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Pharmacoeconomic impact of up-front use of plerixafor for autologous stem cell mobilization in patients with multiple myeloma
Cytotherapy, 2014; 16: 1584e1589
Pharmacoeconomic impact of up-front use of plerixafor for autologous stem cell mobilization in patients with multiple myeloma
SARA S. KIM1, ANNE S. RENTERIA2, AMIR STEINBERG2, KAREN BANOFF3 & LUIS ISOLA2 1
Department of Pharmacy, 2Blood and Marrow Transplantation Program and 3Business and Strategic Planning The Mount Sinai Medical Center, New York, New York, USA
Abstract Background aims. Stem cell collection can be a major component of overall cost of autologous stem cell transplantation (ASCT). Plerixafor is an effective agent for mobilization; however, it is often reserved for salvage therapy because of its high cost. We present data on the pharmacoeconomic impact of the use of plerixafor as an up-front mobilization in patients with multiple myeloma (MM). Methods. Patients with MM who underwent ASCT between January 2008 and April 2011 at the Mount Sinai Medical Center were reviewed retrospectively. In April 2010, practice changes were instituted for patients with MM to delay initiation of granulocyte-colony-stimulating factor (G-CSF) support from day 0 to day þ5 and to add plerixafor to G-CSF as an up-front autologous mobilization. Targets of collection were 5e10 106 CD34þ cells/kg. Results. Of 50 adults with MM who underwent ASCT, 25 received plerixafor/filgrastim and 25 received G-CSF alone as an up-front mobilization. Compared with the control, plerixafor mobilization yielded higher CD34þ cell content (16.1 versus 8.4 106 CD34þ cells/kg; P ¼ 0.0007) and required fewer sessions of apheresis (1.9 versus 3.1; P ¼ 0.0001). In the plerixafor group, the mean number of plerixafor doses required per patient was 1.8. Although the overall cost of medications was higher in the plerixafor group, the cost for blood products and overall cost of hospitalization were similar between the two groups. Conclusions. Up-front use of plerixafor is an effective mobilization strategy in patients with MM and does not have a substantial pharmacoeconomic impact in overall cost of hospitalization combined with the apheresis procedure. Key Words: autologous stem cell transplantation, mobilization, multiple myeloma, plerixafor, stem cell collection
Introduction Autologous stem cell transplantation (ASCT) is an effective treatment for multiple myeloma (MM) [1,2]. The most commonly used up-front mobilizing agent for autologous stem cell collection is granulocyte-colony-stimulating factor (G-CSF), which is associated with approximately 25% of unsuccessful mobilization [3,4]. Strong predictors for poor mobilization include advanced age, bone marrow (BM) failure, extensive prior chemotherapy treatment and previous treatment with lenalidomide or alkylating agents. Another common mobilization strategy is to combine chemotherapy, such as cyclophosphamide, with G-CSF [5,6]. This approach is associated with an unpredictable stem cell yield and, in some patients, neutropenic fever requiring hospitalization [7]. Mobilization of stem cells is induced through the interaction between stem cells and cells of the BM microenvironment. The binding of stromal cellederived factor 1 (SDF-1), a chemokine
expressed in BM stromal cells, to CXCR-4 plays a major role in regulating trafficking and retaining hematopoietic stem cells (HSC) in the BM [8]; however, the predominant source of SDF-1 (ie, osteoblasts, reticular cells in endosteal and vascular niches, endothelial cells and bones) is not clearly understood [9]. G-CSF promotes HSC mobilization by altering the BM niche; it downregulates osteoblast SDF-1 by altering the signaling of sympathetic nervous system to osteoblast, thereby attenuating CXCR signaling [10e12]. Plerixafor promotes HSC mobilization by reversibly blocking the binding of SDF-1 to its receptor, CXCR-4. Concurrent administration of plerixafor and G-CSF was shown to exert a synergistic effect on the mobilization of CD34þ progenitor cells [13]. Plerixafor, in combination with G-CSF, was granted US Food and Drug Administration approval in 2008. Its approval was based on the improved rate of successful mobilization when used up-front for ASCT in patients with
Correspondence: Sara S. Kim, PharmD, BCOP, Department of Pharmacy, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029. E-mail: [email protected] (Received 26 November 2013; accepted 2 May 2014) ISSN 1465-3249 Copyright Ó 2014, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2014.05.003
Plerixafor for autologous stem cell mobilization in multiple myeloma non-Hodgkin’s lymphoma and multiple myeloma (MM). Because of its high cost, plerixafor is often reserved for patients who failed previous standard mobilization [14e16]. The use of plerixafor as a salvage mobilization strategy can increase the number of apheresis sessions required to achieve an adequate peripheral blood stem cell (PBSC) collection and potentially impose delays on the timing of ASCT, especially for patients with MM who often require sufficient CD34þ cells for two ASCTs. In the present study, we evaluated 50 patients with MM who were mobilized up-front with G-CSF with or without plerixafor. The purpose of this study was to assess the pharmacoeconomic impact of the addition of plerixafor to G-CSF as an up-front autologous mobilization regimen for patients with MM. Methods Study design We performed a retrospective analysis to assess economic and clinical outcomes of 50 adult patients with MM who received ASCT between January 2008 and April 2011 at The Mount Sinai Medical Center, New York, New York. In the control group, 25 consecutive patients received single-agent G-CSF as a mobilizing agent and started G-CSF support from day 0 after PBSC infusion. In the plerixafor group, 25 consecutive patients received plerixafor in combination with GCSF, as an up-front mobilization therapy, and started G-CSF support from day þ5 after PBSC infusion.
