Bone Marrow Transplantation (2011) 46, 936–942 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt

ORIGINAL ARTICLE Ancestim (r-metHuSCF) plus filgrastim and/or chemotherapy for mobilization of blood progenitors in 513 poorly mobilizing cancer patients: the French compassionate experience

V Lapierre1, J-F Rossi2,3, F Heshmati4, N Azar5, A Vekhof 6, C Makowski7, P Moreau8, D Caillot9, A Auperin1 and C Chabannon10,11

1Institut Gustave Roussy, Villejuif, France; 2Centre Hospitalier et Universitaire, Montpellier, France; 3Inserm, CIC-B509, Centre d’Investigations Cliniques en Biothe´rapie, Montpellier, France; 4Hoˆpital Cochin, Assistance Publique des Hoˆpitaux de Paris, Paris, France; 5Hoˆpital de la Pitie´-Salpeˆtrie`re, Assistance Publique des Hoˆpitaux de Paris, Paris, France; 6Hoˆpital de l’Hoˆtel-Dieu, Assistance Publique des Hoˆpitaux de Paris, Paris, France; 7Centre Hospitalier et Universitaire, Grenoble, France; 8Centre Hospitalier et Universitaire, Nantes, France; 9Centre Hospitalier et Universitaire, Dijon, France; 10Institut Paoli-Calmettes, Marseille, France and 11Inserm, CIC-B510, Centre d’Investigations Cliniques en Biothe´rapie, Marseille, France

Ancestim (r-MetHuSCF) is available in France for Keywords: stem cell mobilization; high-dose chemo- compassionate use in patients who are candidates for therapy; clinical transplantation; SCF; G-CSF high-dose chemotherapy and autologous transplantation, and who failed in previous attempts at mobilization and collection. We report here data from 513 adult patients who benefited from this program, between January 1998 and July 2007. Given with systematic premedication, Introduction ancestim was generally well tolerated, although severe but not life-threatening adverse events were reported in 12 Despite the introduction of innovative therapies that target individuals. Overall, a graft was obtained or completed for identified molecular and cellular mechanisms in various 235 patients (46%). The median number of collected cancers, dose intensification remains a useful option for a CD34 þ cells was 3.00 Â 106/kg (range: 0.03–39.50). The number of patients with mostly stage II/III multiple target threshold of 2 Â 106 CD34 þ cells/kg was reached myelomas and a variety of lymphomas.1,2 Patients receiving in 161 patients (31%). Factors associated with collection high-dose chemotherapy also receive autologous trans- were diagnosis of myeloma, no previous autologous plantation, which can be performed if they have successful transplant, no more than one previous failed attempt and mobilization and collection of hematopoietic stem and a mobilization regimen including cytotoxic agents. A total progenitor cells from peripheral blood. Mobilization of 207 patients (40%) proceeded to high-dose chemother- procedures require G-CSF alone or with certain cytotoxic apy and autologous transplantation. The median time to agents, including alkylating agents such as cyclophosphamide.2 reach 0.5 Â 109/L neutrophils and 20 Â 109/L platelets The quantity of collected and then infused autologous was 12 (6–40) and 13 (0–31) days, respectively. We CD34 þ cells is a predictor of neutrophil and platelet conclude that a combination of ancestim with filgrastim recovery following high-dose chemotherapy.3–5 There is a successfully mobilized CD34 þ cells in peripheral blood, large interindividual variability in response to mobilizing and allowed adequate collection in preparation for agents; reasons for this variability are not completely autologous transplantation in approximately one-third of elucidated, and include genetic polymorphisms6–8 and poorly mobilizing patients. elements of medical history, such as the amount and Bone Marrow Transplantation (2011) 46, 936–942; duration of previous myelotoxic treatments. Recently, doi:10.1038/bmt.2010.231; published online 18 October 2010 plerixafor, formerly known as AMD-3100, was shown to be useful in association with G-CSF for a proportion of poorly mobilizing patients.9–12 Recombinant human SCF (rhSCF) or ancestim has also been used in this patient subset. Correspondence: Dr V Lapierre, Centre de The´rapie Cellulaire, Institut 13 Gustave Roussy, Centre de Lutte Contre le Cancer, 39 rue Camille Endogenous SCF is the ligand for c-kit, a membrane Desmoulins, Villejuif cedex 94805, France. receptor with tyrosine kinase activity that is expressed on E-mail: [email protected] several tissues, including subsets of the hematopoietic This work was reported in part at the 2004 American Society for Clinical system. SCF is known to induce stem and progenitor cell Oncology (ASCO) annual meeting and the 2007 American Society of Hematology (ASH) annual meeting. mobilization from the marrow to the blood compartment. Received 11 November 2009; revised 14 June 2010; accepted 18 July However, its effects on basophils and mastocytes may 2010; published online 18 October 2010 result in intense allergy-like phenomena,14 which makes its Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 937 clinical use less convenient than that of G-CSF. Never- Table 1 Patients’ characteristics theless, subcutaneously administered SCF has been used in Sex (M/F) 258/255 small series of poorly mobilizing patients, allowing auto- logous collection and transplantation in a proportion of Age, years, median (range) 55 (18–74) these individuals, in association with antihistaminic and 18–54 years old 244 (48%) broncho-dilatators and under close clinical surveillance.15–20 455 years old 269 (52%) We report here the largest series of 513 poorly mobilizing Weight, kg, median (range) 68 (40–115) adult patients, with a variety of malignancies, who received ancestim plus filgrastim following one or several previous Diagnosis failed attempts with G-CSF; French investigators took Lymphoma 280 (55%) advantage of the compassionate program allowing access Multiple myeloma 163 (32%) Chronic lymphocytic leukemia 35 (7%) to this drug. We further report that SCF can be successfully Sarcoma 13 (3%) and safely used in this subset of patients. Testis and ovarian tumor 11 (2%) Other 11 (2%)

