Bone Marrow Transplantation (2020) 55:613–622 https://doi.org/10.1038/s41409-019-0693-z ARTICLE Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor Anna Sureda1 Christian Chabannon 2 Tamás Masszi3 David Pohlreich4 Christof Scheid5 ● ● ● ● ● Catherine Thieblemont6 Björn E. Wahlin7 Ioanna Sakellari 8 Nigel Russell9 Andrea Janikova10 ● ● ● ● ● Anna Dabrowska-Iwanicka11 Cyrille Touzeau12 Albert Esquirol13 Esa Jantunen14 Steffie van der Werf15 ● ● ● ● ● Paul Bosman15 Ariane Boumendil16 Qianying Liu17 Marina Celanovic17 Silvia Montoto18 Peter Dreger19 ● ● ● ● ● Received: 14 February 2019 / Revised: 3 July 2019 / Accepted: 20 July 2019 / Published online: 30 September 2019 © The Author(s) 2019. This article is published with open access Abstract Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor 1234567890();,: 1234567890();,: mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups. * Anna Sureda 9 Nottingham University Hospital, Nottingham, UK asureda@iconcologia.net 10 University Hospital Brno, Brno, Czech Republic 1 11 Institut Català d’Oncologia, Hospital Duran i Reynals, Maria Sklodowska-Curie Institute-Oncology Center, Barcelona, Spain Warsaw, Poland 2 12 Institut Paoli-Calmettes, Marseille, France CHU Nantes, Nantes, France 3 13 Semmelweis University, Budapest, Hungary Hospital de la Santa Creu Sant Pau, Barcelona, Spain 4 14 Charles University Hospital, Prague, Czech Republic University of Eastern Finland and Kuopio University Hospital, 5 Kuopio, Finland University of Cologne, Cologne, Germany 15 6 EBMT Data Office, Leiden, Netherlands APHP, Hôpital Saint-Louis, Service d’hémato-oncologie, 16 Université Paris Diderot - and Université Sorbonne Paris Cité, EBMT Statistical Unit, Paris, France Paris, France 17 Sanofi Genzyme, Cambridge, MA, USA 7 Karolinska University Hospital, Stockholm, Sweden 18 St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK 8 George Papanicolaou General Hospital, Thessaloniki, Greece 19 University of Heidelberg, Heidelberg, Germany 614 A. Sureda et al. Introduction who received an autologous HSCT (ClinicalTrials.gov number NCT01362972). All patients ≥18 years from the Lymphomas are the second most common indication for EBMT registry, with a diagnosis of lymphoma who were autologous hematopoietic stem cell (HSC) transplantation considered poor mobilizers and had undergone their first (HSCT). The most common method for mobilizing HSCs autologous HSCT between 2008 and 2012, were considered from the peripheral blood is treatment with granulocyte- eligible for the study. Patients in the plerixafor groups who colony stimulating factor (G-CSF) alone or combined with were poor mobilizers were those treated according to the chemotherapy [1, 2]. However, a sizable minority of label. Patients enrolled in the registry and evaluated in this patients fail to mobilize sufficiently with G-CSF-based study were from Austria, Belgium, Bulgaria, Czech regimens [3, 4]. Republic, Finland, France, Germany, Greece, Hungary, Plerixafor has a mode of action different from other HSC Ireland, Israel, Italy, Netherlands, Poland, Romania, Spain, mobilizing agents and acts by binding to chemokine (C-X-C Sweden, Switzerland, and the United Kingdom. motif) receptor 4 (CXCR4), preventing the binding of its The study was conducted in accordance with the ligand stromal cell-derived factor 1 (SDF-1, now C-X-C Declaration of Helsinki and the International Conference on motif chemokine 12, CXCL12) and thereby inhibiting Harmonization Guidelines for Good Clinical Practice. events downstream of CXCL12 including SDF-1-mediated Approval of the protocol was obtained from all participating G-protein activation, receptor internalization, calcium flux, sites, local governmental authorities, and Institutional and chemotaxis [5, 6]. The CXCL12/CXCR4 interaction is Review Boards. This was a non-inferiority study, with a an integral part of the mechanism of homing and retention non-inferiority margin of a 30% increase in PFS and OS of HSC in the bone marrow and inhibition of this interaction corresponding to a hazard ratio (HR) upper bound of 1.3; no by plerixafor mobilizes HSCs from the bone marrow [7, 8]. lower limit was set. Unlike cytokines used for HSC mobilization (e.g., G-CSF), plerixafor is not a growth factor and does not cause cell Poor mobilizers proliferation or expansion. Therefore, the approved use for plerixafor is in combination with G-CSF [9, 10]. Predicted poor mobilizers were defined as patients who had As there is a theoretical risk of tumor cell mobilization received prior irradiation to marrow bearing areas or had with any stem cell mobilization method for HSCT, the high exposure to marrow-damaging chemotherapy. Proven