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Method for growth factor support after ASCT Before April 2010, G-CSF was administered as 5 mg/ kg per day intravenously, starting on day 0 after PBSC infusion and until engraftment. Starting in April 2010, the initiation of G-CSF was delayed from day 0 to day þ5 after PBSC infusion. Data collection By use of the pharmacy database, patients with MM who underwent ASCT were identified, and data collection was performed with the use of patients’ electronic medical records. Data collection included patients’ baseline characteristics, total CD34þ cells collected, total CD34þ cells infused, number of doses of G-CSF and plerixafor administered for mobilization, number of apheresis sessions, number of doses of G-CSF required for engraftment, time to engraftment, length of hospital stay from day 0 and cost analysis for the two groups. Engraftment criteria Center for International Blood and Marrow Transplant Research criteria were used to define engraftment. Neutrophil engraftment is defined as an absolute neutrophil count 0.5 109 cells/L for 3 consecutive days after HSC transplantation. Platelet engraftment is defined as a platelet count 20 109 cells/L for 3 consecutive days after HSC transplantation and without platelet transfusion support for the preceding 7 days.
Method for mobilization
Pharmacoeconomic analysis
Before April 2010, G-CSF was used as an up-front mobilizing agent as 10 mg/kg per day subcutaneously for 5 days in patients with MM scheduled to undergo ASCT. Starting in April 2010, plerixafor was added to G-CSF as an up-front mobilization strategy in patients with MM. Plerixafor was administered as 0.24 mg/kg per day subcutaneously in the evening (approximately 6e7 PM) for up to 4 days, starting on the fourth day of G-CSF. The dose of plerixafor was capped at 40 mg/ d. In patients with renal insufficiency (defined as creatinine clearance 50 mL/min), the dose of plerixafor was reduced to 0.16 mg/kg per day, not exceeding 27 mg/d. Peripheral CD34þ cells were not routinely measured in these patients before apheresis. Minimum and optimal collection cell targets were 5 106 and 10 106 CD34þ cells/kg, respectively. If the yielded CD34þ stem cell content was >5 106/kg, half of the content of the collection was infused during the ASCT. Melphalan was administered intravenously at a target dosage of 200 mg/m2 and with dose adjustment on the basis of renal function.
All costs related to hospitalization were captured by our institution’s cost accounting system. Average wholesale price was used to calculate the outpatient cost of plerixafor ($8073 per 24-mg vial) and G-CSF ($298 per 300-mg dose) required for mobilization. Expenditure for apheresis procedure was $3200 per session. Statistical analysis The Student’s t-test was used to compare significance of difference between the two groups, and the twotailed Fisher’s exact test was used to compare frequencies of incidence between the two groups. A value of P < 0.05 was considered of statistical significance. Results Baseline characteristics A total of 50 patients with MM who underwent ASCT between January 2008 and April 2011 were
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identified using the pharmacy database. Twentyfive patients received plerixafor in combination with G-CSF, and 25 patients received singleagent G-CSF for PBSC mobilization. Baseline characteristics of the patients were well balanced between the two groups; however, more patients in the plerixafor group had prior treatment with lenalidomide compared with the control group (64% versus 33%; P ¼ 0.046) (Table I). Compared with the control, a significantly higher yield of CD34þ cells was achieved in the plerixafor group (mean, 8.4 versus 16.1 10 6 /kg; P ¼ 0.007). Accordingly, a significantly higher content of CD34 þ cells was infused to plerixafor-mobilized patients (mean, 4.4 versus 7.6 10 6 /kg; P ¼ 0.0017).
Doses of G-CSF with or without plerixafor for PBSC collection The number of G-CSF doses required to achieve a PBSC yield of 5 to 10 106 CD34þ cells/kg was an average of 7.1 doses in the control group and 5.9 doses in the plerixafor group (P ¼ 0.0001) (Table I). In the plerixafor group, an average number of plerixafor doses required was 1.8. Number of apheresis sessions The average number of apheresis sessions required for PBSC collection was 3.1 in the control group and 1.9 in the plerixafor group (P ¼ 0.0001) (Table I). Doses of G-CSF for engraftment
Time to engraftment Time to neutrophil engraftment was shortened by an average of 1 day in the control group (mean, 9.8 days in control versus 10.8 days in plerixafor group; P < 0.0001). Time to platelet engraftment was similar between the control and plerixafor groups (mean, 15.3 versus 16 days; P ¼ 0.41). Length of hospital stay after auto-SCT There was no statistical difference in length of hospital stay between the control and the plerixafor groups (mean, 14.1 versus 15.2 days; P ¼ 0.24).