Disease status Patients and methods CR 160 (34%) PR and good response 267 (56%) Patients Progressive disease or relapse 49 (10%) A total of 550 adult patients were considered as poor Prior chemotherapy cycles, median (range) 8 (1–59) 6 mobilizers, because less than 2 Â 10 CD34 þ cells/kg were p8 cycles 278 (54%) collected during one or several attempts at mobilization/ 48 cycles 235 (46%) apheresis with standard mobilization regimens. They benefited from a French compassionate program (‘Auto- Prior HDCT and autologous transplantation 19 (4%) risation Temporaire d’Utilisation, ATU nominative’ or Prior attempts at mobilization and collection individual temporary authorization for use) over a 10-year 1 315 (61%) period, between April 1998 and July 2007. The program 41 198 (39%) Autorisation Temporaire d’Utilisation was delivered by the Mobilization procedure French Health Regulatory Authority (AFSSaPS, Agence G-CSF 132 (26%) Franc¸aise de Se´curite´Sanitaire) on an individual basis, in Chemotherapy+G-CSF 297 (58%) compliance with the criteria defined by the Groupe de Both procedures 84 (16%) Travail sur les Me´dicaments Anti-Cance´reux (a working Prior CD34+ cell collection group at AFSSaPS, which defines acceptable and non- No 394 (77 %) acceptable use of anticancer agents, using an evidence- Yes 119 (23%) based approach). These patients were candidates for Collected CD34+ cells per kg of weight, 1.2 Â 106 (0.0–6.0) high-dose chemotherapy and autologous transplantation, median (range) for stage II/III multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, refractory chronic lymphocytic leukae- Abbreviations: F ¼ female; M ¼ male. Note: data were not systematically available for all patients (see the section mia, stage IV neuroblastoma, Ewing’s sarcoma, testis Patients and methods, and Figure 1). cancer or ovarian cancer. Data on treatment administration, tolerance, mobiliza- tion and collection were available for 513 of these 550 registered patients (93.3%), and are presented in this report. Patients’ characteristics are described in Table 1. AFSSaPS and Amgen (through a clinical research organi- Among these 513 patients, 394 (77%) had total failure zation). Filgrastim (Neupogen, Amgen Inc) is also an (no apheresis) and 119 (23%) had partial failure (one or E. coli-genetically engineered recombinant protein. The several aphereses were performed, but yielded insufficient administration of r-metHuSCF (20 mg/kg/day, s.c.) was numbers of progenitors) after mobilization and collection given with premedication that included daily ranitidine p.o. attempts. A total of 2, 7, 25, 165 and 314 patients had (started 24 h before initiation of ancestim), cetririzine HCl had, respectively, 5, 4, 3, 2 and 1 previous mobilization/ p.o. and salbutamol sulphate inhalation shortly before each collection attempts when they received SCF. The peak of the ancestim s.c. injections. Health-care personnel were mean value of CD34 þ cells at the last mobilization instructed to exclusively administer ancestim through s.c. attempt before ancestim use was 5.75/mL (SD 5.74). injections. The combination of cytokines was administered either after blood count recovery following the last cycle of anticancer treatment (in this case, the prescribed Ancestim administration dose of filgrastim was 10 mg/kg/d), or starting on day 1 r-metHuSCF used in this setting was produced using after myelosuppressive chemotherapy (in this case, the E. coli, genetically engineered to express a methionine- prescribed dose of filgrastim was 5 mg/kg/d); the clinical terminated recombinant version of human SCF (ancestim: investigator filing the ATU with AFSSaPS was responsible Stemgen, Amgen Inc, Thousand Oaks, CA, USA). Ances- for the choice of the mobilization regimen. In all, 57% tim was provided by Amgen, on acceptance by AFSSaPS of of patients received ancestim combined with filgrastim an ATU for designated patients; data were reported to (10 mg/kg/day) for a median of 6 days (range: 2–21); the