European Medicines Agency requested a postapproval poor mobilizers were defined as patients who in a previous analysis of plerixafor to evaluate the possible long-term mobilization attempt failed to mobilize sufficient CD34+ negative impact related to tumor cell mobilization. cells in peripheral blood to proceed to apheresis or to pro- The European Society for Blood and Marrow Trans- ceed to transplantation, or who, in the current mobilization, plantation (EBMT) database is run and accessed through a failed to achieve a sufficient increase in peripheral blood project manager internet server and is accessible to all CD34+ cells at the predicted time for peak mobilization EBMT registered centers. Our analysis of the EBMT reg- [11]. In this study, only poor mobilizers (either predicted or istry data for long-term clinical outcomes included proven) have been considered in the propensity score progression-free survival (PFS), overall survival (OS), and matching and analyses. cumulative incidence of relapse (CIR) in patients with lymphoma. Patients who received plerixafor for mobiliza- Data collection tion of HSCs were matched by propensity scoring with patients who received other standard mobilization methods. The data were entered, managed, and maintained centrally Only patients who had a subsequent HSCT were included in in an internet accessible database. Variables present on the the study. EBMT Minimum Essential Data A and B forms were used to derive the data for the study and Medical C form was used to obtain plerixafor data. Methods Outcomes Study design The primary efficacy outcomes were OS, PFS, and CIR. This was an international, multicenter, non-interventional Secondary efficacy outcomes were hematological recovery registry study, with patient follow-up ranging from 3.5 to (time to achieve absolute neutrophil counts of ≥0.5 × 109/L 7.5 years, which evaluated the outcomes for patients with and platelet counts of ≥50 × 109/L). All transplant compli- lymphoma who received G-CSF + plerixafor compared cations occurring within 100 days of transplantation were with other mobilization methods for HSC mobilization and recorded. Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry. . . 615 The following mobilization regimens were assessed: Sample size was estimated using the following assumptions: 15% of transplanted lymphoma patients ● G-CSF + plerixafor versus G-CSF alone; would receive G-CSF alone and 85% would receive G- ● G-CSF + plerixafor versus G-CSF + chemotherapy; CSF + chemotherapy; 10% of patients transplanted from ● G-CSF + plerixafor + chemotherapy versus G-CSF + each regimen would receive plerixafor treatment; and chemotherapy. 70% of patients receiving plerixafor would be matched at a ratio of 1:2 plerixafor to comparator. Graft failure was defined as: (1) the loss of the graft with neutrophils reaching ≥ 0.5 × 109 cells/L but subsequently decreasing to a lower level of cells until additional treatment Results for engraftment was provided, or (2) no engraftment, where neutrophils never reached ≥0.5 × 109 cells/L. Participants and demographics Statistical analyses Overall, 3764 patients were screened and 3749 were eligible to be included in the study (Fig. 1). These Due to the observational nature of the study, no formal included 140 patients treated with G-CSF + plerixafor, statistical hypothesis testing was planned with adequate 173 patients treated with G-CSF + chemotherapy + power or Type 1 error control. plerixafor, 549 patients treated with G-CSF alone, and Propensity score method was used to identify study com- 2887 patients treated with G-CSF + chemotherapy. The parison groups that were balanced with respect to baseline propensity score matching of predicted and proven poor characteristics, including, demographics, lymphoma type, mobilizers identified matched groups for the comparative disease characteristics and staging, prior treatment character- analysis (Table 1). The number of patients classified as istics, and disease status [12]. The baseline variables and predicted or proven poor mobilizers was 136 treated with patient demographics used for propensity score matching are G-CSF + plerixafor, 173 treated with G-CSF + che- shown in Table 1. Only patients who were identified as a motherapy + plerixafor, 54 treated with G-CSF alone, and “proven or predicted poor mobilizer” were included in the 245 treated with G-CSF + chemotherapy. analysis. After propensity scoring, 70 patients in the G-CSF + A single imputation approach was implemented to create plerixafor were matched with 36 patients in the G-CSF alone complete data sets for analyses. Propensity scores were then cohort, 124 matched with 124 in