Blood Res 2017; 52(4): 307-310  https://doi.org/10.5045/br.2017.52.4.307
Is long term storage of cryopreserved stem cells for hematopoietic stem cell transplantation a worthwhile exercise in developing countries?
Santhosh Kumar Devadas1, Minal Khairnar2, Sumathi S Hiregoudar2, Shashank Ojha2, Sachin Punatar1, Alok Gupta1, Anant Gokarn1, Pallavi Bhole3, Sadhana Kannan3, and Navin Khattry1*

1Department of Medical Oncology and Bone Marrow Transplantation, Tata Memorial Center, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Mumbai, India.

2Department of Transfusion Medicine, Tata Memorial Center, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Mumbai, India.

3Statistics, Tata Memorial Center, Advanced Center for Treatment, Research and Education in Cancer (ACTREC), Mumbai, India.

Correspondence to: Navin Khattry, M.D. Department of Medical Oncology, Bone Marrow Transplant Unit, ACTREC, Tata Memorial Center, Mumbai 410210, India. nkhattry@gmail.com
Received: March 26, 2017; Revised: August 6, 2017; Accepted: September 28, 2017; Published online: December 26, 2017.
© The Korean Journal of Hematology. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Background

Stem cell units (SCUs) that are cryopreserved prior to both autologous and allogeneic hematopoietic stem cell transplants (for donor lymphocyte infusion) remain unused or partially used several times, and become an increased burden to blood banks/SCU repositories. Because of the scarcity of data regarding the duration for which the storage is useful, there is no general consensus regarding disposal of SCUs.

Methods

We conducted a retrospective audit of SCU utilization in 435 patients who planned to undergo either autologous stem cell transplantation (auto-SCT) (N=239) or allogeneic stem cell transplantation (allo-SCT) (N=196) at a tertiary cancer care center between November 2007 to January 2015.

Results

Our cohort consisted of 1,728 SCUs stored for conducting auto-SCT and 729 SCUs stored for conducting donor lymphocyte infusions (DLIs) after allo-SCT. Stem cells were not infused in 12.5% of patients who had planned to undergo auto-SCT, and 80% of patients who underwent allo-SCT never received DLI. Forty-one percent of SCUs intended for use in auto-SCT remained unutilized, with a second auto-SCT being performed only in 4 patients. Ninety-four percent of SCUs intended for carrying out DLIs remained unused, with only minimal usage observed one year after undergoing allo-SCT.

Conclusion

The duration of storage of unused SCUs needs to be debated upon, so that a consensus can be reached regarding the ethical disposal of SCU.

Keywords: Cryopreservation, Stem cell, Long term, Developing
INTRODUCTION

It is a common practice to cryopreserve the collected hematopoietic stem cells (HSCs) of a patient prior to an autologous stem cell transplant (auto-SCT), as stem cells are reinfused after administering high doses of chemotherapy with or without radiotherapy [1]. Before conducting allogeneic stem cell transplantation (allo-SCT), donor stem cells are cryopreserved in some centers for enabling their future use in donor lymphocyte infusions (DLIs) [2]. Because a second auto-transplant would be needed in conditions such as multiple myeloma, transplant centers tend to collect stem cells needed for multiple transplants in a single sitting for using them in future transplants [3]. Investigators have also advocated second/tandem transplants for Hodgkin's lymphoma (HD) and neuroblastoma (NB) [45]. Hence, transplant centers tend to collect stem cells for more than one auto-SCT.

After conducting the first auto-SCT, the remaining cryopreserved stem cells are stored in the transplant center for a certain duration. Except in cases where a patient has died, discarding these stored stem cells may be considered unethical. The duration of storage of these cryopreserved stem cells is a matter of debate. We retrospectively analyzed the kinetics of stem cell harvest, storage, and infusion in a tertiary care hospital in India.

MATERIALS AND METHODS

This is a retrospective audit of 435 patients who planned to undergo either auto- or allo-SCT between November 2007 and January 2015; the data was analyzed in June 2016. A total of 239 patients underwent stem cell mobilization for a planned auto-SCT, out of which 30 patients eventually did not undergo auto-SCT because of disease progression prior to the planned auto-SCT. As an institutional practice, most patients (N=227) undergoing auto-SCT underwent chemo-mobilization, while 10 patients underwent granulocyte colony stimulating factor (G-CSF) mobilization and 2 patients underwent bone marrow harvest. For allo-SCT, 185 related donors underwent G-CSF mobilization, 9 donors underwent bone marrow harvest, and cord blood grafts were obtained from 2 patients. Thirty-one patients did not have DLIs.