Bone Marrow Transplantation Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 938 other patients received chemotherapy followed by ancestim despite recommendations for s.c. administration; these two combined with filgrastim (5 mg/kg/day) for a median of patients developed grade III mast-cell-mediated toxicities, 11 days (range: 1–33), similar to practices described in and the drug was discontinued. Three other patients previous reports.16 developed severe but reversible pharyngo-laryngeal oedema with hypotension. Three patients experienced dyspnea, in Biological monitoring of mobilization and peripheral blood one of whom was documented interstitial pneumonia. collections Three patients presented with neurological symptoms (epilepsy, syncope, facial palsy), one of which was rapidly Peripheral blood CD34 þ cell counts, aphereses and fatal (epilepsy, with documented central nervous system CD34 þ cell counts in collected cell products were determined at each of the 64 centres that reported data, localization); it was unclear whether ancestim or tumour according to local standard operating procedures. Our progression was partly or totally responsible for the clinical report summarizes results observed in individual cases and symptoms in the other two individuals. One patient centres; thus, there was no attempt to standardize medical developed acute and reversible hepatic cytolysis of probably and laboratory practices in clinical, collection and proces- toxic origin, as suggested by histological analysis of a liver sing facilities. However, French regulations apply to the biopsy. In all cases, ancestim was immediately stopped, and processing facilities that are authorized by AFSSaPS, which the collection was abandoned. With the exception of the one death mentioned above, all these events were reversible participate in a nationwide annual survey on CD34 þ cell enumeration, thus ensuring the standardization of collec- without sequelae, with a follow-up of 6 months. tion, processing and quality control procedures performed in these facilities.21 Aphereses were conducted as per Ancestim combined with filgrastim allows for adequate standard operating procedures of French centres , in which mobilization and collection in approximately 40% of collection facilities tend to process a minimum of two total poorly mobilizing patients blood volumes when patients poorly mobilize. A total of 235 patients (46%) did proceed to apheresis following mobilization with an ancestim-based regimen Statistical analyses (Table 2). Peripheral blood CD34 þ counts reached a Continuous variables are presented by median and range, median number of 19.1 mL (range: 0.1–145.0) for these and categorical variables by frequency and percentage. The patients. A median number of two aphereses were analysis of factors associated with collection of CD34 þ performed (range: 1–6). The median number of collected cell numbers above 2 Â 106/kg and the analysis of factors CD34 þ cells was 3.00 Â 106/kg (range: 0.03–39.50). The associated with proceeding to autologous transplantation procedure allowed the collection of a cumulative number were performed by logistic regression. Multiple logistic of CD34 þ cells above 2 Â 106/kg in 161 patients. This regression with stepwise selection was used to identify represents 68.5% of patients in whom collection was independent factors associated with CD34 þ cell numbers performed and in 31% of all individuals in this survey above 2 Â 106/kg and autologous transplantation. The (30% of patients with no previous collection, 36% of those factors included in the multivariate analysis were those with insufficient numbers of previously collected cells; the with a P-value lower than 0.20 in univariate analysis. proportion was identical whether patients had previously Associations were described by odds ratio with 95% had one, two, three or four attempts at mobilization/ confidence interval. All P-values were based on a two- collection; none of the two patients who had five previous sided hypothesis. Analyses were performed using SAS 9.1 software. Table 2 Mobilization procedure and results with ancestim

