esis procedure, as compared with 2 in patients receiving result was reported in the DiPersio study [42] compar- the lower dose (P\.001) to achieve a minimum CD341 ing plerixafor combined with filgrastim to filgrastim cell dose of 2.5 Â 106/kg. In patients with MM receiving alone for HSC mobilization in patients with NHL. plerixafor as part of their mobilization strategy to collect In this study, 135 of 150 patients receiving plerixafor an adequate graft for 2 transplantations, the median proceeded to transplantation after initial mobilization, number of aphereses to achieve a target of 6 Â 106 compared with 82 of 148 patients receiving filgrastim CD341 cells/kg decreased from 4 to 1 (P \ .001) [41]. alone (P \ .001). In this study, patients failing to col- Sixteen articles reported the proportion of patients lect at least 0.8 Â 106 CD341 cells/kg after 2 apheresis failing to collect the minimum number of HSCs days or at least 2 Â 106/kg in up to 4 apheresis days had 1198 D. Sheppard et al. Biol Blood Marrow Transplant 18:1191-1203, 2012

Table 6. HSC Mobilization Efﬁcacy

Median CD34+ Cell Median No. Proportion Failing to Yield (Â 106/kg) Aphereses Mobilize (Number, Percentage)

Study Gp1 Gp2 Gp1 Gp2 Gp1 Gp2

Cyclophosphamide with Growth Factor Ahn et al. [28] 9.9 22.4 3 2.5 NS NS Demuynck et al. [33] 23.7 12.7 NS NS NS NS Facon et al. [43] 12.4b 8.2b 1b 2b 8/55, 14.5% 9/47, 19.1% Gazitt et al. [44]a NS/NS NS 2/1 3 4/10, 40%/5/12, 41.7% 3/13, 23% Martinez et al. [47] 1.4b 0.5b 6.4c 7.2c 1/8, 12.5% 1/7, 14.3% Min et al. [51] 6.8 8.5 3.5 4 NS NS Narayanasami et al. [50] 2.5b 7.2b ND ND NS NS Pavone et al. [18] 5.9 7.1 2 2 5/38, 13.2% 4/34, 11.8% Quittet et al. A [27] 18.3 9.0 2 2 4/56, 7.1%d 4/56, 7.1%d Quittet et al. B [27] 15.9 8.1 2 2 3/53, 5.7%d 3/53, 5.7%d Vela-Ojeda et al. [48] 3.1 5.3 3 3 4/28, 14.3% 3/28, 10.7% Growth Factor Alone Ataergin et al. [30] 2.0 3.2 2 1 1/20, 5% 1/20, 5% DiPersio et al. [41] 11.0b 6.2b 1b 4b 0/148, 0% 7/154, 4.5% DiPersio et al. [42] 5.7b 2.0b NS NS NS NS Spitzer et al. [36] 13.3 21.5 NS NS NS NS Stiff et al. [37] 3.6 2.4 NS NS 12/46, 26% 9/55, 16.4% Weisdorf et al. [53] NS NS NS NS NS NS Combination/Non–Cyclophosphamide-Based Chemotherapy Regimens with Growth Factor Andre et al. [39] 12.0 7.2 2 2 NS NS Arora et al. [40] 12.8 16.4 NS NS 7/72, 9.7%d 7/72, 9.7%d Copelan et al. [31] 9.9b 5.6b 3 4 1/28, 3.6% 4/27, 14.8% Demirer et al. [32] 8.2b 4.7b 1b 2b NS NS Hohaus et al. [34] 5.6 7.6 NS NS NS NS Hart et al. [29] 15.4 12.6 1.3 1.8 0/14, 0% 2/12, 16.7% Kim et al. [45] 15.8 19.4 1 1 0/40, 0%d 0/40, 0%d Kopf et al. [46]a 5.8/4.0 8.4 1/1 1 NS/NS NS Ozcelik et al. [52] 10.8 10.5 1 1 3/23, 13% 4/25, 16% Shi et al. [35] 27.3 36.0 3 3 0/30, 0%d 0/30, 0%d Weaver et al. [49] 8.5 11.1 NS NS NS NS Weaver et al. [38]a 5.4/10.5 12.0 3/2 2 4/49, 8.2%/1/52, 1.9% 2/49, 4.1%