After ASCT, the average number of G-CSF doses administered was 11.8 in the control group and 8 in the plerixafor group (P < 0.0001) (Table I). It is noteworthy that the initiation of G-CSF support was delayed by 5 days in the plerixafor group as a result of implementation of practice change. Pharmacoeconomic assessment Compared with the control group, the plerixafor group was associated with a reduction in the inpatient pharmacy cost by an average of $3904 per patient; however, the overall pharmacy cost (including the mobilization regimen used in the ambulatory setting) was higher in the plerixafor-mobilized group
Table I. Baseline characteristics. G-CSF alone (n ¼ 25)
Age, y Sex Male, n (%) Weight, kg Previous ASCT, n (%) Prior lenalidomide therapy, n (%) No. of prior chemotherapy regimens CD34+ cells, 106/kg Collected Infused Melphalan dose, mg/m2 Cumulative dose of G-CSF required, mg For collection For engraftment No. of doses of G-CSF, n For collection For engraftment No. of doses of plerixafor, n No. of apheresis sessions, n a
Mean ( SD)
Median (range)
Mean ( SD)
56.4 ( 6.3)
58 (46e68)
57.4 ( 8.7)
Median (range) 57 (42e74)
P valuea 0.66
13 (52%) 75 (57e125) 3 (12%) 8 (33%)b 1.4 ( 0.6) 1 (1e3)
17 (68%) 74.6 ( 15.9) 73 (50e112) 1 (4%) 16 (64%) 1.7 ( 0.9) 1 (1e4)
0.39 0.23 0.61 0.046 0.2
8.4 ( 4.6) 4.4 ( 1.7) 193 ( 19.9)
16.1 ( 9.7) 7.6 ( 4.6) 193 ( 19.9)
13.2 (4e43.4) 6.1 (2.8e17.9) 200 (140e200)
0.0007 0.0017 1
4445 ( 1144) 3401 ( 1073)
4500 (3000e7200) 3360 (2100e6240)
0.0005 0.0001
75 ( 19.7)
5570 ( 999) 5249 ( 1952)
7.4 (2.3e21.2) 4.1 (0.6e7.7) 200 (140e200) 5460 (3600e7680) 5280 (3300e11700)
7.1 ( 1) 11.8 ( 1.1)
7 (5e9) 12 (10e14) n/a
3.1 ( 1)
3 (1e5)
Mean values were used to perform the Student’s t-test. Documentation of previous chemotherapy history was not retrievable in one patient.
b
Plerixafor/G-CSF (n ¼ 25)
5.9 8 1.8 1.9
( ( ( (
1.1) 1.8) 1) 1.1)
6 8 1 2
(5e8) (5e14) (1e4) (1e4)
0.0001 <0.0001 n/a 0.0001
Plerixafor for autologous stem cell mobilization in multiple myeloma
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Table II. Pharmacoeconomic analysis: per-patient cost comparison. G-CSF alone Cost per patient (US $) Mean ( SD) Outpatient cost Overall apheresis cost G-CSF for collection Plerixafor Apheresis procedure Inpatient cost Overall hospitalization Inpatient pharmacy G-CSF support Blood bank Blood products Overall pharmacy costb Overall hospitalization þ overall apheresis cost
15,673 ( 3666) 5689 ( 1104) 9984 ( 3242) 61,474 22,442 5527 2332
( ( ( (
10,464) 5451) 2259) 1160)
28,132 ( 5711) 77,147 ( 9889)
Plerixafor/G-CSF Cost per patient (US $)
Median (range)
Mean ( SD)
P valuea
Median (range)
15,858 (7670e21,364) 5691 (3576e8240) n/a 9600 (3200e16,000)
24,713 4488 14,209 6016
( ( ( (
1184) 1120) 8167) 3496)
19,837 4470 8073 6400
(14,253e49,860) (2980e7152) (8073e32,292) (3200e12,800)
0.0007 0.0004 n/a 0.0001
61,026 23,082 5665 1912
57,424 18,538 3560 2029
( ( ( (
12,306) 5418) 1190) 2263)
55,613 19,884 3605 1421
(34,302e84,206) (4601e24,757) (2086e6504) (387e12,075)
0.22 0.014 0.0003 0.69
(36,103e82,903) (4978e27,407) (3278e13,390) (536e4788)
28,691 (9746e39,824) 78,693 (53,671e95,293)
37,234 ( 11,095) 82,137 ( 1944)
35,418 (17,824e58,574) 75,653 (50,725e134,066)
0.0007 0.26
Note: Outpatient costs represent expenditures to the payer; inpatient costs represent hospital costs. Average wholesale price: filgrastim, 300 mg-vial ¼ $298; filgrastim, 480 mg-vial ¼ $515; plerixafor, 24-mg vial ¼ $8073. Cost charged for apheresis procedure ¼ $3200 per session. a Mean values were used to perform the Student’s t-test. b Included all medications received during hospitalization and in the clinic.