Patients Patients who who were were not Results collected collected

Ancestim is well tolerated in poorly mobilizing patients No. 235 278 Information on toxicity was available for 508 of the 513 Mobilization procedure observed patients. Most patients experienced reversible G-CSF 125 (53%) 167 (60%) grade I–II toxicities despite premedication with antihista- Cyclophosphamide+G-CSF 74 (31%) 74 (27%) mine agents and broncho-dilatators. In all, 66% of the Other 36 (15%) 37 (13%) patients experienced a local reaction at the site of injection. Collection Other toxicities were reported in 16.5% (84 of 508) of Peripheral blood CD34+ cell 19.1 (0.1–145.0) 3.0 (0.0–15.0) treated patients; some of the symptoms experienced include count (/mL), median (range) diffuse erythema (12%), bone or joint pain (8%), influenza- Collected CD34+ cells ( Â 106 3.00 (0.03–39.05) NA like syndrome (4%), fever (3%), moderate oedema (2%), CD34+ cells/kg), median (range) pruritus (1%) and vomiting (1%). Ancestim was not No. of apheresis, median (range) 2 (1–6) NA discontinued, and patients proceeded to blood CD34 þ a cell enumeration and eventual apheresis. Patients transplanted 207 (40%) NA Severe adverse events were reported for 12 (2.4%) Abbreviation: NA ¼ not applicable. patients; all but one were grade III. Two of the 12 patients aWith SCF-mobilized cells only or plus progenitors collected in previous inadvertently received ancestim through the i.v. route, attempts or BM harvest.

Bone Marrow Transplantation Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 939

550 registered patients

513 patients with available data

119 patients with an 394 patients with no already available graft available graft

46 patients who failed 73 patients underwent 162 patients underwent 232 patients who failed mobilization with aphereses after aphereses after mobilization with ancestim ancestim mobilization ancestim mobilization ancestim

30 patients with < 43 patients with ≥ 118 patients with ≥ 44 patients with < 6 + 6 + 2x10 CD34 cells/kg 2x10 CD34 cells/kg 2x106 CD34+ cells/kg 2x106 CD34+ cells/kg

9 patients not 21 patients 25 patients 19 patients not transplanted transplanted transplanted transplanted

207 patients transplanted

138 patients for whom data are available on engraftment

Figure 1 A flowchart of patient analysis, showing figures at each step and in each subgroup.

attempts at mobilization/collection were apheresed follow- Peripheral blood grafts mobilized and collected with ing SCF administration); 74 additional patients were ancestim and filgrastim support adequate engraftment apheresed, which resulted in ancestim-mobilized peripheral after autologous transplantation blood progenitor cell grafts with less than 2 Â 106 CD34 þ Data on engraftment were available for 138 of the cells/kg; 46 of these patients finally underwent intensive 207 transplanted patients. The median time to neutrophil chemotherapy and autologous transplantation with a recovery (40.5 Â 109/L) and platelet recovery (420 Â 109/L, combination of several autologous peripheral blood pro- without platelet transfusion) was 12 (range: 5–40) and 13 genitor cell collections or of peripheral blood progenitor (range: 3–51) days, respectively. cell collection with marrow collection (Figure 1); in total, 207 out of 513, that is, 40% of the patients, proceeded to autologous transplantation and received a graft that was Discussion obtained exclusively or partially after an ancestim-based mobilization regimen. We report here that the combination of ancestim with A total of 278 patients were not apheresed, as their filgrastim allowed successful mobilization and collection of peripheral blood CD34 þ cell counts remained low: 3 CD34 þ progenitors in the peripheral blood of approxi- (range: 0–15) CD34 þ cells/mL. mately one-third of patients who failed previous attempts Table 3 presents the results of the variables that at mobilization and collection. An insufficient number of correlated with collection success. Diagnosis, previous autologous blood progenitors can compromise the use of treatments (numbers of previous chemotherapy cycles, an efficacious systemic therapy program that includes high- previous high-dose chemotherapy supported by autologous dose chemotherapy as a final consolidation step. Thus, transplantation), the number of previous failed attempts at identifying agents to improve stem and progenitor cell mobilization, the type of procedure used in previous mobilization in peripheral blood is an important issue. collection attempts and the type of mobilization procedure, The use of ancestim in poorly mobilizing patients was along with ancestim and its duration, significantly affected previously reported for several small groups of patients. the success of ancestim mobilization. In multivariate Patients who had been heavily pretreated for Hodgkin’s or analysis, factors independently associated with mobiliza- non-Hodgkin’s lymphoma mobilized more efficiently in tion and transplantation success were diagnosis (patients response to ancestim plus filgrastim than to filgrastim with multiple myeloma had a higher probability of success alone.15 A higher success rate was reported in two small than did patients with lymphoma), the absence of previous subgroups of heavily pretreated patients.16,17 Dawson high-dose chemotherapy supported by autologous trans- et al.18 reported a 38% success rate in poorly mobilizing plantation, no more than one previous failed attempt and patients treated for malignant blood diseases, mostly patients who had received a mobilization regimen including lymphoid neoplasms. Herbert et al.19 recently reported an cytotoxic agents (cyclophosphamide or others). improved rate of collection success in patients with chronic