HSC indicates hematopoietic stem cell; Gp1, comparator 1; Gp2, comparator 2; NS, not stated; ND, no difference. aStudies with 3 arms; data for 2 experimental arms separated by forward slash. bStatistically significant difference. cMean (rather than median) calculated. dResult provided for the study cohort combined. the option of a rescue procedure using plerixafor and neutrophil recovery was shorter with a higher dose of filgrastim. Of the 10 patients in the plerixafor arm filgrastim (9 vs 12 days for 16 vs 8 mcg/kg/day; P \ and the 52 patients in the filgrastim-alone arm eligible .001) [32] and without the addition of cisplatin (13 vs for rescue, 4 (40%) and 33 (64%), respectively, 15 days; P \ .0001) [49]. In the three-arm study com- achieved a CD341 cell count of at least 2 Â 106/kg paring filgrastim to sargramostim to both sequentially, in #4 aphereses. Fifty-two of these patients (84%) pro- neutrophil recovery was more rapid with a filgrastim- ceeded to transplantation. containing regimen (11 days with filgrastim vs 14 The majority of studies (83%) defined neutrophil days with sargramostim; P \ .0001 and 12 days with recovery post autologous HSCT as a neutrophil count both given sequentially; P \ .001) [38]. of at least 0.5 Â 109/L for 1 to 3 days. Platelet recovery Platelet recovery was faster with cyclophospha- was defined as a platelet count of 20 Â 109/L in 68% of mide plus filgrastim compared to DHAP plus filgras- studies (Table 7). In the group of studies that used a cy- tim (10 vs 13 days; P 5 .022) [18]. In a growth clophosphamide with growth factor strategy, time to factor-alone strategy, filgrastim was associated with neutrophil recovery was improved with filgrastim more rapid platelet recovery than molgramostim (17 over molgramostim (11 vs 15 days; P \ .001) [41] vs 28; P 5 .04) [53]. In a non–cyclophosphamide- and with cyclophosphamide over ifosfamide (13 vs 16 based chemotherapy with growth factor strategy, the days; P \ .02) [48]. Similarly, in patients that under- addition of cisplatin resulted in a delayed time to plate- went mobilization with growth factor alone, neutro- let recovery (14 vs 13 days; P 5 .009) [49]. phil recovery was faster with filgrastim compared with molgramostim (13 vs 15 days; P 5 .01) [53].In Safety patients receiving combination chemotherapy or Limited safety data were reported in the reviewed non–cyclophosphamide-based chemotherapy, time to studies. The most commonly reported adverse event Biol Blood Marrow Transplant 18:1191-1203, 2012 Hematopoietic Stem Cell Mobilization Strategies 1199