by an average of $9102 per patient (Table II). The plerixafor group required a fewer number of apheresis sessions, which led to a reduction in the cost of the overall apheresis procedures by an average of $9040 per patient. By delaying the initiation of G-CSF support by 5 days in the plerixafor-mobilized group, the cost of G-CSF used for neutrophil recovery was significantly reduced by an average of $1967 per patient. The cost of overall hospitalization per patient was similar between the two groups, as well as for the combined cost of overall hospitalization and the apheresis procedure (including mobilization regimen). The total costs of expenditures in each group are compared in Table III.
Discussion Poor mobilization increases the overall number of apheresis sessions to attain an adequate PBSC collection, increases the risk for catheter-related complications (ie, pain and infection at the site of catheter insertion, pneumothorax, embolism, bleeding and catheter occlusion) and incurs possible delays in the timing of ASCT. In our study, plerixafor-mobilized patients required a fewer number of apheresis sessions (mean, 3.1 in control versus 1.9 in plerixafor group; P ¼ 0.0001) and consequently, the cost of apheresis was significantly reduced in the plerixafor group. Inpatient pharmacy cost in the plerixafor group was significantly lower by an average of $3904 per patient. The lower inpatient pharmacy cost in the plerixafor group was not solely the result of delayed G-CSF support, which accounts for cost
savings of $1967 per patient. It is also of note that the high cost of plerixafor (mean, $14,209 per patient) led to significantly higher overall pharmacy costs; however, the total cost of hospitalization, mobilization and apheresis was not significantly impacted. Our study demonstrates that compared with the control group, up-front use of plerixafor for autologous mobilization in patients with MM is associated with significantly improved stem cell Table III. Pharmacoeconomic analysis: total cost comparison between the two groups. G-CSF alone (US $) Outpatient cost Overall apheresis cost G-CSF for collection Plerixafor Apheresis procedure Inpatient cost Overall hospitalization Inpatient pharmacy G-CSF support Blood bankBlood products Overall pharmacy costa Overall hospitalization þ overall apheresis cost
Plerixafor/G-CSF (US $)
388,860 139,260 0 249,600
617,814 112,202 355,212 150,400
1,536,838 561,060 138,187 59,295
1,435,610 463,447 88,999 50,724
703,288 1,928,665
930,861 2,053,424
Note: Outpatient costs represent expenditures to the payer; inpatient costs represent hospital costs. Average wholesale price: filgrastim, 300 mg-vial ¼ $298; filgrastim, 480 mg-vial ¼ $515; plerixafor, 24-mg vial ¼ $8073. Cost charged for apheresis procedure ¼ $3200 per session. a Included all medications received during hospitalization and in the clinic.
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yields and fewer apheresis procedures and does not have a substantial impact on overall costs. The number of patients whose stem cell yield was inadequate (<5 106 CD34þ cells/kg) were two (8%) in the plerixafor-mobilized group and six (24%) in the control group, all of whom were not candidates for second ASCT. Limitations of our study include the retrospective nature of the study and small sample size. Of note, two practice changes were instituted simultaneously in our patients with MM: addition of plerixafor to GCSF as an up-front mobilization strategy and delayed G-CSF support after ASCT. Nevertheless, the ability to achieve improved yields in CD34þ cell collection with a non-significant difference in overall costs is an important finding with implications regarding the up-front use of plerixafor for stem cell mobilization in patients with MM undergoing ASCT. Several groups have examined a variety of approaches for the use of plerixafor in patients with MM for autologous mobilization that are different from the approach described in our study, such as preemptive mobilization strategy or real-time rescue mobilization strategy [17e21]. Despite these efforts, optimal autologous mobilization in this population is still a subject of ongoing debate [22]. Regarding cost analysis studies, the findings are not unanimous. Some studies showed a positive impact on costs associated with stem cell collection [23,24], whereas others suggest that the increase in mobilization cost may be offset by performing a fewer apheresis sessions, a lower failure rate of mobilization and the greater likelihood of attaining an adequate stem cell count in a shorter period of time before proceeding to ASCT [25e28]. This is in line with our results in which the costs are not negatively affected by the upfront use of plerixafor. In summary, our single-institution, retrospective analysis demonstrated that up-front use of plerixafor for ASCT in patients with MM is an optimal mobilization strategy and without a significant negative impact on overall costs. Different predictors of poor mobilization have been defined on the basis of premobilization and post-mobilization period factors. Developing an institution-specific risk-adapted algorithm on the basis of patient populations may further improve the cost-effectiveness of plerixaforbased mobilization. Prospective trials with larger sample sizes are needed to address questions of optimal use of plerixafor for autologous mobilization and its impact on long-term healthcare costs. Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
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Pharmacoeconomic impact of up-front use of plerixafor for autologous stem cell mobilization in patients with multiple myeloma
