Comparison of cryoprotectants in hematopoietic cell infusion–related adverse events
Corresponding Author
Kazuhiko Ikeda
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Correspondence
Kazuhiko Ikeda, Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Email: [email protected]
Search for more papers by this authorKeiji Minakawa
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorKenichi Yamahara
Laboratory of Medical Innovation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan
Search for more papers by this authorMinami Yamada-Fujiwara
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Blood Transfusion and Cell Therapy, Tohoku University Hospital, Sendai, Japan
Search for more papers by this authorYoshiki Okuyama
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Transfusion and Cell Therapy, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
Search for more papers by this authorShin-ichiro Fujiwara
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Shimotsuke, Japan
Search for more papers by this authorRie Yamazaki
Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHeiwa Kanamori
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
Search for more papers by this authorTohru Iseki
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
Search for more papers by this authorTokiko Nagamura-Inoue
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Institution of Medical Science, University of Tokyo, Tokyo, Japan
Search for more papers by this authorKazuaki Kameda
Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan
Search for more papers by this authorKazuhiro Nagai
Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
Search for more papers by this authorNobuharu Fujii
Department of Transfusion Medicine, Okayama University Hospital, Okayama, Japan
Search for more papers by this authorTakashi Ashida
Center for Transfusion and Cell Therapy, Kindai University Hospital, Osakasayama, Japan
Search for more papers by this authorAsao Hirose
Department of Hematology, Osaka City University, Osaka, Japan
Search for more papers by this authorTsutomu Takahashi
Department of Oncology/Hematology, Shimane University Hospital, Shimane, Japan
Search for more papers by this authorHitoshi Ohto
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorKoki Ueda
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorRyuji Tanosaki
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Kazuhiko Ikeda
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Correspondence
Kazuhiko Ikeda, Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Email: [email protected]
Search for more papers by this authorKeiji Minakawa
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorKenichi Yamahara
Laboratory of Medical Innovation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan
Search for more papers by this authorMinami Yamada-Fujiwara
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Blood Transfusion and Cell Therapy, Tohoku University Hospital, Sendai, Japan
Search for more papers by this authorYoshiki Okuyama
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Transfusion and Cell Therapy, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
Search for more papers by this authorShin-ichiro Fujiwara
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Shimotsuke, Japan
Search for more papers by this authorRie Yamazaki
Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHeiwa Kanamori
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
Search for more papers by this authorTohru Iseki
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
Search for more papers by this authorTokiko Nagamura-Inoue
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Institution of Medical Science, University of Tokyo, Tokyo, Japan
Search for more papers by this authorKazuaki Kameda
Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan
Search for more papers by this authorKazuhiro Nagai
Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
Search for more papers by this authorNobuharu Fujii
Department of Transfusion Medicine, Okayama University Hospital, Okayama, Japan
Search for more papers by this authorTakashi Ashida
Center for Transfusion and Cell Therapy, Kindai University Hospital, Osakasayama, Japan
Search for more papers by this authorAsao Hirose
Department of Hematology, Osaka City University, Osaka, Japan
Search for more papers by this authorTsutomu Takahashi
Department of Oncology/Hematology, Shimane University Hospital, Shimane, Japan
Search for more papers by this authorHitoshi Ohto
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorKoki Ueda
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
Search for more papers by this authorRyuji Tanosaki
Cell Therapy Committee, Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan
Center for Transfusion Medicine and Cell Therapy, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorFunding information: Japan Agency for Medical Research and Development; Japan Society of Transfusion Medicine and Cell Therapy; Ministry of Health, Labour and Welfare
Abstract
Background
The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP-1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP-1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP-1 in association with HCI-AEs has not been investigated.
Study Design and Methods
To compare CP-1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI-AEs. Moreover, we validated the toxicity of CP-1 in 90 rats following various dose administration.
Results
The PBSC products cryopreserved with CP-1 (CP-1 group) and those with other cryoprotectants, mainly 10% DMSO (non-CP-1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI-AEs was higher in the CP-1 group, but that of overall or ≥grade 3 HCI-AEs was not significantly different, compared to the non-CP-1 group. Similarly, after propensity score matching, ≥grade 2 HCI-AEs were more frequent in the CP-1 group, but the ≥grade 3 HCI-AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP-1 dose in the 90 rats.
Conclusions
Infusion of a CP-1-containing PBSC product is feasible with the respect of HCI-AEs.
CONFLICT OF INTEREST
A research fund to Kazuhiko Ikeda was provided from Kyokuto Pharmaceutical Industrial. There are no other conflicts.
Supporting Information
| Filename | Description |
|---|---|
| trf16877-sup-0001-Figures.pdfPDF document, 6.2 MB | Figure S1. Blood cell counts and blood coagulation tests of male rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1. Data of (A) one day after administration (n = 10 in each group) and (B) 14 days after administration (n = 5 in each group). Statistical differences with controls were calculated using the Dunnett's test. No statistically significant differences were observed. #; an outlier of 5.20 was excluded from the graph but is included in the calculation of statistical significance. Figure S2. Blood cell counts and blood coagulation tests of female rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1. Data of (A) one day after administration (n = 10 in each group) and (B) 14 days after administration (n = 5 in each group). Statistical differences with controls were calculated using the Dunnett's test. *: 0.01 ≤ p < 0.05, **: 0.001 ≤ p < 0.01. Figure S3. Biochemical tests of male rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 one day before blood collection (n = 10 in each group). Statistical differences with controls were calculated using the Dunnett's test. *: 0.01 ≤ p < 0.05. Figure S4. Biochemical tests of male rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 14 days before blood collection (n = 5 in each group). Statistical differences with controls were calculated using the Dunnett's test. *: 0.01 ≤ p < 0.05, **: 0.001 ≤ p < 0.01. #; an outlier of 1781 was excluded from the graph but is included in the calculation of statistical significance. Figure S5. Biochemical tests of female rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 one day before blood collection (n = 10 in each group). Statistical differences with controls were calculated using the Dunnett's test. *: 0.01 ≤ p < 0.05. Figure S6. Biochemical tests of female rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 14 days before blood collection (n = 5 in each group). Statistical differences with controls were calculated using the Dunnett's test. *: 0.01 ≤ p < 0.05, **: 0.001 ≤ p < 0.01, ***: p < 0.001 Figure S7. Body weight (BW) and weight of main organs of male rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 at the time of necropsy. Data of (A) one day after administration (n = 10 in each group) and (B) 14 days after administration (n = 5 in each group). Statistical differences with controls were calculated using Dunnett's test. No statistical differences were observed. #; an outlier of 1500 was excluded from the graph but is included in the calculation of statistical significance. Figure S8. Body weight (BW) and weight of main organs of female rats administered 13.62 ml/kg saline (cont.), or 2.27 (CP-1-L), 6.81 (CP-1-I) or 13.62 (CP-1-H) mL/kg CP-1 at the time of necropsy. Data of (A) one day after administration (n = 10 in each group) and (B) 14 days after administration (n = 5 in each group). Statistical differences with controls were calculated using the Dunnett's test. No statistical differences were observed. |
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