Table 7. Neutrophil and Platelet Recovery DISCUSSION

Neutrophil Platelet Autologous HSCT is an important treatment mo- Recovery, Recovery, Median Days Median Days dality in the management of patients with hematologic malignancies. Requisite for auto-HSCT is the collec- Study Gp1 Gp2 Gp1 Gp2 tion of an adequate number of HSCs. Our systematic Cyclophosphamide with Growth Factor review identified 29 RCTs of HSC mobilization strat- Ahn et al. [28] 11 9.5 11 8 egies before autologous transplantation for hemato- Demuynck et al. [33] 15b 11b NS NS Facon et al. [43] 10 10 9 10 logic malignancies. Gazitt et al. [44]a 10/11 11 11/11 11 Although differences were reported with the vari- Martinez et al. [47] 13.3 17.2 11.6 13.4 ous approaches, and some strategies were superior Min et al. [51] 11 11 19 16 Narayanasami et al. [50] 11 11 14 13 with regard to the reported outcomes, all approaches Pavone et al. [18] 91013b 10b were successful in mobilizing adequate numbers of Quittet et al. A [27] 11 11 15 15 CD341 cells in the majority of patients. In general, Quittet et al. B [27] 11 11 15 15 1 Vela-Ojeda et al. [48] 16b 13b 17 15 more CD34 cells were collected by strategies using Growth Factor Alone higher doses of G-CSF, by adding chemotherapy to Ataergin et al. [30] 11 10 12 11 G-CSF, or by combining G-CSF with either ancestim DiPersio et al. [41] 11 11 18 18 DiPersio et al. [42] 10 10 20 20 or the novel agent plerixafor. In addition, some strate- Spitzer et al. [36] 18 21 16 16 gies decreased the number of aphereses required to Stiff et al. [37] 10 10 12 12 reach a target CD341 cell dose. These gains came Weisdorf et al. [53] 15b 13b 28b 17b Combination/Non–Cyclophosphamide-Based Chemotherapy with the issues of tolerability (allergic potential of Regimens with Growth Factor ancestim), the risk of febrile neutropenia and hospital- Andre et al. [39] 88 99ization, and potential delay of collection with chemo- Arora et al. [40] 10 10 11 11 Copelan et al. [31] 10 10 16 17 therapy or up front higher costs of the novel agent Demirer et al. [32] 9b 12b 12 13 plerixafor. Unfortunately, the reported studies Hohaus et al. [34] 13 11.5 NS NS provided little information regarding these ancillary Hart et al. [29] 10.7 10.9 ND ND Kim et al. [45] 10 10 11 12 issues. Kopf et al. [51]a NS/NS NS NS/NS NS Despite multiple attempts to improve HSC yield, Ozcelik et al. [52] 13.6 12.6 NS NS in 5% to 46% [54,55] of patients, there is failure to Shi et al. [35] 10 10 12 12 Weaver et al. [49] 15b 13b 14b 13b collect adequate HSCs. Predictors of mobilization Weaver et al. [38]a 14b/12b 11b ND/ND ND failure include older age [56], previous chemotherapy Gp1 indicates comparator 1; Gp2, comparator 2; NS, not stated; ND, no [57,58], exposure to lenalidomide [59], and extensive difference. bone marrow involvement by malignancy. However, aStudies with 3 arms; data for 2 experimental arms separated by forward there is presently no reliable way to determine which slash. patients are most likely to fail mobilization and, hence, bStatistically significant difference. could potentially benefit from a novel mobilization strategy. The Italian Group for Stem Cell Transplan- tation (GITMO) recently proposed a set of clinical cri- was febrile neutropenia, which was reported in 43% of teria defining patients predicted to be poor mobilizers, studies in which chemotherapy formed part of the although this has not yet been validated [60]. Others mobilization strategy. The percentage of patients de- have reported on the utility of CD341 cell counts to veloping this complication varied from 2% to 100%. determine which patients might benefit from the pre- The proportion of patients requiring hospital admis- emptive addition of plerixafor [61,62]. sion was documented in 3 studies, all of which used In 2 recent phase III studies in patients with MM a combination chemotherapy-plus-growth factor strat- [41] and lymphoma [42], plerixafor combined with fil- egy [38,49,50]. In studies where chemotherapy was grastim resulted in a significantly higher proportion of used, the percentage of patients requiring hospital patients achieving the minimum CD341 cell yield admission ranged from 20% to 48% [38,49,54]. than filgrastim alone. Moreover, patients failing initial The number of patients requiring admission to an collection could be effectively rescued with plerixafor intensive care unit was not reported in any of the and filgrastim, such that 100% of patients with MM, studies. Mortality at 100 days was reported in 2 and 84% of patients with lymphoma could proceed studies [31,43]. In the Copelan publication [31],1 to transplantation. However, it is notable that in death was observed in each of the groups receiving both these studies, there was higher than anticipated etoposide and filgrastim with and without rituximab. primary mobilization failure in the control (filgrastim In the Facon [43] study of the addition of ancestim to alone) arm. The Food & Drug Administration- cyclophosphamide and filgrastim, no deaths were approved filgrastim dose of 10 mcg/kg may have observed. been suboptimal, particularly if these results are to 1200 D. Sheppard et al. Biol Blood Marrow Transplant 18:1191-1203, 2012 be applied to a population of patients with known risk detect differences, and most were of modest methodo- factors for mobilization failure. logical quality. The study populations varied in terms Beyond the data previously cited, published experi- of diseases, number and type of prior treatments, and ence with the newest agent, plerixafor, is limited, and interventions studied. Additionally, the summary sta- many groups are exploring how best to use it in mobi- tistics varied between studies. These factors precluded lization. One strategy is to use plerixafor pre-emptively a meaningful meta-analysis and make it difficult to for patients deemed to be at high risk for mobilization draw definitive conclusions from these data. failure based on a pre mobilization risk profile, pre How then to apply these data? If all approaches are collection peripheral blood CD341 cell count, or reasonable, other criteria must be considered when de- day 1 CD341 cell yield. A recent study used recursive ciding on a mobilization strategy for a group of pa- partitioning analysis to define a day 1 CD341 cell tients or a program. The choice should reflect the yield of #0.7 Â 106/kg that predicts mobilization fail- unique circumstances of the program and the health ure [61]. Abhyankar et al. [62] described a pre-emptive care system in which they function. Identifying which or risk-based algorithm for the use of plerixafor. Pa- issue or issues limit the efficiency of graft collection tients were identified as being at risk for mobilization will enable the program to