Bone Marrow Transplantation Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 940 Table 3 Analysis of variables correlating with collection success and autologous transplantation, a small subset of indivi- (X2 Â 106 CD34+ cells/kg) duals treated for sarcomas, as well as for testis or ovarian Variable Rate Univariate Multivariate cancers, was also included in our study. of analysis, analysis Observations from this large cohort of patients suggest success P-value P-value, OR that variables that are positively or negatively associated (95%CI) with the success of mobilization with G-CSF also predict to Sex some extent the success or failure of an ancestim-based Male 31% 0.78 mobilization regimen (and subsequent autologous trans- Female 32% plantation); these variables include diagnosis (myeloma patients mobilize their hematopoietic progenitors better Age than do patients with other diagnoses), cumulative and 18–54 years 27% 0.07 NS X55 years 35% previous treatments (having already received an intensive chemotherapy regimen supported by autologous transplan- Weight tation), previous insufficient collection of an autologous 65 kg 32% 0.94 blood graft in response to a standard mobilization regimen 465 kg 31% and the use of ancestim and filgrastim in combination with Diagnosis o0.0001 o0.0001 a myelosuppressive chemotherapy rather than by them- Lymphoma 24% 1 selves. Conversely, tumour response was not a predictor of Myeloma 44% 2.8 (1.8–4.4) success for ancestim mobilization, as there was a non- Other 33% 1.6 (0.9–2.9) significant excess of patients in PR in the ‘success’ group: Disease status 0.08 NS this is probably the consequence of the higher rate of CR 24% mobilization success in patients with multiple myeloma, PR 35% whereas only a minority of these patients obtain complete Progressive disease 33% remission before receiving high-dose melphalan and auto- No. of previous 0.02 NS logous transplantation. 22 chemotherapy cycles Choice of mobilizing agents is limited, as many p8 36% hematopoietic growth factors and cytokines are not or 48 26% are no longer available for clinical use.23 The use of biosimilars24,25 or of a pegylated and long-lasting form of Previous high-dose chemotherapy 0.046 0.022 26,27 and autologous transplant rhG-CSF is unlikely to significantly improve the Yes 11% 1 ‘mobilization index’. Parathyroid hormone was even tested No 32% 5.8 (1.3–27.0) in a phase I trial for mobilization, and was well tolerated, with successful collection in 9 out of 20 poorly mobilizing No. of previous and/or failed 0.048 0.053 28 attempts patients. In addition, administration of recombinant human 1 35% 1.5 (1.0–2.3) growth hormone plus G-CSF was associated with 13 of X2 26% 1 15 successful collections compared with none with G-CSF alone in patients who had failed one previous attempt.29 Procedure for previous attempts 0.024 NS Recently, drugs targeting the CXCR-4/CXCL12 axis at collection Cytokine alone 38% showed interesting results. Plerixafor has been tested in Cytokine and chemotherapy 32% several clinical studies, which demonstrated its efficacy on agents progenitor cell collection when used upfront in combina- Both 20% tion with G-CSF in healthy volunteers30,31 or in patients 32–35 Mobilization procedure along with 0.003 0.0008 with lymphoid malignancies. In addition, several ancestim studies reported the use of plerixafor in poorly mobilizing Ancestim and filgrastim 25% 1 patients, with a success rate ranging from 66 to 85% in Cytokines and cyclophosphamide 40% 2.0 (1.3–3.1) small- to medium-sized patient groups.9–12 On the basis of Cytokines and other 39% 2.4 (1.4–4.2) these findings, plerixafor is being used more widely in chemotherapy clinical practice.36,37 Nevertheless, no direct comparison Duration of exposure to ancestim 0.009 NS data between plerixafor and ancestim are currently avail- o8 days 26% able in poorly mobilizing patients. Patients in our cohort X8 days) 37% were heavily pretreated, and may differ from patients who received plerixafor in the above-mentioned studies. Finally, Abbreviation: 95% CI ¼ 95% confidence interval. one-fourth to one-third of patients who were candidates for autologous blood cell collection and transplantation experi- enced failure after treatment with G-CSF and plerixafor; lymphoid leukaemia who were previously treated with this situation leaves room for further improvement. fludarabine. Our data further extend these observations to In conclusion, this large French survey of individuals a larger and more diverse population of patients, with a who were candidates for high-dose chemotherapy and variety of malignancies; although, expectedly, most of the autologous transplantation suggests that the use of SCF cases were multiple myeloma and lymphomas, because of can benefit a significant proportion of poorly mobilizing current practices for the use of high-dose chemotherapy patients.