the G-CSF + plerixafor fit using logistic regression models. Matches for plerixafor versus G-CSF + chemotherapy cohort, and 130 matched patients were identified from the non-plerixafor groups based with 130 in the G-CSF + plerixafor + chemotherapy versus on the estimated propensity scores. Matching was performed G-CSF + chemotherapy cohort. Disease history and baseline without replacement. Model success was based on whether demographics of the patients are shown in Table 1. balance between the plerixafor and the control groups The proportion of patients who were proven poor matched samples was achieved. mobilizers was greater in the plerixafor cohorts (ranging Following the propensity score analysis, the outcomes from 97.1 to 98.4%) compared with the comparator cohorts for each mobilization treatment group were analyzed for (ranging from 68.3 to 75.0%). More patients in the plerix- comparable groups. Cox proportional hazards model with afor groups failed to mobilize sufficient CD34+ cells at the covariates was used for OS and PFS. The 95% confidence predicted peak mobilization time compared with patients in intervals (CI) and HR for the effect of treatment were cal- the comparator groups (Table 2). culated. Potential covariates included: interval from diag- nosis to transplantation, disease status at conditioning and Primary outcomes conditioning regimen, and disease status at time of transplantation. Progression-free survival Survival curves were developed for each treatment group using nonparametric Kaplan–Meier estimates [13], The estimated PFS at 3 years are shown in Table 3 and were as well as survival rates at 6 months, and at 1, 2, 3, 4, and similar between comparison groups. The Kaplan–Meier 5 years. estimates for PFS were also similar for all the comparisons, A competing risk model was developed for CIR; death G-CSF + plerixafor versus G-CSF alone (Fig. 2a), G-CSF + without prior progression/relapse was treated as a compet- plerixafor versus G-CSF + chemotherapy (Fig. 2b), and ing event. The 95% CI and cumulative incidence at each G-CSF + plerixafor + chemotherapy versus G-CSF + che- year post transplantation were estimated. motherapy (Fig. 2c). Table 1 Patient demographics in the matched comparison groups used for propensity score matching 616 Comparison 1 Comparison 2 Comparison 3 G-CSF + plerixafor G-CSF alone G-CSF + plerixafor G-CSF + chemotherapy G-CSF + plerixafor G-CSF + chemotherapy (N = 70) (N = 36) (N = 124) (N = 124) + chemotherapy (N = 130) (N = 130) Age at first mobilization, mean ± SD, years (N = 65) (N = 32) (N = 117) (N = 107) (N = 130) (N = 115) 51.4 ± 13.5 51.2 ± 15.8 52.5 ± 12.6 51.5 ± 12.8 52.6 ± 13.6 52.3 ± 12.3 Females, n (%) 33 (47.1) 15 (41.7) 56 (45.2) 47 (37.9) 51 (39.2) 54 (41.5) Bone marrow involvement at the start of 2/66 (3.0) 2/33 (6.1) 8/104 (7.7) 4/102 (3.9) 8/112 (7.1) 4/105 (3.8) mobilization, n/N (%) Status of disease at collection, n (%) N = 67 N = 34 N = 113 N = 108 N = 117 N = 115 Complete response 1 or partial response 1 42 (62.7) 23 (67.6) 61 (54.0) 57 (52.8) 63 (53.8) 58 (50.4) or very good partial response Refractory disease 2 (3.0) 1 (2.9) 14 (12.4) 9 (8.3) 15 (12.8) 12 (10.4) Sensitive disease, complete response >1, 23 (34.3) 10 (29.4) 38 (33.6) 42 (38.9) 39 (33.3) 45 (39.1) partial response >1 Ann Arbor stage at diagnosis, n (%) N = 65 N = 35 N = 111 N = 111 N = 112 N = 117 I 5 (7.7) 5 (14.3) 8 (7.2) 9 (8.1) 5 (4.5) 6 (5.1) II 10 (15.4) 4 (11.4) 23 (20.7) 24 (21.6) 24 (21.4) 23 (19.7) III 13 (20.0) 5 (14.3) 22 (19.8) 21 (18.9) 23 (20.5) 26 (22.2) IV 37 (56.9) 21 (60.0) 58 (52.3) 57 (51.4) 60 (53.6) 62 (53.0) Interval between diagnosis and first N = 65 N = 32 N = 117 N = 107 N = 130 N = 115 collection, mean ± SD, months Year of first transplant 18.9 ± 20.2 16.3 ± 20.6 32.5 ± 48.1 30.6 ± 45.3 23.6 ± 28.7 23.7 ± 28.4 2009 20 (28.6) 12 (33.3) 32 (25.8) 39 (31.5) 21 (16.2) 34 (26.2) 2010 23 (32.9) 13 (36.1) 31 (25.0) 35 (28.2) 44 (33.8) 48 (36.9) 2011 16 (22.9) 7 (19.4) 37 (29.8) 39 (31.5) 46 (35.4) 37 (28.5) 2012 11 (15.7) 4 (11.1) 24 (19.4) 11 (8.9) 19 (14.6) 11 (8.5) Geographic region, n (%) South and East Europe 28 (40.0) 18 (50.0) 52 (41.9) 42 (33.9) 43 (33.1) 41 (31.5) North and West Europe 42 (60.0) 18 (50.0) 72 (58.1) 82 (66.1) 87 (66.9) 89 (68.5) Lymphoma disease types, n (%) Hodgkin’s lymphoma 13 (18.4) 8 (22.2) 22 (17.7) 26 (21.0) 21 (16.2) 24 (18.5) Aggressive B-cell lymphoma 24 (34.3) 12 (33.3) 43 (34.7) 44 (35.5) 56 (43.1) 52 (40.0) Indolent B-cell lymphoma 12 (17.1) 6 (16.7) 21 (16.9) 23 (18.5) 25 (19.2) 24 (18.5) Mantle cell lymphoma 20 (28.6) 9 (25.0) 26 (21.0) 19 (15.3) 13 (10.0) 14 (10.8) T-cell lymphoma 1 (1.4) 1 (2.8) 12 (9.7) 12 (9.7) 14 (10.8) 14 (10.8) Othersa 0 0 0 0 1 (0.8) 2 (1.5) G-CSF granulocyte-colony stimulating factor, SD standard deviation a Not disclosed A. Sureda et al. Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry. . . 617 **Proven poor mobilizers were defined as patients who in a previous mobilization attempt failed to mobilize sufficient CD34+ cells in the peripheral blood to proceed to apheresis or to proceed to Screened G-CSF + chemotherapy N =3764 60/127 (47.2) 89/129 (69.0) 13/53 (24.5) 8.8 (n = 17) (N = 130) Eligible patients N =3749 *Predicted poor mobilizers were defined as patients who had received prior irradiation to marrow bearing areas or had high exposure to marrow-damaging chemotherapy transplantation or who, in the current mobilization, failed to achieve a sufficient increase in peripheral blood CD34+ cells at the predicted time for peak mobilization G+P G+P+C G alone G+C G-CSF + plerixafor + N =140 N =173 N =549 N =2887 127/130 (97.7) Comparison 3 chemotherapy Propensity score matching 26/130 (20.0) 72/97 (74.2) 5.0 (n = 76) (N = 130) G+P G alone G+P G+C G+P+C G+C N=70 N=36 N =124 N =124 N =130 N =130 Comparison 1 Comparison 2 Comparison 3 G-CSF + chemotherapy Fig. 1 Patient eligibility and treatment. Key: G G-CSF, P plerixafor, C chemotherapy 62/122 (50.8) 84/123 (68.3) 12/47 (25.5) 8.9 (n = 16) (N = 124) Overall survival Due to censoring median follow-up and interquartile ran- G-CSF + plerixafor ges were not calculable for some comparison groups. 120/122 (98.4) Kaplan–Meier estimates of OS for the G-CSF + plerixafor Comparison 2 29/116 (25.0) 56/81 (69.1) 5.2 (n = 66) versus the G-CSF alone group (comparison 1, Fig. 3a) (N = 124) were similar. Similarly, Kaplan–Meier estimates of OS for the G-CSF + plerixafor group versus G-CSF + che- motherapy group (comparison 2, Fig. 3b) were also similar, although the G-CSF + plerixafor group trended 16.0 (n = 10) G-CSF alone 14/34 (41.2) 27/36 (75.0) lower after 0.5 years compared with the G-CSF + che- 6/16 (37.5) (N = 36) Table 2 Mobilization characteristics for the matched comparator groups motherapy group. For the G-CSF + plerixafor + che- G-CSF granulocyte-colony stimulating factor, SD standard deviation motherapy group compared with the G-CSF + chemotherapy group OS was also similar between groups G-CSF + plerixafor (comparison 3, Fig. 3c). As the upper limit of the HR was >1.3, based on predetermined boundaries, non-inferiority Comparison 1 16/64 (25.0) 68/70 (97.1) Failed to mobilize sufficient CD34+ 33/46 (71.7) 5.0 (n = 39) of plerixafor was not demonstrated for any of the com- (N = 70) parison groups. Estimated OS at 3 years are shown in Table 3. Cumulative incidence of relapse rates Predicted poor mobilizers,* n/N (%) (%) CD34+ cell count, median × Proven poor mobilizers,** n/N (%) Cumulative incidence of relapse rates at 3 years are shown cells at predicted time, n/N in Table 3. The CIR trended higher in the G-CSF alone group compared with the G-CSF + plerixafor group until Current mobilization year 5. However, the CIR was similar between the G-CSF + plerixafor versus the G-CSF + chemotherapy group, and was similar between the G-CSF + plerixafor + chemotherapy group versus the G-CSF + chemotherapy 109/L group (Fig. 4). Table 3 Primary outcomes progression-free survival, overall survival, and cumulative incidence of relapse for each of the comparator groups 618 Comparison 1 Comparison 2 Comparison 3 G-CSF + plerixafor G-CSF alone G-CSF + plerixafor G-CSF + chemotherapy G-CSF + plerixafor + G-CSF + chemotherapy (N = 70) (N = 36) (N = 124) (N = 124) chemotherapy (N = 130) (N = 130) Estimated PFS, at 3 years, [95% CI] 0.59 [0.46, 0.70] 0.50 [0.32, 0.65] 0.56 [0.47, 0.65] 0.59 [0.50, 0.67] 0.48 [0.39, 0.57] 0.56 [0.46, 0.64] PFS hazard ratio [95% CI]a 0.82 [0.44, 1.53] 1.16 [0.78, 1.73] 1.16 [0.80, 1.67] Estimated OS at 3 years, [95% CI] 0.75 [0.62, 0.84] 0.70 [0.51, 0.83] 0.69 [0.59, 0.76] 0.76 [0.68, 0.83] 0.67 [0.58, 0.75] 0.71 [0.62, 0.78] OS hazard ratio [95% CI]a 0.97 [0.47, 2.03] 1.45 [0.91, 2.32] 1.29 [0.78, 2.11] Deaths, n (%) 20 (28.6) 11 (30.6) 41 (33.1) 31 (25.0) 45 (34.6) 38 (29.2) Deaths Hazard ratio [95% CI]a 0.97 [0.47, 2.03] 1.45 [0.91, 2.32] 1.29 [0.78, 2.11] CIR, 3 years [95% CI] 0.33 [0.22, 0.45] 0.44 [0.27, 0.61] 0.38 [0.29, 0.47] 0.36 [0.28, 0.45] 0.44 [0.35, 0.52] 0.38 [0.30, 0.47] CI confidence interval, CIR cumulative incidence of relapse, G-CSF granulocyte-colony stimulating factor, OS overall survival, PFS progression-free survival a Hazard ratio with covariate adjustment including status of disease at time of transplant, conditioning regimens, and interval from diagnosis to transplantation and performance status (Karnofsky) c a b (comparison 3) Event-free