Bone Marrow Transplantation (2015) 50, 663–667 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt
ORIGINAL ARTICLE
Utilization of stored autologous PBSCs to support second autologous transplantation in multiple myeloma patients in the era of novel agent therapy C Phipps1,2, M Linenberger1, LA Holmberg1, D Green1, P Becker3, L Connelly-Smith1, Z Klippel4, N Burwick5, A Gopal1,5, WI Bensinger1 and E Libby1 Outcomes in multiple myeloma (MM) have improved significantly with novel agent therapy and autologous stem cell transplantation (ASCT). ASCTs are typically planned as either tandem or a single transplant with additional stored PBSCs available for a second salvage transplant. To accommodate these strategies, many centers routinely collect and store adequate PBSCs for two ASCTs. We analyzed the cost associated with this practice by determining the expenses of PBSC collection, cryopreservation and storage, and the ultimate use of additional cryopreserved PBSCs in patients who had undergone at least one ASCT. There were 889 MM patients transplanted between 1993 and 2011 at our center. Most (N=726) had residual PBSCs in storage after their first ASCT (ASCT1). Only 135 patients underwent a second ASCT within a median of 14 months after ASCT1. The percentage of patients receiving a second ASCT declined over time. The resources required to collect and store unused PBSCs added up to 336 extra patient days of apheresis and 41 587 extra patient months of cryopreservation, translating into an average extra cost per patient of US$4981.12. A reconsideration of conventional PBSC collection and storage practices would save significant cost for the majority of MM patients who never undergo a second ASCT. Bone Marrow Transplantation (2015) 50, 663–667; doi:10.1038/bmt.2015.13; published online 2 March 2015
INTRODUCTION Autologous stem cell transplantation (ASCT) was initially established as the standard of care to treat multiple myeloma (MM) based on superior EFS and OS in randomized prospective trials comparing conventional chemotherapy to a single ASCT.1,2 Later prospective randomized studies comparing tandem ASCT with a single transplant showed that tandem ASCT was most beneficial for patients not achieving CR, near CR or very good PR after their first ASCT (ASCT1).3,4 Subsequent studies addressed the role of a second ASCT for salvage treatment after progression from a successful ASCT1.5–7 These studies highlighted the difficulties of mobilizing and collecting additional stem cells following recovery from the myeloablative ASCT1.8 As a result, most centers adopted the policy to collect and store adequate PBSCs for two transplants before ASCT1, with the preferred PBSC cell dose ranging from 2 to 5 × 106 CD34+ cells per kilogram of recipient weight (CD34+ cells per kg) per transplant. Recently, the use of novel and more effective agents for MM have led to deeper responses before and after ASCT1, challenging the rationale for planned, upfront tandem ASCTs and the utility of a second ASCT for salvage treatment. Considering this changing landscape of therapies for MM, we sought to evaluate the collection, storage and utilization practices of PBSC for ASCT, with an emphasis on the priority to collect and store adequate CD34+ cells per kg for two transplants. 1
SUBJECTS AND METHODS The clinical databases at the Fred Hutchinson Cancer Research Center and the Seattle Cancer Care Alliance and the laboratory databases from the Cellular Therapy Laboratory were searched to obtain demographic, clinical, PBSC collection and storage information on all patients with MM who underwent ASCT between 1993 and 2011. The Fred Hutchinson Cancer Research Center Institutional Review Board approved this study. Final collated data sets were analyzed in June 2013. The numbers of days of apheresis and PBSC product collection yields were determined for patients who were mobilized by any method (G-CSF alone, G-CSF with plerixafor or mobilization chemotherapy with growth factor). The need for blood product transfusions during apheresis was not captured in this data set nor was information on the use of large volume vs standard volume apheresis. The target cell dose for one transplant at our center is 5 × 106 CD34+ cells per kg. We determined the time course and frequency of a first ASCT following PBSC collection and storage. We also determined the frequencies and trends of all second ASCTs (including tandem and second salvage transplant). Tandem transplant was defined as a second ASCT occurring within 180 days of the first. To analyze trends over time, we divided the sample populations into groups of 3 or 4 year periods. Second ASCTs were counted and reported as a percentage of the total number of ASCTs performed during these defined time periods. We estimated the costs involved in PBSC collection (apheresis) and cryopreservation storage based on our institution-specific charges as of July 2012. For analyses of costs related to usage of the products that remained in cryopreservation for a second/subsequent ASCT, we first determined the number of days required to collect sufficient PBSC for one
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Department of Haematology, Singapore General Hospital, Singapore, Singapore; Department of Medicine, University of Washington, Seattle, WA, USA; 4Amgen Inc., Thousand Oaks, CA, USA and 5Medical Oncology, University of Washington, Seattle, WA, USA. Correspondence: Dr C Phipps, Clinical Research Division, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Seattle, WA 98109-1023, USA. E-mail:
[email protected] This study or any of its parts have not been presented elsewhere. Received 2 September 2014; revised 29 December 2014; accepted 14 January 2015; published online 2 March 2015 3
Cost and usage of stem cells for second transplant in myeloma C Phipps et al
664 ASCT, and then the number of additional days to complete the actual collection. The number of days was then multiplied with an estimate of cost as follows: 1 day PBSC collection US$3016, 1 day processing for cryopreservation US$5955 and yearly storage fees US$408 (US$34 per month). We also analyzed the cumulative costs associated with long-term cryopreservation storage in our facility. The cost of mobilization chemotherapy and G-CSF (whether used as part of the mobilization regimen or otherwise) were not included. Plerixafor was used in 34 of the 889 patients, which resulted in a total of 11 extra patient days of collection. Most received plerixafor under a clinical trial and thus the related cost was excluded from this analysis.