Bone Marrow Transplantation Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 941 Conflict of interest 7 Bogunia-Kubik K, Gieryng A, Dlubek D, Lange A. The CXCL12-30A allele is associated with a higher mobilization The authors declare no conflict of interest. yield of CD34 progenitors to the peripheral blood of healthy donors for allogeneic transplantation. Bone Marrow Trans- plant 2009; 44: 273–278. 8 Vasu S, Leitman SF, Tisdale JF, Hsieh MM, Childs RW, Acknowledgements Barrett AJ et al. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an The authors deeply acknowledge the strong support of all the ethnically diverse population. Blood 2008; 112: 2092–2100. staff at Amgen France for providing ancestim to patients who 9 Calandra G, McCarty J, McGuirk J, Tricot G, Crocker SA, benefited from an ATU, and Agnes Balog and her team at Badel K et al. AMD3100 plus G-CSF can successfully mobilize Parexel France for organizing the distribution of ancestim to CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s hospitals and the collection of data from treated patients. The disease and multiple myeloma patients previously failing following centres requested ATU for ancestim for one or several mobilization with chemotherapy and/or cytokine treatment: patients: Hoˆpitaux Henri-Mondor, Avicenne, Beaujon, Saint- compassionate use data. Bone Marrow Transplant 2008; 41: Antoine, Saint-Louis, Necker, Paul Brousse, Tenon, Hoˆpital 331–338. Europe´en Georges Pompidou all at Assistance Publique des 10 Fowler CJ, Dunn A, Hayes-Lattin B, Hansen K, Hansen L, Hoˆpitaux de Paris (AP-HP); Centres Hospitaliers et Universi- Lanier K et al. Rescue from failed growth factor and/or taires de Bordeaux, Nancy, Brest, Caen, Reims, Toulouse, Lille, chemotherapy HSC mobilization with G-CSF and plerixafor Besanc¸on, Poitiers, Clermont-Ferrand, Nice, Rennes, Tours, (AMD3100): an institutional experience. Bone Marrow Lyon, Limoges, Strasbourg; Centres de Lutte Contre le Cancer Transplant 2009; 43: 909–917. Caen (Centre Franc¸ois Baclesse), Rouen (Centre Henri Bec- 11 Pusic I, Jiang SY, Landua S, Uy GL, Rettig MP, Cashen AF querel), Paris (Institut Curie), Clermont-Ferrand (Centre Jean et al. Impact of mobilization and remobilization strategies on Perrin), Montpellier (Centre Val d’Aurelle), Bordeaux (Institut achieving sufficient stem cell yields for autologous transplant- Bergonie´), Nancy (Centre Alexis Vautrin), Toulouse (Institut ation. Biol Blood Marrow Transplant 2008; 14: 1045–1056. Claudius Regaud); Centres Hospitaliers de Metz, Mulhouse, 12 Tricot G, Cottler-Fox MH, Calandra G. Safety and efficacy Meaux, Argenteuil, Saint-Denis de la Re´union, Corbeil- assessment of plerixafor in patients with multiple myeloma Essonnes, Avignon, Blois, Pontoise, Boulogne-sur-Mer, Valen- proven or predicted to be poor mobilizers, including assess- ciennes, Lens; Army Hospitals in Percy and Toulon, Hoˆpital ment of tumor cell mobilization. Bone Marrow Transplant Foch, Clinique Victor Hugo in Le Mans, Polyclinique du Parc in 2010; 45: 63–68. Caen and Polyclinique Nord-Aquitaine in Bordeaux. The 13 Galli SJ, Zsebo KM, Geissler EN. The kit ligand, stem cell authors thank all personnel at the departments of Hematology factor. Adv Immunol 1994; 55: 1–96. and Medical Oncology within these institutions, and at 14 Costa JJ, Demetri GD, Harrist TJ, Dvorak AM, Hayes DF, associated apheresis departments, for