Because the indications and kinetics of stem cell usage are different between auto- and allo-SCT, they would be described separately. Stem cell apheresis for auto-SCT was performed in a single day or in multiple days, based on the target CD34+ cell count required and the indications regarding transplantation. In our center, 3–5×106/kg of CD 34+ cells were usually collected before auto-SCT. The collected stem cells were divided into bags and cryopreserved with an equal volume of 8.7% dimethyl sulfoxide (DMSO), so that the final concentration of DMSO was 4.35%. Each bag contained not more than 100 ml of cryopreserved product. These bags were referred to as stem cell units (SCUs). Between November 2007 and January 2015, a total of 239 patients underwent stem cell apheresis prior to auto-SCT; of these, 209 underwent auto-SCT. A total of 1,728 SCUs obtained from 239 patients were cryopreserved during this period.

Similarly, out of 196 patients who underwent allo-SCT, 165 patients had cryopreserved their stem cells for receiving DLIs. The stem cells were stored for DLIs only if the peripheral blood stem cell harvest yielded a CD 34+ dose greater than 4×106/kg. A total of 729 SCUs were stored for DLIs. Each SCU stored for conducting a DLI contained approximately 1×107/kg CD3+ lymphocytes.

The cost of storing the cryopreserved stem cells for each patient was calculated. The cost of 50 mL of 8.7% DMSO is approximately US $100. Therefore, for each patient, the cost of cryopreservation was calculated with the amount of 8.7% DMSO used for storing the SCU. The cost of electricity, maintenance, and space required were not included.

RESULTS

The cryopreserved stem cells were included in the inventory during November 2007 to January 2015. At the time of analysis in June 2016, the median duration for which cryopreserved stem cells were stored was 4.1 years (range, 1.34–8.4 yr).

Autologous stem cell transplant

The median CD34+ HSCs collected per patient was 7.69×106/kg. The mean number of leukapheresis sessions required was 1.6. The mean number of SCUs stored per patient was 7.34. The mean number of SCUs infused was 4.89 and median CD34+ HSC dose used was 5.28×106/kg. A total of 209 (87.44%) patients underwent at least 1 auto-SCT. Only 4 multiple myeloma patients underwent a second auto-SCT during this period. Details regarding the kinetics of SCU usage for each differently diagnosed subset of patients undergoing auto-SCT are depicted in Table 1.

Allogeneic stem cell transplant

The median CD34+ HSCs collected per patient was 7.9×106/kg. The mean number of leukapheresis sessions required was 1.27. The mean number of SCUs per patient that was stored for DLIs was 4.07. A total of 33 (20%) patients underwent reinfusion with at least 1 SCU. Details regarding the kinetics of SCU usage for each subset of diagnosed patients undergoing allo-SCT (excluding 31 patients for whom SCUs were not stored for DLI) is depicted in Table 2.

Cost of storing unused SCU

The total cost of cryopreserving 704 unused SCUs for auto-SCT was $70,400, while the cost of cryopreserving 687 unused SCUs for DLI was $43,100.

DISCUSSION

It is a common practice to cryopreserve hematopoietic stem cells prior to auto-SCT. Stem cell centers target the harvest of around 3–5×106/kg CD34+ cells per transplant prior to auto-SCT. Many centers also cryopreserve immunocompetent donor cells for enabling DLIs to be received after allo-SCT, because it may be difficult to locate the donor and mobilize stem cells from the donor when DLI needs to be performed urgently. When a transplant center mobilizes, cryopreserves, and stores stem cells, three possible outcomes emerge: all the SCUs are reinfused into the patient; a part of the stored SCUs is used; or none of the stored SCUs are used. If the SCUs remain entirely or partially unused, an unresolved question arises regarding the duration for which the unused SCUs should be stored.

Non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HD), and multiple myeloma (MM) remain the main indications for auto-SCT [6]. A second autologous stem cell transplantation procedure conducted after relapse is considered to be a standard practice in patients with multiple myeloma, while tandem transplants are less common at present [789]. A few experts also advocate a second auto SCT/tandem auto-SCT for relapsed/refractory HD [410]. Similarly, stem cell rescue following high-dose MIBG therapy prolongs survival in patients at high risk for neuroblastoma who relapse after auto-SCT [5]. Because of these reasons, if SCUs remain at the transplant center after the first auto-SCT, it may be considered unethical to discard them as long as the patient is alive [11].