probability Event-free probability Event-free probability Number at risk Number at risk 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Number at risk 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Post transplantation Secondary outcomes 0 0.5 1 0 0.5 1 0 0.5 1 G-CSF + chemo 130 102 87 Plerixafor + G-CSF + chemo 130 93 81 G-CSF alone 36 28 27 Plerixafor + G-CSF 70 56 48 G-CSF + chemo 124 104 91 Plerixafor + G-CSF 124 95 84 2 2 2 22 40 74 70 68 66 G-CSF alone G-CSF + chemo G-CSF + chemo 3 3 3 58 51 13 29 57 48 Plerixafor + G-CSF Plerixafor + G-CSF 4 4 4 37 32 11 22 38 35 Time (years) Time (years) Time (years) Plerixafor + G-CSF + chemo 5 5 5 3 8 20 15 18 16 7 4 4 1 0 1 6 6 6 0 0 0 0 0 7 7 7 G-CSF + plerixafor versus G-CSF alone (comparison 1); b G-CSF + CSF + plerixafor + chemotherapy versus G-CSF + chemotherapy treatment group up to 100 days post first transplantation are A. Sureda et al. Adverse events occurring in more than one patient in any plerixafor versus G-CSF + chemotherapy (comparison 2); and c G- Fig. 2 Progression-free survival for each of the comparison groups, a Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry. . . 619 a 1.0 a 0.5 0.9 0.8 0.4 Event-free probability Cumulative incidence estimate 0.7 0.6 0.5 0.3 0.4 0.3 0.2 0.2 0.1 Plerixafor + G-CSF G-CSF alone 0.1 0.0 0 0.5 1 2 3 4 5 6 7 Plerixafor + G-CSF Time (years) G-CSF alone Number at risk 0.0 Plerixafor + G-CSF 70 62 57 47 38 28 13 1 0 0 1 2 3 4 5 6 7 G-CSF alone 36 32 31 27 19 16 5 2 0 Time (years) b 1.0 b 0.5 0.9 0.8 0.4 Event-free probability Cumulative incidence estimate 0.7 0.6 0.5 0.3 0.4 0.3 0.2 0.2 0.1 Plerixafor + G-CSF G-CSF + chemo 0.0 0.1 0 0.5 1 2 3 4 5 6 7 Plerixafor + G-CSF Time (years) G-CSF + chemo Number at risk 0.0 Plerixafor + G-CSF 124 108 97 82 64 44 22 4 0 0 1 2 3 4 5 6 7 G-CSF + chemo 124 116 107 91 70 51 29 9 0 Time (years) c 1.0 c 0.5 0.9 0.8 Event-free probability 0.7 0.4 Cumulative incidence estimate 0.6 0.5 0.3 0.4 0.3 0.2 0.2 0.1 Plerixafor + G-CSF + chemo G-CSF + chemo 0.0 0.1 0 0.5 1 2 3 4 5 6 7 Time (years) Plerixafor + G-CSF + chemo Number at risk G-CSF + chemo Plerixafor + G-CSF + chemo 130 105 96 81 62 43 22 1 0 0.0 G-CSF + chemo 130 117 106 84 70 49 26 5 0 0 1 2 3 4 5 6 7 Time (years) Fig. 3 Overall survival for each of the comparison groups, a G-CSF + plerixafor versus G-CSF alone (comparison 1); b G-CSF + plerixafor Fig. 4 Cumulative incidence of relapse for each of the comparison versus G-CSF + chemotherapy (comparison 2); and c G-CSF + pler- groups, a G-CSF + plerixafor versus G-CSF alone (comparison 1); b ixafor + chemotherapy versus G-CSF + chemotherapy (comparison 3) G-CSF + plerixafor versus G-CSF + chemotherapy (comparison 2); and c G-CSF + plerixafor + chemotherapy versus G-CSF + che- motherapy (comparison 3) shown in Table 4. Infections and infestations were the most common standard organ class complication in all plerixafor and comparator groups. number of days to reach a platelet count of ≥20 × 109/L was Engraftment was reported in ≥88% of patients in each 14 days for each of the plerixafor groups and 12–13 days treatment group of the three comparisons. Similarly, for the respective comparator groups. The median number engraftment of both platelets and neutrophils was reported of days to reach a neutrophil count of ≥0.5 × 109/L was in ≥82% of patients in each treatment group. The median 11–12 days for each group. 620 A. Sureda et al. Discussion G-CSF + chemotherapy This study was a postapproval measure to investigate clin- ical disease outcome as a surrogate of potential enhance- ment of tumor cell release when combining G-CSF + (N = 130) (52.3) (45.4) (27.7) (13.1) plerixafor. The study was not designed to evaluate the (2.3) (3.1) (1.5) (1.5) (1.5) (2.3) (0.8) benefit of stem cell mobilization with plerixafor compared 68 59 36 3 4 17 2 2 2 3 0 1 0 with other methods. In general, no major differences were observed in PFS, OS, or CIR between the plerixafor and the G-CSF + plerixafor + comparison groups. In line with the plerixafor label all patients in the study Comparison 3 chemotherapy had to be poor mobilizers, either as proven poor mobilizers, (N = 130) (42.3) (32.3) (25.4) (16.2) (1.5) (2.3) (2.3) (1.5) (0.8) (1.5) (2.3) (1.5) based on their mobilization history, or as predicted poor mobilizers through exposure to high-dose chemotherapy. 