their help in collecting Merica EA et al. Recombinant human stem cell factor data presented in this report. (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 1996; 183: 2681–2686. References 15 Stiff P, Gingrich R, Luger S, Wyres MR, Brown RA, LeMaistre CF et al. A randomized phase 2 study of PBPC 1 Gratwohl A, Baldomero H, Frauendorfer K, Niederwieser D. mobilization by stem cell factor and filgrastim in heavily Why are there regional differences in stem cell transplantation pretreated patients with Hodgkin’s disease or non-Hodgkin’s activity? An EBMT analysis. Bone Marrow Transplant 2008; 42 lymphoma. Bone Marrow Transplant 2000; 26: 471–481. (Suppl 1): S7–S10. 16 Chin-Yee IH, Keeney M, Stewart AK, Belch A, Bence-Buckler 2 Gratwohl A, Baldomero H, Schwendener A, Rocha V, I, Couban S et al. Optimising parameters for peripheral Frauendorfer K et al. The EBMT activity survey 2007 with blood leukapheresis after r-metHuG-CSF (filgrastim) and focus on allogeneic HSCT for AML and novel cellular r-metHuSCF (ancestim) in patients with multiple myeloma: a therapies. Bone Marrow Transplant 2009; 43: 275–291. temporal analysis of CD34(+) absolute counts and subsets. 3 Bensinger WI, Longin K, Appelbaum F, Rowley S, Weaver C, Bone Marrow Transplant 2002; 30: 851–860. Lilleby K et al. Peripheral blood stem cells (PBSCs) collected 17 To LB, Bashford J, Durrant S, MacMillan J, Schwarer AP, after recombinant granulocyte colony stimulating factor Prince HM et al. Successful mobilization of peripheral blood (rhG-CSF): an analysis of factors correlating with the tempo stem cells after addition of ancestim (stem cell factor) in patients of engraftment after transplantation. Br J Haematol 1994; 87: who had failed a prior mobilization with filgrastim (granulocyte 825–831. colony-stimulating factor) alone or with chemotherapy plus 4 Hartmann O, Le Corroller AG, Blaise D, Michon J, Philip I, filgrastim. Bone Marrow Transplant 2003; 31: 371–378. Norol F et al. Peripheral blood stem cell and bone marrow 18 Dawson MA, Schwarer AP, Muirhead JL, Bailey MJ, Bollard transplantation for solid tumors and lymphomas: hematologic GM, Spencer A. Successful mobilization of peripheral blood recovery and costs. A randomized, controlled trial. Ann Intern stem cells using recombinant human stem cell factor in heavily Med 1997; 126: 600–607. pretreated patients who have failed a previous attempt with 5 Weaver CH, Hazelton B, Birch R, Palmer P, Allen C, a granulocyte colony-stimulating factor-based regimen. Bone Schwartzberg L et al. An analysis of engraftment kinetics as Marrow Transplant 2005; 36: 389–396. a function of the CD34 content of peripheral blood progenitor 19 Herbert KE, Morgan S, Prince HM, Westerman DA, Wolf cell collections in 692 patients after the administration of MM, Carney DA et al. Stem cell factor and high-dose twice myeloablative chemotherapy. Blood 1995; 86: 3961–3969. daily filgrastim is an effective strategy for peripheral blood 6 Benboubker L, Watier H, Carion A, Georget MT, Desbois I, stem cell mobilization in patients with indolent lymphoproli- Colombat P et al. Association between the SDF1-30A allele ferative disorders previously treated with fludarabine: results and high levels of CD34(+) progenitor cells mobilized into of a Phase II study with an historical comparator. Leukemia peripheral blood in humans. Br J Haematol 2001; 113: 247–250. 2008; 23: 305–312.