In our series of 239 patients, in whom stem cell apheresis was done prior to auto-SCT (Table 1), 12.5% of patients never underwent transplantation because of disease progression/death during the waiting period, 28% of patients underwent auto-SCT and they received all the cryopreserved SCUs, and 59% of patients only partially received their SCUs. When compared with large series of patients studied in Europe, the ratio of infused to stored stem cells was lower in our series [11]. In other words, we had a higher percentage of unused SCUs. Nearly 40% of SCUs collected prior to auto-SCT remained in our blood bank, with a second infusion being done only in 4 myeloma patients.

DLIs could be used in various settings in the post allo-SCT phase, namely preemptive, prophylactic, and therapeutic [12]. It is sometimes difficult to harvest stem cells again from donors because of societal and financial reasons in developing countries such as India when the patient requires DLI; hence as a policy our center stores excess stem cells collected as DLIs to avoid a second harvest when required [13]. With respect to SCUs stored for DLI, only 5.7% of stored SCUs were reinfused (Table 2), while 15% of the patients for whom SCUs were stored received DLI. As shown in Fig. 1, beyond 12 months, only 6 DLIs were performed, asserting the impracticality of storing these SCUs beyond 1 year. However, the FACT-JACIE standards that are followed by a majority of the European and American transplant centers advocate the continued storage of cellular products till the death of the patient or transfer of SCUs to other facilities after obtaining informed consent from the patient/guardian [14].

The limited use of DLIs raises the following question: Is the cryopreservation of SCUs for DLI cost effective and required? The storage of SCUs for long durations is laborious and escalates the cost of the transplantation process [15]. The cost of inventory management and electricity costs for freezing and freezer space etc add up to substantial costs in the long run. The cost of cryopreservation per patient in the West is between US $1,500 and US $5,000, depending on the volume of cells cryopreserved and the duration of cryopreservation [161718]. With the mounting costs of cancer care in general and hematopoietic stem cell transplantation in particular, there is a renewed focus on cutting costs by both institutions and the government [192021]. The cost of a stem cell transplant in India is between US $12,000 and US $17,000 [20]. In this retrospective analysis, we have looked only at the cost of cryopreservation. The cost of unused SCUs was approximately US $260 per patient, which is approximately 2% of the transplant cost.

A recently published paper by an Italian group has recommended certain criteria for disposal of SCUs based on a large survey on cryopreservation practices and outcomes [1122]. This guideline proposes that stem cells should be discarded after 10 years of storage if the patient continues to survive. Our study is the first of its kind in the developing world, which could help in building a consensus regarding the issue of stem cell disposal in developing countries.

In conclusion, the SCUs stored prior to auto-SCT and allo-SCT (for DLI) are only partially used most of the time. Their continued storage after a certain point of time needs to be debated upon, so that a consensus could be built regarding the ethical disposal of such SCUs.

Figures
Fig. 1.

Donor lymphocyte infusion after allogeneic stem cell transplantation.


Tables
Table 1 Details of stem cell units stored for autologous stem cell transplantation.

Abbreviations: AML, acute myeloid leukemia; HL, Hodgkin's lymphoma; MM, multiple myeloma; NB, neuroblastoma; NHL, Non-Hodgkin's lymphoma; SCU, stem cell unit; Other, other solid tumors.


Table 2 Use of SCUs stored for donor lymphocyte infusion.

Abbreviations: AA, aplastic anemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; DLI, donor lymphocyte infusion; HL, Hodgkin's lymphoma; MDS, myelodysplastic syndrome; SCU, stem cell unit.