55 42 33 2 3 21 0 3 2 1 2 3 2 However, despite propensity score matching, which tried to balance the groups, there were still substantially more G-CSF + chemotherapy proven poor mobilizers in the plerixafor cohorts, which may have led to an imbalance between comparison groups. Consistently the median pre-apheresis CD34+ cell counts Table 4 Adverse events occurring in more than one patient in any treatment group up to 100 days post first transplantation (N = 124) in the plerixafor cohorts during the current mobilization at (50.0) (41.1) (25.0) (11.3) (4.0) (2.4) (1.6) (0.8) (0.8) (1.6) (0.8) the predicted time of peak mobilization were lower com- 62 51 31 5 3 14 2 1 1 2 0 1 0 pared with comparison cohorts. Therefore, it appears that the groups were not well balanced for disease and G-CSF + plerixafor HSCT risk. Comparison 2 Others have shown that lymphoma patients’ poor (N = 124) (53.2) (45.2) (23.4) mobilization of autologous stem cells, defined as the (6.5) (3.2) (8.9) (1.6) (0.8) inability to obtain ≥1 × 106 CD34+ cells/kg body weight, 66 56 29 8 4 11 0 2 0 0 1 0 0 resulted in substantially lower PFS and OS compared with good mobilizers [14, 15]. Therefore, in our study, the higher G-CSF alone proportion of proven poor mobilizers in the plerixafor (52.8) (36.1) (22.2) (N = 36) (8.3) (2.8) (2.8) (2.8) (2.8) groups may, at least in part, explain the PFS, OS, and CIR results versus those in the comparison groups. Furthermore, 19 13 8 3 1 1 0 1 1 0 0 0 0 there are two confounders, which might have skewed the analysis of the data in the current study. Firstly, poor G-CSF + plerixafor mobilization could be an indicator of more severe or Comparison 1 prognostically worse disease. Therefore, the post-plerixafor (52.9) (45.7) (22.9) (11.4) (N = 70) (7.1) (2.9) (1.4) outcomes trending toward slightly worse OS, PFS, and CIR could be the result of more advanced lymphoma disease and 37 32 16 5 2 8 0 1 0 0 0 0 0 not a trend toward inferiority of plerixafor-mobilized grafts. Secondly, data on the lymphoma biology were not avail- Any adverse event up to 100 days post transplantation able, which does not allow the confirmation that the pler- G-CSF granulocyte-colony stimulating factor General disorders and administration site disorders Respiratory, thoracic, and mediastinal disorders ixafor and comparator groups were balanced in relation to the stage of the lymphoma disease. Engraftment was reported in ≥88% of patients in each of Metabolism and nutritional disorders the three comparator cohorts and the median number of Skin and subcutaneous disorders days to achieve the target levels of platelets and neutrophils Blood and lymphatic disorders Renal and urinary disorders standard organ class, n (%) was similar for all cohorts (12–13 days and 11–12 days, Infections and infestations Nervous system disorders Gastrointestinal disorders respectively), which was in line with findings from a pre- Bacterial infections vious study [16]. Vascular disorders Cardiac disorders In support of our findings, results from a 5-year, long- Adverse event preferred term term, phase 3, follow-up study (not restricted to poor mobilizers) suggested that the use of G-CSF + plerixafor did not have a negative outcome on PFS and OS in patients Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry. . . 621 with lymphoma, with more than a half of patients with sufficient CD34+ cells at the predicted time. Therefore, lymphoma remaining alive 5 years post transplantation [17]. these patients represent a group that is likely predisposed to Propensity scores are increasingly used in non- worse outcomes. Infections and infestations were the most randomized studies to assess marginal treatment effects and common standard organ class posttransplant complication to reduce potential bias and imbalances of baseline cov- for plerixafor and comparator cohorts. Without plerixafor ariates [12]. The assumption of propensity scores is that treatment, it is likely that some patients may not have none of the unmeasured covariates affecting treatment proceeded to transplantation. Altogether, this study does not choice confound the association between treatment and provide evidence that plerixafor mobilization is associated outcome [18]. Unobserved differences between groups with an increased risk of relapse or post-transplant toxicities cannot be adjusted by propensity scores; therefore, this is in patients undergoing HSCT for lymphoma. both a source of potential bias and a limitation of propensity scores [19]. Despite the modest sample size in the com- Data availability parisons resulting from propensity scoring matching, in our study, an adequate balance for certain key disease char- Qualified researchers may request access to patient level acteristics collected in the database was maintained. How- data and related study documents including the clinical ever, we acknowledge that some key factors affecting study report, study protocol with any amendments, blank mobilization outcome were unavailable in the database, case report form, statistical