RESULTS AND DISCUSSION From May 1993 to June 2011, 1000 MM patients underwent PBSC collection and subsequent ASCT. A total of 111 patients were excluded because of incomplete collection or storage data. Therefore, 889 patients were included in the analyses. The median age of patients at the time of PBSC collection was 57 years (range 22–75). As expected, there was an increase in the number of MM 400 Patients with 2 transplants Patients with 1 transplant
9%
Number of patients
300 24%
200 9%
18%
100
23%
0 1993 -1995
1996 -1999
2000 - 2003
2004 - 2007
2008 - 2011
Transplant year
Figure 1. Histogram showing the number of patients transplanted from 1993 to 2011 and the percentage of second transplants of the total number during that period.
20 18
patients who underwent ASCT over time: 1993–1995, 39 patients; 1996–1999, 100 patients; 2000–2003, 162 patients, 2004–2007, 251 patients; and 2008–2011, 337 patients. Treatment and PBSC collection characteristics The median number of induction treatment regimens received before PBSC mobilization and collection was 1 (range 1–8). The median times from diagnosis to initiation of PBSC collection and from final PBSC storage to ASCT were 9 months (range 1–146) and 1 month (range 0.1–114), respectively. The median number of days of PBSC collection was 2 (range 1–10), with a median total CD34+ cell yield (all collections) of 13.18 × 106/kg (range 1.98– 177.07). The median number of days to collect sufficient CD34+ cells for one ASCT (i.e. 5 × 106 CD34+ cells per kg) was 1 day (range 1–9) and 383 patients (43%) collected adequate cells for two ASCTs (i.e. 10 × 106 CD34+ cells per kg) after a single apheresis procedure. Two hundred and sixty-five patients required additional days of collection to achieve an adequate number of cells for two ASCTs, with a median of 1 extra collection day (range 1–4). A total of 241 patients (27%) failed to yield at least 10 × 106 CD34+ cells per kg. These patients had a median number of collection days of 4 (range 2–9), with a median CD34+ yield of 6.9 × 106/kg collected. Second transplants Of 889 patients who underwent a first ASCT, 726 patients had residual PBSC products in cryopreservation storage. Among these, 580 patients’ products (80%) contained ⩾ 5 × 106 CD34+ cells per kg. One hundred and thirty-five of these 726 patients (19%) underwent a second ASCT, either as early tandem or salvage second transplant, at a median of 14 months (range 2.5–113) after ASCT1. The median age of patients at the time of their second ASCT was 59 years (range 28–70 years). The numbers and frequencies of any second ASCTs per time period were as follows: 1993–1995, 9 of 39 patients (23%); 1996–1999, 18 of 100 (18%); 2000–2003, 15 of 162 (9%); 2004–2007, 62 of 251 (24%); and 2008– 2011, 31 of 337 (9%) (Figure 1). Fifty patients underwent early tandem ASCTs and these accounted for 89, 72, 7, 24 and 42% of all second ASCTs during the respective time periods. The other 85 patients had their second ASCT more than 6 months after the first (Figure 2). In the years of 2012–2013, there were no early tandem ASCTs at our center. The use of early tandem transplants
Tandem transplant Non-tandem second transplant
16
Number of patients
14 12 10 8 6 4 2 0 1995 1996 1997 1998 2000 2001 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Year of second transplant
Figure 2.
Tandem and second salvage transplant over the years.