SARA S. KIM1, ANNE S. RENTERIA2, AMIR STEINBERG2, KAREN BANOFF3 & LUIS ISOLA2 1
Department of Pharmacy, 2Blood and Marrow Transplantation Program and 3Business and Strategic Planning The Mount Sinai Medical Center, New York, New York, USA
Abstract Background aims. Stem cell collection can be a major component of overall cost of autologous stem cell transplantation (ASCT). Plerixafor is an effective agent for mobilization; however, it is often reserved for salvage therapy because of its high cost. We present data on the pharmacoeconomic impact of the use of plerixafor as an up-front mobilization in patients with multiple myeloma (MM). Methods. Patients with MM who underwent ASCT between January 2008 and April 2011 at the Mount Sinai Medical Center were reviewed retrospectively. In April 2010, practice changes were instituted for patients with MM to delay initiation of granulocyte-colony-stimulating factor (G-CSF) support from day 0 to day þ5 and to add plerixafor to G-CSF as an up-front autologous mobilization. Targets of collection were 5e10 106 CD34þ cells/kg. Results. Of 50 adults with MM who underwent ASCT, 25 received plerixafor/filgrastim and 25 received G-CSF alone as an up-front mobilization. Compared with the control, plerixafor mobilization yielded higher CD34þ cell content (16.1 versus 8.4 106 CD34þ cells/kg; P ¼ 0.0007) and required fewer sessions of apheresis (1.9 versus 3.1; P ¼ 0.0001). In the plerixafor group, the mean number of plerixafor doses required per patient was 1.8. Although the overall cost of medications was higher in the plerixafor group, the cost for blood products and overall cost of hospitalization were similar between the two groups. Conclusions. Up-front use of plerixafor is an effective mobilization strategy in patients with MM and does not have a substantial pharmacoeconomic impact in overall cost of hospitalization combined with the apheresis procedure. Key Words: autologous stem cell transplantation, mobilization, multiple myeloma, plerixafor, stem cell collection
Introduction Autologous stem cell transplantation (ASCT) is an effective treatment for multiple myeloma (MM) [1,2]. The most commonly used up-front mobilizing agent for autologous stem cell collection is granulocyte-colony-stimulating factor (G-CSF), which is associated with approximately 25% of unsuccessful mobilization [3,4]. Strong predictors for poor mobilization include advanced age, bone marrow (BM) failure, extensive prior chemotherapy treatment and previous treatment with lenalidomide or alkylating agents. Another common mobilization strategy is to combine chemotherapy, such as cyclophosphamide, with G-CSF [5,6]. This approach is associated with an unpredictable stem cell yield and, in some patients, neutropenic fever requiring hospitalization [7]. Mobilization of stem cells is induced through the interaction between stem cells and cells of the BM microenvironment. The binding of stromal cellederived factor 1 (SDF-1), a chemokine
expressed in BM stromal cells, to CXCR-4 plays a major role in regulating trafficking and retaining hematopoietic stem cells (HSC) in the BM [8]; however, the predominant source of SDF-1 (ie, osteoblasts, reticular cells in endosteal and vascular niches, endothelial cells and bones) is not clearly understood [9]. G-CSF promotes HSC mobilization by altering the BM niche; it downregulates osteoblast SDF-1 by altering the signaling of sympathetic nervous system to osteoblast, thereby attenuating CXCR signaling [10e12]. Plerixafor promotes HSC mobilization by reversibly blocking the binding of SDF-1 to its receptor, CXCR-4. Concurrent administration of plerixafor and G-CSF was shown to exert a synergistic effect on the mobilization of CD34þ progenitor cells [13]. Plerixafor, in combination with G-CSF, was granted US Food and Drug Administration approval in 2008. Its approval was based on the improved rate of successful mobilization when used up-front for ASCT in patients with
Correspondence: Sara S. Kim, PharmD, BCOP, Department of Pharmacy, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029. E-mail: [email protected] (Received 26 November 2013; accepted 2 May 2014) ISSN 1465-3249 Copyright Ó 2014, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2014.05.003
Plerixafor for autologous stem cell mobilization in multiple myeloma non-Hodgkin’s lymphoma and multiple myeloma (MM). Because of its high cost, plerixafor is often reserved for patients who failed previous standard mobilization [14e16]. The use of plerixafor as a salvage mobilization strategy can increase the number of apheresis sessions required to achieve an adequate peripheral blood stem cell (PBSC) collection and potentially impose delays on the timing of ASCT, especially for patients with MM who often require sufficient CD34þ cells for two ASCTs. In the present study, we evaluated 50 patients with MM who were mobilized up-front with G-CSF with or without plerixafor. The purpose of this study was to assess the pharmacoeconomic impact of the addition of plerixafor to G-CSF as an up-front autologous mobilization regimen for patients with MM. Methods Study design We performed a retrospective analysis to assess economic and clinical outcomes of 50 adult patients with MM who received ASCT between January 2008 and April 2011 at The Mount Sinai Medical Center, New York, New York. In the control group, 25 consecutive patients received single-agent G-CSF as a mobilizing agent and started G-CSF support from day 0 after PBSC infusion. In the plerixafor group, 25 consecutive patients received plerixafor in combination with GCSF, as an up-front mobilization therapy, and started G-CSF support from day þ5 after PBSC infusion.