References
  1. Lennard, AL, Jackson, GH. Stem cell transplantation. BMJ, 2000;321;433-437.
    Pubmed
  2. Frey, NV, Lazarus, HM, Goldstein, SC. Has allogeneic stem cell cryopreservation been given the ‘cold shoulder’? An analysis of the pros and cons of using frozen versus fresh stem cell products in allogeneic stem cell transplantation. Bone Marrow Transplant, 2006;38;399-405.
    Pubmed
  3. Bladé, J, Rosiñol, L, Fernández, de. How I treat relapsed myeloma. Blood, 2015;125;1532-1540.
    Pubmed
  4. Ritchie, DS. The role of second autografts in the treatment of Hodgkin lymphoma. Leuk Lymphoma, 2007;48;847-848.
    Pubmed
  5. Kayano, D, Kinuya, S. Iodine-131 metaiodobenzylguanidine therapy for neuroblastoma: reports so far and future perspective. ScientificWorldJournal, 2015;2015;189135.
    Pubmed
  6. European Society for Blood and Marrow Transplantation. EBMT Annual report 2014. Leiden, The Netherlands: EBMT; [Accessed February 4, 2017]. , https://www.ebmt.org/Contents/Resources/Library/Annualreport/Documents/EBMT_AnnualReport_2014.pdf
  7. Mohty, M, Harousseau, JL. Treatment of autologous stem cell transplant-eligible multiple myeloma patients: ten questions and answers. Haematologica, 2014;99;408-416.
    Pubmed
  8. Attal, M, Harousseau, JL, Facon, T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med, 2003;349;2495-2502.
    Pubmed
  9. Singh Abbi, KK, Zheng, J, Devlin, SM, Giralt, S, Landau, H. Second autologous stem cell transplant: an effective therapy for relapsed multiple myeloma. Biol Blood Marrow Transplant, 2015;21;468-472.
    Pubmed
  10. Morschhauser, F, Brice, P, Fermé, C, et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol, 2008;26;5980-5987.
    Pubmed
  11. Olivieri, J, Pierelli, L, Introna, M, et al. Kinetics of the use of cryopreserved autologous stem cell grafts: a GITMO-SIDEM survey. Cytotherapy, 2014;16;101-110.
    Pubmed
  12. Chang, YJ, Huang, XJ. Donor lymphocyte infusions for relapse after allogeneic transplantation: when, if and for whom?. Blood Rev, 2013;27;55-62.
    Pubmed
  13. Bakken, R, van Walraven, AM, Egeland, T, Ethics Working Group of the World Marrow Donor Association. Donor commitment and patient needs. Bone Marrow Transplant, 2004;33;225-230.
    Pubmed
  14. FACT-JACIE Hematopoietic Cellular Therapy Accreditation Manual. Omaha, NE: The Foundation for the Accreditation of Cellular Therapy; 2017. p. 434-435.
  15. Jaime-Perez, JC, Monreal-Robles, R, Colunga-Pedraza, J, Mancías-Guerra, C, Rodríguez-Romo, L, Gómez-Almaguer, D. Cord blood banking activities at a university hospital in northeast Mexico: an 8-year experience. Transfusion, 2012;52;2606-2613.
    Pubmed
  16. Mishra, V, Andresen, S, Brinch, L, et al. Cost of autologous peripheral blood stem cell transplantation: the Norwegian experience from a multicenter cost study. Bone Marrow Transplant, 2005;35;1149-1153.
    Pubmed
  17. Shaughnessy, P, Islas-Ohlmayer, M, Murphy, J, et al. Cost and clinical analysis of autologous hematopoietic stem cell mobilization with G-CSF and plerixafor compared to G-CSF and cyclophosphamide. Biol Blood Marrow Transplant, 2011;17;729-736.
    Pubmed
  18. Cameron, G, Tantiworawit, A, Halpenny, M, et al. Cryopreserved mobilized autologous blood progenitors stored for more than 2 years successfully support blood count recovery after high-dose chemotherapy. Cytotherapy, 2011;13;856-863.
    Pubmed
  19. Khera, N, Zeliadt, SB, Lee, SJ. Economics of hematopoietic cell transplantation. Blood, 2012;120;1545-1551.
    Pubmed
  20. Sharma, SK, Choudhary, D, Gupta, N, et al. Cost of hematopoietic stem cell transplantation in India. Mediterr J Hematol Infect Dis.
    Pubmed
  21. Lee, SJ, Klar, N, Weeks, JC, Antin, JH. Predicting costs of stem-cell transplantation. J Clin Oncol, 2000;18;64-71.
    Pubmed
  22. Perseghin, P, Marchetti, M, Pierelli, L, et al. A policy for the disposal of autologous hematopoietic progenitor cells: report from an Italian consensus panel. Transfusion, 2014;54;2353-2360.
    Pubmed


e-submission

This Article

Current Issue

ba_link01

Indexed/Covered by

Today : 40  /
Total : 84,429