Bone Marrow Transplantation Ancestim (r-metHuSCF) for poorly mobilizing patients V Lapierre et al 942 20 da Silva MG, Pimentel P, Carvalhais A, Barbosa I, Machado 29 Carlo-Stella C, Di Nicola M, Milani R, Guidetti A, Magni M, A, Campilho F et al. Ancestim (recombinant human stem cell Milanesi M et al. Use of recombinant human growth hormone factor, SCF) in association with filgrastim does not enhance (rhGH) plus recombinant human granulocyte colony-stimulat- chemotherapy and/or growth factor-induced peripheral blood ing factor (rhG-CSF) for the mobilization and collection of progenitor cell (PBPC) mobilization in patients with a prior CD34+ cells in poor mobilizers. Blood 2004; 103: 3287–3295. insufficient PBPC collection. Bone Marrow Transplant 2004; 30 Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, 34: 683–691. Cooper S et al. Mobilization of hematopoietic progenitor cells 21 Panterne B, Sabatini C, Huyghe G, Maquin C, Mouillot L, in healthy volunteers by AMD3100, a CXCR4 antagonist. TIissier MH. External quality controls of cellular products: the Blood 2003; 102: 2728–2730. French experience. Cytotherapy 2006; 8(Suppl 1): 176. 31 Devine SM, Vij R, Rettig M, Todt L, McGlauchlen K, Fisher 22 Pusic I, DiPersio JF. The use of growth factors in hemato- N et al. Rapid mobilization of functional donor hematopoietic poietic stem cell transplantation. Curr Pharm Des 2008; 14: cells without G-CSF using AMD3100, an antagonist of the 1950–1961. CXCR4/SDF-1 interaction. Blood 2008; 112: 990–998. 23 MacVittie TJ, Farese AM, Davis TA, Lind LB, McKearn JP. 32 Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, Myelopoietin, a chimeric agonist of human interleukin 3 and McCarty JM, Rowley SD et al. The use of AMD3100 plus granulocyte colony-stimulating factor receptors, mobilizes G-CSF for autologous hematopoietic progenitor cell mobiliza- CD34+ cells that rapidly engraft lethally x-irradiated non- tion is superior to G-CSF alone. Blood 2005; 106: 1867–1874. human primates. Exp Hematol 1999; 27: 1557–1568. 33 Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf 24 del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau D, Badel K et al. Rapid mobilization of CD34+ cells H. XM02 is superior to placebo and equivalent to Neupogen in following administration of the CXCR4 antagonist reducing the duration of severe neutropenia and the incidence AMD3100 to patients with multiple myeloma and non- of febrile neutropenia in cycle 1 in breast cancer patients Hodgkin’s lymphoma. J Clin Oncol 2004; 22: 1095–1102. receiving docetaxel/doxorubicin chemotherapy. BMC Cancer 34 DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff 2008; 8: 332. PJ, Kaufman JL et al. Plerixafor and G-CSF versus placebo 25 Varki R, Pequignot E, Leavitt MC, Ferber A, Kraft WK. A and G-CSF to mobilize hematopoietic stem cells for auto- glycosylated recombinant human granulocyte colony stimulat- logous stem cell transplantation in patients with multiple ing factor produced in a novel protein production system myeloma. Blood 2009; 113: 5720–5726. (AVI-014) in healthy subjects: a first-in human, single dose, 35 Stiff P, Micallef I, McCarthy P, Magalhaes-Silverman M, controlled study. BMC Clin Pharmacol 2009; 9:2. Weisdorf D, Territo M et al. Treatment with plerixafor in non- 26 Viens P, Chabannon C, Pouillard P, Janvier M, Hodgkin’s lymphoma and multiple myeloma patients to increase Brugger W, Blay JY et al. Randomized, controlled, dose- the number of peripheral blood stem cells when given a mobilizing range study of Ro 25-8315 given before and after a high- regimen of G-CSF: implications for the heavily pretreated patient. dose combination chemotherapy regimen in patients with Biol Blood Marrow Transplant 2009; 15: 249–256. metastatic or recurrent breast cancer patients. J Clin Oncol 36 Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, 2002; 20: 24–36. Bensinger W, Comenzo RL et al. International myeloma 27 Bruns I, Steidl U, Kronenwett R, Fenk R, Graef T, Rohr UP working group (IMWG) consensus statement and guidelines et al. A single dose of 6 or 12 mg of pegfilgrastim for peripheral regarding the current status of stem cell collection and high- blood progenitor cell mobilization results in similar yields of dose therapy for multiple myeloma and the role of plerixafor CD34+ progenitors in patients with multiple myeloma. (AMD 3100). Leukemia 2009; 23: 1904–1912. Transfusion 2006; 46: 180–185. 37 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo 28 Ballen KK, Shpall EJ, Avigan D, Yeap BY, Fisher DC, A, Bensinger W et al. Mobilization in myeloma revisited: McDermott K et al. Phase I trial of parathyroid hormone to IMWG consensus perspectives on stem cell collection follow- facilitate stem cell mobilization. Biol Blood Marrow Transplant ing initial therapy with thalidomide-, lenalidomide-, or 2007; 13: 838–843. bortezomib-containing regimens. Blood 2009; 114: 1729–1735.

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