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Method for growth factor support after ASCT Before April 2010, G-CSF was administered as 5 mg/ kg per day intravenously, starting on day 0 after PBSC infusion and until engraftment. Starting in April 2010, the initiation of G-CSF was delayed from day 0 to day þ5 after PBSC infusion. Data collection By use of the pharmacy database, patients with MM who underwent ASCT were identified, and data collection was performed with the use of patients’ electronic medical records. Data collection included patients’ baseline characteristics, total CD34þ cells collected, total CD34þ cells infused, number of doses of G-CSF and plerixafor administered for mobilization, number of apheresis sessions, number of doses of G-CSF required for engraftment, time to engraftment, length of hospital stay from day 0 and cost analysis for the two groups. Engraftment criteria Center for International Blood and Marrow Transplant Research criteria were used to define engraftment. Neutrophil engraftment is defined as an absolute neutrophil count 0.5 109 cells/L for 3 consecutive days after HSC transplantation. Platelet engraftment is defined as a platelet count 20 109 cells/L for 3 consecutive days after HSC transplantation and without platelet transfusion support for the preceding 7 days.
Method for mobilization
Pharmacoeconomic analysis
Before April 2010, G-CSF was used as an up-front mobilizing agent as 10 mg/kg per day subcutaneously for 5 days in patients with MM scheduled to undergo ASCT. Starting in April 2010, plerixafor was added to G-CSF as an up-front mobilization strategy in patients with MM. Plerixafor was administered as 0.24 mg/kg per day subcutaneously in the evening (approximately 6e7 PM) for up to 4 days, starting on the fourth day of G-CSF. The dose of plerixafor was capped at 40 mg/ d. In patients with renal insufficiency (defined as creatinine clearance 50 mL/min), the dose of plerixafor was reduced to 0.16 mg/kg per day, not exceeding 27 mg/d. Peripheral CD34þ cells were not routinely measured in these patients before apheresis. Minimum and optimal collection cell targets were 5 106 and 10 106 CD34þ cells/kg, respectively. If the yielded CD34þ stem cell content was >5 106/kg, half of the content of the collection was infused during the ASCT. Melphalan was administered intravenously at a target dosage of 200 mg/m2 and with dose adjustment on the basis of renal function.
All costs related to hospitalization were captured by our institution’s cost accounting system. Average wholesale price was used to calculate the outpatient cost of plerixafor ($8073 per 24-mg vial) and G-CSF ($298 per 300-mg dose) required for mobilization. Expenditure for apheresis procedure was $3200 per session. Statistical analysis The Student’s t-test was used to compare significance of difference between the two groups, and the twotailed Fisher’s exact test was used to compare frequencies of incidence between the two groups. A value of P < 0.05 was considered of statistical significance. Results Baseline characteristics A total of 50 patients with MM who underwent ASCT between January 2008 and April 2011 were
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identified using the pharmacy database. Twentyfive patients received plerixafor in combination with G-CSF, and 25 patients received singleagent G-CSF for PBSC mobilization. Baseline characteristics of the patients were well balanced between the two groups; however, more patients in the plerixafor group had prior treatment with lenalidomide compared with the control group (64% versus 33%; P ¼ 0.046) (Table I). Compared with the control, a significantly higher yield of CD34þ cells was achieved in the plerixafor group (mean, 8.4 versus 16.1 10 6 /kg; P ¼ 0.007). Accordingly, a significantly higher content of CD34 þ cells was infused to plerixafor-mobilized patients (mean, 4.4 versus 7.6 10 6 /kg; P ¼ 0.0017).
Doses of G-CSF with or without plerixafor for PBSC collection The number of G-CSF doses required to achieve a PBSC yield of 5 to 10 106 CD34þ cells/kg was an average of 7.1 doses in the control group and 5.9 doses in the plerixafor group (P ¼ 0.0001) (Table I). In the plerixafor group, an average number of plerixafor doses required was 1.8. Number of apheresis sessions The average number of apheresis sessions required for PBSC collection was 3.1 in the control group and 1.9 in the plerixafor group (P ¼ 0.0001) (Table I). Doses of G-CSF for engraftment
Time to engraftment Time to neutrophil engraftment was shortened by an average of 1 day in the control group (mean, 9.8 days in control versus 10.8 days in plerixafor group; P < 0.0001). Time to platelet engraftment was similar between the control and plerixafor groups (mean, 15.3 versus 16 days; P ¼ 0.41). Length of hospital stay after auto-SCT There was no statistical difference in length of hospital stay between the control and the plerixafor groups (mean, 14.1 versus 15.2 days; P ¼ 0.24).