analysis plan, and dataset spe- such as, the number of rounds and the type of chemotherapy cifications. Patient level data will be anonymized and study administered, and for those who received radiotherapy the documents will be redacted to protect the privacy of trial extension of irradiated fields. These limitations in data participants. Further details on Sanofi’s data sharing criteria, collection may have had a major impact on the outcomes in eligible studies, and process for requesting access can be our study. found at: https://www.clinicalstudydatarequest.com. Moreover, in line with the reimbursement criteria for the drug and the obligation on some clinicians to closely Acknowledgements The study was sponsored by Sanofi, Cambridge, MA, USA. The authors were responsible for all content and editorial manage treatment costs [20], plerixafor may have been decisions and received no honoraria related to the development of this selectively given to patients who were the poorest mobi- publication. Medical writing assistance was provided by John Clarke, lizers at highest risk, and this may have been a factor in Ph.D., Elevate Scientific Solutions, Horsham, UK, funded by Sanofi. the trend for slightly worse outcomes in the plerixafor- The authors would like to thank Remi Castan for comments and helpful discussion of the content of the manuscript, the data managers treated groups. Conversely, only patients with successful at the contributing centers, and at the EBMT office for their invaluable mobilization were included in the study, this may have contributions to the conduct of the study. inadvertently introduced selection bias in favor of the non-plerixafor cohorts. Furthermore, our study was not Compliance with ethical standards adequately powered, as there were small to moderate numbers of patients in each cohort after propensity score Conflict of interest AS has received personal fees from Sanofi, grants matching. Although every effort was made to remove and personal fees from BMS and Celgene, personal fees from Janssen, potential biases in this study, biases may not have been Gilead, Novartis, and Takeda. CC reports receiving fees for data transfer from EBMT during the conduct of the study and grants, and removed completely due to the observational nature of personal fees and nonfinancial support from Sanofi outside the scope the data. of the submitted work. TM received financial supports for advisory board membership for AbbVie, BMS, Janssen-Cilag, Novartis, Pfizer, and Takeda outside the scope of the submitted work. CS reports personal fees from Sanofi. CT received financial supports for advisory Conclusions board membership for Roche, Takeda, Janssen-Cilag, Bayer, and Celgene outside the scope of the submitted work. IS received personal Although non-inferiority of the plerixafor groups could not fees from Sanofi. AD-I received personal fees from the EBMT foun- be formally shown, PFS, OS, and CIR were numerically dation for data transfer during the conduct of the study. EJ received speaker’s fee and research grant from Sanofi. QL and MC are similar between comparators. Results from this study employees of Sanofi. SM received grants for travel from Gilead, and should be interpreted with caution due to a number of speaker fees from Roche and is an advisory board member for Bayer, limitations. These include an imbalance between treatment outside the scope of submitted work. PD has received speaker’s groups due to the greater proportion of proven poor mobi- honoraria from Gilead, Kite; Consultancy: AbbVie, Gilead, Janssen, and Roche. SvdW, PB, AB, DP, BEW, NR, AJ, CT, and AE declare lizers in the groups treated with plerixafor, the limited scope that they have no conflict of interest. of the EBMT database, the lack of power, and the obser- vational nature of the study. In particular, a higher pro- Publisher’s note Springer Nature remains neutral with regard to portion of patients treated with plerixafor failed to mobilize jurisdictional claims in published maps and institutional affiliations. 622 A. Sureda et al. Open Access This article is licensed under a Creative Commons 9. DiPersio JF, Uy GL, Yasothan U, Kirkpatrick P. Plerixafor. Nat Attribution 4.0 International License, which permits use, sharing, Rev Drug Discov. 2009;8:105–6. https://doi.org/10.1038/ adaptation, distribution and reproduction in any medium or format, as nrd2819. long as you give appropriate credit to the original author(s) and the 10. Nervi B, Link DC, DiPersio JF. Cytokines and hematopoietic stem source, provide a link to the Creative Commons license, and indicate if cell mobilization. J Cell Biochem. 