Bone Marrow Transplantation (2015) 663 – 667
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Cost and usage of stem cells for second transplant in myeloma C Phipps et al
665 was based on ongoing clinical trials that mandated second transplant and clinical response to ASCT1. PBSC product usage Over time, the number and percentages of patients with residual, unused cryopreserved PBSCs in storage after ASCT1 increased progressively. In the 1993–1995 period, 11% of patients had residual PBSCs after the first ASCT. Data for subsequent time periods were as follows: 1996–1999, 61%; 2000–2003, 45%; 2004–2007, 67%; 2008–2011, 88%. Patients with PBSC products in long-term storage A total of 637 patients (88% of those with residual PBSC products after ASCT1) had unused PBSCs in cryopreservation storage for more than 1 year. The trend for long-term storage over 1 year increased over time as follows: 1993–1995, 7 (1%); 1996–1999, 65 (10%); 2000–2003, 77 (12%); 2004–2007, 185 (29%); and 2008–2011, 303 (48%). Among these patients, the duration of storage was o2 years for 34 (5%), 2–5 years for 346 (54%) and 45 years for 257 (40%). The overall median PBSC product storage time was 40 months. PBSC products from 260 patients were discarded (or sent to repository) after a median storage of 54 months for the following reasons: 5 patients underwent allogeneic transplant, 74 patients were alive but elected to release their cells from storage, 3 PBSC products had cell viability issues and 178 patients had died. Cost of collection and storage The estimated costs incurred for additional days of PBSC collection to achieve adequate cells for a second ASCT and the associated costs for cryopreservation and storage were as follows: 5 additional days of collection—US$44 855, N = 1 patient; 4 additional days of collection—US$35 844, N = 2; 3 additional days of collection—US$26 913, N = 10; 2 additional days of collection— US$17 942, N = 41; and 1 additional day of collection—US$8971, N = 211 (Table 1). The estimated total average cost per patient for PBSC collection, cryopreservation and storage was US$19 349.78, with US$4981.12 per patient spent to collect and store additional PBSC for a potential second ASCT that was never performed. The first randomized trial comparing single vs tandem ASCT by the Intergroupe Francophone du Myèlome showed improved EFS and OS in favor of planned tandem ASCT.3 In selected patients who do not achieve at least a very good PR after a first ASCT, second ASCT has shown to have the most benefit and improve OS.9 However, with higher response rates using novel combination therapy, more patients now go into ASCT with less disease burden, making it less likely they will need an early second ASCT.10–12 In addition, the use of newer agents, such as lenalidomide, as maintenance therapy after a single ASCT has been shown to deepen responses and significantly delay time to progression when compared with placebo.13–17 Economic considerations impact the choice of a second transplant as well; many insurance providers in the United States including Medicare do
Table 1.
Costs related to extra PBSC collection days
Number of extra days required 1 2 3 4 5
not pay for tandem ASCTs. The use of a salvage second transplant, performed at relapse after first ASCT, is supported mainly by retrospective data.18–20 The most recent study by the Center for International Blood and Marrow Transplant Research looked retrospectively at patients who had undergone second ASCT for relapsed myeloma. Their analysis showed that patients relapsing more than 36 months from the first ASCT derived more benefit than patients with a shorter disease-free survival. This select group of patients accounted for only 19% of their patient population.7 Thus, a single ASCT remains the standard of care as part of initial therapy for transplant-eligible patients. The optimal timing of ASCT1 was assessed in one randomized trial, which found no difference in OS whether performed early or as late, rescue therapy.21 Most guidelines, however, recommend ASCT1 as upfront consolidation treatment.22–24 Our PBSC collection and storage practices are likely a reflection of the change in treatment paradigms with time as novel immunomodulatory agents, and proteasome inhibitors became available. We observed a decreasing trend in the frequencies of second ASCTs over the past decade, from 24% in the period 2004 and 2007 to 9% in the period 2008 and 2011. Early tandem ASCT accounted for roughly 20% of the total number of second ASCTs, with the majority being used for salvage treatment (Figure 2). The reduction in tandem ASCTs at our center is likely because of changes in clinical trials that previously mandated early planned tandem ASCTs, use of more maintenance therapy after ASCT1, deeper responses achieved with induction therapy before ASCT1 and socioeconomic issues such as the impact of Medicare and private insurance reimbursement. The use of second salvage ASCT may be lower in the later years in our center because of longer time to progression after ASCT1 and because more treatment options for relapsed disease became available. Additional factors relate to age of patients and other socioeconomic issues. Collectively, these trends along with the development of second-generation proteasome inhibitors, newer immunomodulatory agents and MoAbs for maintenance or alternative therapies predict even fewer indications for a second ASCT in the future. Despite the limited use of PBSC products for a second tandem or salvage ASCT at our center, most MM patients still undergo PBSC harvesting with the aim of achieving enough CD34+ cells per kg for two transplants. Our single-center experience is that 88% of patients continue to store PBSC products beyond 1 year and ~ 70% store cryopreserved products beyond 2 years after ASCT1. Roughly one-third maintained continuous storage beyond 5 years. This figure is notable because PBSC storage for a period of 2 years is built into our current contract that is signed at the time of PBSC collection. Twenty-eight percent of patients who had PBSC storage beyond 1 year died without ever using their cryopreserved products. The estimated cost of collection and storage of PBSC beyond that needed for a single ASCT accounted for roughly a quarter of total costs. Our current practice resulted in 336 extra patient days of apheresis and processing for cryopreservation and 41 587 extra patient months of stem cell product storage. A change in practice