After ASCT, the average number of G-CSF doses administered was 11.8 in the control group and 8 in the plerixafor group (P < 0.0001) (Table I). It is noteworthy that the initiation of G-CSF support was delayed by 5 days in the plerixafor group as a result of implementation of practice change. Pharmacoeconomic assessment Compared with the control group, the plerixafor group was associated with a reduction in the inpatient pharmacy cost by an average of $3904 per patient; however, the overall pharmacy cost (including the mobilization regimen used in the ambulatory setting) was higher in the plerixafor-mobilized group
Table I. Baseline characteristics. G-CSF alone (n ¼ 25)
Age, y Sex Male, n (%) Weight, kg Previous ASCT, n (%) Prior lenalidomide therapy, n (%) No. of prior chemotherapy regimens CD34+ cells, 106/kg Collected Infused Melphalan dose, mg/m2 Cumulative dose of G-CSF required, mg For collection For engraftment No. of doses of G-CSF, n For collection For engraftment No. of doses of plerixafor, n No. of apheresis sessions, n a
Mean ( SD)
Median (range)
Mean ( SD)
56.4 ( 6.3)
58 (46e68)
57.4 ( 8.7)
Median (range) 57 (42e74)
P valuea 0.66
13 (52%) 75 (57e125) 3 (12%) 8 (33%)b 1.4 ( 0.6) 1 (1e3)
17 (68%) 74.6 ( 15.9) 73 (50e112) 1 (4%) 16 (64%) 1.7 ( 0.9) 1 (1e4)
0.39 0.23 0.61 0.046 0.2
8.4 ( 4.6) 4.4 ( 1.7) 193 ( 19.9)
16.1 ( 9.7) 7.6 ( 4.6) 193 ( 19.9)
13.2 (4e43.4) 6.1 (2.8e17.9) 200 (140e200)
0.0007 0.0017 1
4445 ( 1144) 3401 ( 1073)
4500 (3000e7200) 3360 (2100e6240)
0.0005 0.0001
75 ( 19.7)
5570 ( 999) 5249 ( 1952)
7.4 (2.3e21.2) 4.1 (0.6e7.7) 200 (140e200) 5460 (3600e7680) 5280 (3300e11700)
7.1 ( 1) 11.8 ( 1.1)
7 (5e9) 12 (10e14) n/a
3.1 ( 1)
3 (1e5)
Mean values were used to perform the Student’s t-test. Documentation of previous chemotherapy history was not retrievable in one patient.
b
Plerixafor/G-CSF (n ¼ 25)
5.9 8 1.8 1.9
( ( ( (
1.1) 1.8) 1) 1.1)
6 8 1 2
(5e8) (5e14) (1e4) (1e4)
0.0001 <0.0001 n/a 0.0001
Plerixafor for autologous stem cell mobilization in multiple myeloma
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Table II. Pharmacoeconomic analysis: per-patient cost comparison. G-CSF alone Cost per patient (US $) Mean ( SD) Outpatient cost Overall apheresis cost G-CSF for collection Plerixafor Apheresis procedure Inpatient cost Overall hospitalization Inpatient pharmacy G-CSF support Blood bank Blood products Overall pharmacy costb Overall hospitalization þ overall apheresis cost
15,673 ( 3666) 5689 ( 1104) 9984 ( 3242) 61,474 22,442 5527 2332
( ( ( (
10,464) 5451) 2259) 1160)
28,132 ( 5711) 77,147 ( 9889)
Plerixafor/G-CSF Cost per patient (US $)
Median (range)
Mean ( SD)
P valuea
Median (range)
15,858 (7670e21,364) 5691 (3576e8240) n/a 9600 (3200e16,000)
24,713 4488 14,209 6016
( ( ( (
1184) 1120) 8167) 3496)
19,837 4470 8073 6400
(14,253e49,860) (2980e7152) (8073e32,292) (3200e12,800)
0.0007 0.0004 n/a 0.0001
61,026 23,082 5665 1912
57,424 18,538 3560 2029
( ( ( (
12,306) 5418) 1190) 2263)
55,613 19,884 3605 1421
(34,302e84,206) (4601e24,757) (2086e6504) (387e12,075)
0.22 0.014 0.0003 0.69
(36,103e82,903) (4978e27,407) (3278e13,390) (536e4788)
28,691 (9746e39,824) 78,693 (53,671e95,293)
37,234 ( 11,095) 82,137 ( 1944)
35,418 (17,824e58,574) 75,653 (50,725e134,066)
0.0007 0.26
Note: Outpatient costs represent expenditures to the payer; inpatient costs represent hospital costs. Average wholesale price: filgrastim, 300 mg-vial ¼ $298; filgrastim, 480 mg-vial ¼ $515; plerixafor, 24-mg vial ¼ $8073. Cost charged for apheresis procedure ¼ $3200 per session. a Mean values were used to perform the Student’s t-test. b Included all medications received during hospitalization and in the clinic.