2006;99:690–705. https://doi. changes were made. The images or other third party material in this org/10.1002/jcb.21043. article are included in the article’s Creative Commons license, unless 11. Olivieri A, Marchetti M, Lemoli R, Tarella C, Iacone A, Lanza F, indicated otherwise in a credit line to the material. If material is not et al. Proposed definition of ‘poor mobilizer’ in lymphoma and included in the article’s Creative Commons license and your intended multiple myeloma: an analytic hierarchy process by ad hoc use is not permitted by statutory regulation or exceeds the permitted working group Gruppo ItalianoTrapianto di Midollo Osseo. Bone use, you will need to obtain permission directly from the copyright Marrow Transpl. 2012;47:342–51. https://doi.org/10.1038/bmt. holder. To view a copy of this license, visit http://creativecommons. 2011.82. org/licenses/by/4.0/. 12. Pirracchio R, Resche-Rigon M, Chevret S. Evaluation of the propensity score methods for estimating marginal odds ratios in case of small sample size. BMC Med Res Methodol. 2012;12:70 https://doi.org/10.1186/1471-2288-12-70. References 13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc. 1958;53:457–81. 1. Kim MG, Han N, Lee EK, Kim T. Pegfilgrastim vs filgrastim in 14. Gordan LN, Sugrue MW, Lynch JW, Williams KD, Khan SA, PBSC mobilization for autologous hematopoietic SCT: a sys- Wingard JR, et al. Poor mobilization of peripheral blood stem cells tematic review and meta-analysis. Bone Marrow Transpl. is a risk factor for worse outcome in lymphoma patients under- 2015;50:523–30. https://doi.org/10.1038/bmt.2014.297. going autologous stem cell transplantation. Leuk Lymphoma. 2. Tse WT, Egalka MC. Stem cell plasticity and blood and marrow 2003;44:815–20. https://doi.org/10.1080/1042819031000067585. transplantation: a clinical strategy. J Cell Biochem Suppl. 15. Pavone V, Gaudio F, Console G, Vitolo U, Iacopino P, Guarini A, 2002;38:96–103. et al. Poor mobilization is an independent prognostic factor in 3. Mohty M, Hubel K, Kroger N, Aljurf M, Apperley J, Basak GW, patients with malignant lymphomas treated by peripheral blood et al. Autologous haematopoietic stem cell mobilisation in mul- stem cell transplantation. Bone Marrow Transpl. 2006;37:719–24. tiple myeloma and lymphoma patients: a position statement from https://doi.org/10.1038/sj.bmt.1705298. the European Group for Blood and Marrow Transplantation. Bone 16. Varmavuo V, Rimpilainen J, Kuitunen H, Nihtinen A, Vasala K, Marrow Transpl. 2014;49:865–72. https://doi.org/10.1038/bmt. Mikkola M, et al. Engraftment and outcome after autologous stem 2014.39. cell transplantation in plerixafor-mobilized non-Hodgkin’s lym- 4. Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J, phoma patients. Transfusion. 2014;54:1243–50. https://doi.org/10. et al. Optimizing autologous stem cell mobilization strategies to 1111/trf.12434. improve patient outcomes: consensus guidelines and recommen- 17. Micallef IN, Stiff PJ, Nademanee A, Maziarz RT, Horwitz M, dations. Biol Blood Marrow Transpl. 2014;20:295–308. https:// Stadtmauer EA, et al. Plerixafor plus granulocyte colony- doi.org/10.1016/j.bbmt.2013.10.013. stimulating factor for patients with non-Hodgkin’s lymphoma 5. Fricker SP, Anastassov V, Cox J, Darkes MC, Grujic O, Idzan SR, and multiple myeloma: long-term follow-up report. Biol Blood et al. Characterization of the molecular pharmacology of Marrow Transpl. 2018;24:1187–95. AMD3100: a specific antagonist of the G-protein coupled che- 18. Brooks JM, Ohsfeldt RL. Squeezing the balloon: propensity mokine receptor, CXCR4. Biochem Pharm. 2006;72:588–96. scores and unmeasured covariate balance. Health Serv Res. https://doi.org/10.1016/j.bcp.2006.05.010. 2013;48:1487–507. https://doi.org/10.1111/1475-6773.12020. 6. Hatse S, Princen K, Bridger G, De Clercq E, Schols D. Chemo- 19. Garrido MM, Kelley AS, Paris J, Roza K, Meier DE, Morrison kine receptor inhibition by AMD3100 is strictly confined to RS, et al. Methods for constructing and assessing propensity CXCR4. FEBS Lett. 2002;527:255–62. scores. Health Serv Res. 2014;49:1701–20. https://doi.org/10. 7. Fruehauf S, Seeger T. New strategies for mobilization of hema- 1111/1475-6773.12182. topoietic stem cells. Future Oncol. 2005;1:375–83. https://doi.org/ 20. Veltri L, Cumpston A, Shillingburg A, Wen S, Luo J, Leadmon S, 10.1517/14796694.1.3.375. et al. Hematopoietic progenitor cell mobilization with “just-in- 8. Lapidot T, Dar A, Kollet O. How do stem cells find their way time” plerixafor approach is a cost-effective alternative to routine home? Blood. 2005;106:1901–10. https://doi.org/10.1182/blood- plerixafor use. Cytotherapy. 2015;17:1785–92. https://doi.org/10. 2005-04-1417. 1016/j.jcyt.2015.09.002.