identify the approach that failure based on a low CD341 cell yield on the first best accommodates or addresses the limitations. day of collection. Of 159 patients undergoing HSC Unfortunately, the solution may not necessarily re- collection using this approach, 151 (95%) provided flect optimal medical practice but may reflect resource adequate collections with one mobilization attempt. limitations, budgetary or cost allocation issues, lack of Costa et al. [63] developed a cost-based algorithm access to particular drugs, or other issues unique to based on CD341 cell count on the fourth day of growth a program or patient. For example, if drug acquisition factor and the target CD341 cell count to decide whether cost is limiting, and the program does not have overall to add plerixafor. The mobilization failure rate was budget control that would allow them to recoup the reduced to 2% from 22% in a historical cohort mobilized savings associated with fewer aphereses or the avoid- with cyclophosphamide and growth factor. Others have ance of febrile neutropenia, then plerixafor may not attempted to create similar algorithms based on cost- be an option for that program—at least not until effectiveness analyses [64-66]. Recently, plerixafor has broader arguments can effectively be developed. If ac- been studied in the context of mobilization with cess to transplantation beds is limiting, the center chemotherapy plus growth factor [67,68]. Attolico et al. may wish to use chemotherapy as part of the mobiliza- [68] reportedonthesafetyandefficacy of plerixafor ‘‘res- tion strategy with the hopes of providing some disease cue’’ in predicted poor mobilizers undergoing chemo- control while waiting to start the transplantation con- therapy plus growth factor-based mobilization. ditioning. This may be reasonable, although chemo- HSC yield is not the only consideration when therapy with mobilization has not been shown to choosing an optimal mobilization strategy. Mobiliza- decrease tumor contamination of the graft or result in tion chemotherapy is commonly used to purge the improved survival if patients proceed directly to trans- stem cell product in vivo from circulating malignant plantation [50,73]. In another setting, restrictions put cells or as part of salvage chemotherapy despite the on the use of specific agents by licensing bodies or lack of clear benefit. In a study by Gazitt et al. [69], third-party payers may restrict innovative use of novel lymphoma cell mobilization was identified in 35% of agents or application of them as part of front-line patients tested. Circulating lymphoma cells were approaches. For example, in Canada, the special more prevalent in patients who failed to mobilize in access program, pending plerixafor’s approval, did not 2 days than in those who mobilized successfully. How- allow the addition of plerixafor during mobilization ever, as recently reviewed by DiPersio et al. [70], the for patients identified as failing mobilization based on relevance of clonal B cells collected along with periph- a low peripheral blood CD34 count after 4 or 5 days eral blood HSCs remains uncertain. The technique of G-CSF. On a more positive note, if access to used to collect the stem cells is also important. For ex- apheresis slots is limiting but budget allows, the ample, large volume leukapheresis has been associated introduction of plerixafor could facilitate reproducible with improved yields but increased adverse effects in- scheduling, and, as reported, fewer aphereses per cluding thrombocytopenia and muscle and bone pain patient, easing this bottleneck for a program. [71]. Finally, there is also a growing body of literature Other considerations may be difficult to quantify. suggesting that higher numbers of lymphocytes in the By enhancing CD341 cell yield, plerixafor was able stem cell product and specifically natural killer cell to rescue some patients with NHL who failed to mobi- content, lead to improved survival posttransplantation lize an adequate graft. These patients then had the op- [72]. These issues were not adjusted for nor addressed portunity to undergo a potentially curative autologous in the reviewed studies. HSCT. The downstream benefit of this includes de- This review has several limitations. Most of the creasing the number of patients receiving potentially studies reviewed were small with limited power to expensive but ineffective palliative therapy or a much Biol Blood Marrow Transplant 18:1191-1203, 2012 Hematopoietic Stem Cell Mobilization Strategies 1201 more complicated and expensive salvage approach chemotherapy in multiple myeloma. Intergroupe Français du with an allogeneic HSCT. How to best quantify these Myelome. 1996;335:91-97. 2. Child JA, Morgan GJ, Davies FE, et al. High-dose chemother- tradeoffs in an objective manner should be the focus of apy with hematopoietic stem-cell rescue for multiple myeloma. future studies. N Engl J Med. 2003;348:1875-1883. Important questions remain. First, the value of 3. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone combining cyclophosphamide and growth factor over marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lym- growth factor alone has been shown in one, small, ran- phoma. N Engl J Med. 1995;333:1540-1545. domized study in patients with lymphoma. The opti- 4. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional mal chemotherapy regimen has not been defined in chemotherapy compared with high-dose chemotherapy with au- any patient population, and the benefit of adding tologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. chemotherapy at all has not been studied in an RCT 2002;359:2065-2071. involving patients with MM. Given the apparent lack 5. Demirer T, Buckner CD, Gooley T, et al. Factors influencing of benefit in terms of disease response [73], it is un- collection of peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant. 1996;17:937-941. known whether the potential benefit outweighs the 6. Perea G, Sureda A, Martino R, et al. Predictive factors for a suc- risks and cost associated with febrile neutropenia and cessful mobilization of peripheral blood CD341 cells in multi- the need for hospital admission in a substantial propor- ple myeloma. Ann Hematol. 2001;80:592-597. € tion of patients. Second, the optimal use of plerixafor 7. Kuittinen T, Nousiainen T, Halonen P, Mahlamaki E, Jantunen E. Prediction of mobilisation failure in patients with has yet to be defined. It is likely that a risk-adapted non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2004;33: approach will ultimately provide the greatest clinical 907-912. benefit, while remaining cost-effective. Third, the rel- 8. Akhtar S, Weshi AE, Rahal M, et al. 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