by an average of $9102 per patient (Table II). The plerixafor group required a fewer number of apheresis sessions, which led to a reduction in the cost of the overall apheresis procedures by an average of $9040 per patient. By delaying the initiation of G-CSF support by 5 days in the plerixafor-mobilized group, the cost of G-CSF used for neutrophil recovery was significantly reduced by an average of $1967 per patient. The cost of overall hospitalization per patient was similar between the two groups, as well as for the combined cost of overall hospitalization and the apheresis procedure (including mobilization regimen). The total costs of expenditures in each group are compared in Table III.
Discussion Poor mobilization increases the overall number of apheresis sessions to attain an adequate PBSC collection, increases the risk for catheter-related complications (ie, pain and infection at the site of catheter insertion, pneumothorax, embolism, bleeding and catheter occlusion) and incurs possible delays in the timing of ASCT. In our study, plerixafor-mobilized patients required a fewer number of apheresis sessions (mean, 3.1 in control versus 1.9 in plerixafor group; P ¼ 0.0001) and consequently, the cost of apheresis was significantly reduced in the plerixafor group. Inpatient pharmacy cost in the plerixafor group was significantly lower by an average of $3904 per patient. The lower inpatient pharmacy cost in the plerixafor group was not solely the result of delayed G-CSF support, which accounts for cost
savings of $1967 per patient. It is also of note that the high cost of plerixafor (mean, $14,209 per patient) led to significantly higher overall pharmacy costs; however, the total cost of hospitalization, mobilization and apheresis was not significantly impacted. Our study demonstrates that compared with the control group, up-front use of plerixafor for autologous mobilization in patients with MM is associated with significantly improved stem cell Table III. Pharmacoeconomic analysis: total cost comparison between the two groups. G-CSF alone (US $) Outpatient cost Overall apheresis cost G-CSF for collection Plerixafor Apheresis procedure Inpatient cost Overall hospitalization Inpatient pharmacy G-CSF support Blood bankBlood products Overall pharmacy costa Overall hospitalization þ overall apheresis cost
Plerixafor/G-CSF (US $)
388,860 139,260 0 249,600
617,814 112,202 355,212 150,400
1,536,838 561,060 138,187 59,295
1,435,610 463,447 88,999 50,724
703,288 1,928,665
930,861 2,053,424
Note: Outpatient costs represent expenditures to the payer; inpatient costs represent hospital costs. Average wholesale price: filgrastim, 300 mg-vial ¼ $298; filgrastim, 480 mg-vial ¼ $515; plerixafor, 24-mg vial ¼ $8073. Cost charged for apheresis procedure ¼ $3200 per session. a Included all medications received during hospitalization and in the clinic.
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yields and fewer apheresis procedures and does not have a substantial impact on overall costs. The number of patients whose stem cell yield was inadequate (<5 106 CD34þ cells/kg) were two (8%) in the plerixafor-mobilized group and six (24%) in the control group, all of whom were not candidates for second ASCT. Limitations of our study include the retrospective nature of the study and small sample size. Of note, two practice changes were instituted simultaneously in our patients with MM: addition of plerixafor to GCSF as an up-front mobilization strategy and delayed G-CSF support after ASCT. Nevertheless, the ability to achieve improved yields in CD34þ cell collection with a non-significant difference in overall costs is an important finding with implications regarding the up-front use of plerixafor for stem cell mobilization in patients with MM undergoing ASCT. Several groups have examined a variety of approaches for the use of plerixafor in patients with MM for autologous mobilization that are different from the approach described in our study, such as preemptive mobilization strategy or real-time rescue mobilization strategy [17e21]. Despite these efforts, optimal autologous mobilization in this population is still a subject of ongoing debate [22]. Regarding cost analysis studies, the findings are not unanimous. Some studies showed a positive impact on costs associated with stem cell collection [23,24], whereas others suggest that the increase in mobilization cost may be offset by performing a fewer apheresis sessions, a lower failure rate of mobilization and the greater likelihood of attaining an adequate stem cell count in a shorter period of time before proceeding to ASCT [25e28]. This is in line with our results in which the costs are not negatively affected by the upfront use of plerixafor. In summary, our single-institution, retrospective analysis demonstrated that up-front use of plerixafor for ASCT in patients with MM is an optimal mobilization strategy and without a significant negative impact on overall costs. Different predictors of poor mobilization have been defined on the basis of premobilization and post-mobilization period factors. Developing an institution-specific risk-adapted algorithm on the basis of patient populations may further improve the cost-effectiveness of plerixaforbased mobilization. Prospective trials with larger sample sizes are needed to address questions of optimal use of plerixafor for autologous mobilization and its impact on long-term healthcare costs. Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
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