N
Added cost of apheresis per patient (US$)
Added cost of cryopreservation per patient (US$)
Total additional cost per patient (US$)
Total additional cost for extra days of collection (cost per day × N) (US$)
Number who underwent ASCT2
211 41 10 2 1
3016 6032 9048 12 064 15 080
5955 11 910 17 865 23 820 29 775
8971 17 942 26 913 35 884 44 855
1 892 881 735 622 269 130 71 768 44 855
36 13 3 1 1
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Cost and usage of stem cells for second transplant in myeloma C Phipps et al
666 to collect enough stem cells for just a single ASCT would have translated into savings of US$3 815 730 for our entire cohort of patients. Additional cost recovery would be realized by factoring in the expenses of the extra days of growth factor use, decreased blood product transfusions (to accommodate extra days of apheresis) and associated clinical risks and complications. A change in practice would substantially decrease the number of days of patients experiencing toxicities from growth factors and the apheresis process. As to whose perspective these added cost estimates reflect depends on individual institutional payment models, and may be the transplant center, patient’s insurance company or the patient. This analysis is limited by its retrospective design. We assumed that all patients started PBSC collection with a target CD34+ cell per kg sufficient for two transplants, whether or not it was required by ASCT clinical trial protocols. Our preferred PBSC cell dose of 5 × 106 CD34+ cells per kg is not a standard of care and ASCT can be performed with lower cell doses. This study does not consider the cost of mobilization chemotherapy and G-CSF support, as our objective was to examine the added financial impact of collecting PBSCs for more than one ASCT. An additional consideration is that we reported only on estimated average costs based on July 2012 charges and not on the actual charges incurred by patients over the years. There is not a mathematical model that analyzes cost effectiveness. The nature of our study and findings do not allow us to formulate a risk stratification model of whom would benefit most from a second (or tandem) ASCT. A recent prospective study that allocated tandem transplantation based on response to ASCT1 showed that patients achieving at least a very good PR have superior long-term outcomes, and may not require tandem ASCT.25 Cavo et al.26 performed an integrated analysis of prospective trials using single or double ASCT in the bortezomib era and found an OS advantage with double ASCT in patients with high-risk cytogenetics and/or whom fail to achieve CR after bortezomib-based induction. There is currently a phase 3, multicenter trial of single ASCT with or without consolidation therapy vs tandem ASCT with lenalidomide maintenance (STaMINA trial). Studies like these will shed light on how to better define populations of MM patients whom would benefit from a tandem ASCT approach and guide PBSC collection practices accordingly. The development of immunotherapy using chimeric antigen receptors that can redirect autologous T cells against MM-specific targets may again change collection goals in the future. The ability to successfully collect enough PBSCs after a single ASCT/high-dose melphalan is worth re-examination. Huijgens et al.8 reported a PBSC collection failure rate of 18% (10 of 55 patients) after high-dose melphalan. The authors concluded that more effective mobilization techniques were warranted. Unfortunately, studies of plerixafor in this setting have not been widely reported. The two-phase three randomized trials using plerixafor specifically excluded patients who had previously undergone ASCT, whereas the large compassionate use program did not report on patients who had mobilized after ASCT1.27–29 Therefore, it remains to be seen (and reported) whether plerixafor can overcome the higher collection failure rates after high-dose melphalan. This study is the first to examine the resource utilization and associated cost estimates of collecting and storing PBSC products for two rather than a single ASCT among patients with MM. Our results suggest that this conventional practice is worth reconsideration in view of rising treatment costs and the evolving role of novel agents in induction before and maintenance therapy after ASCT1, with deeper responses achievable before and after a first ASCT. Prospective studies are needed to answer the question of how many cells to collect and store and this decision should ultimately be made on outcome analysis and not cost information. However, there is at present a paucity of studies relating to this important question. Bone Marrow Transplantation (2015) 663 – 667
CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We greatly appreciate the contribution of the database managers at the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance.
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