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Konuma T, Monna-Oiwa M, Kato S, Andoh S, Isobe M, Nannya Y, Takahashi S. Levels of C-Reactive Protein and Body Temperature Elevation During Neutropenia Predict Engraftment and Non-Relapse Mortality for Unrelated Single-Unit Cord Blood Transplantation in Adults. Transplant Cell Ther 2024; 30:1104.e1-1104.e14. [PMID: 39270934 DOI: 10.1016/j.jtct.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/28/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024]
Abstract
Cord blood transplantation (CBT) presents unique challenges related to inflammation during neutropenia, such as mucosal damage, infections, and the potential development of pre-engraftment syndrome or pre-engraftment immune reaction. These factors can contribute to significant inflammation and infection shortly after CBT. However, the effect of severe inflammation during neutropenia, specifically elevated C-reactive protein (CRP) level and body temperature, on post-transplant outcomes after CBT remains unclear. This retrospective study aimed to investigate the association between maximum CRP level, maximum body temperature during neutropenia, and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of maximum CRP level and maximum body temperature during neutropenia on post-transplantation outcomes in adults who underwent single-unit unrelated CBT between 1998 and 2023 at our institution. A total of 336 adult patients were included in this study. The median maximum CRP level before neutrophil recovery was 7.75 mg/dL (interquartile range [IQR], 4.70 to 12.05 mg/dL) at a median of 14 d (IQR, 8 to 16 d). The median maximum body temperature before neutrophil recovery was 39.5°C (IQR, 39.0 to 40.0°C) at a median of 15 d (IQR, 12 to 17 d). In the multivariate analysis, a maximum CRP level≥20 mg/dL was significantly associated with lower neutrophil recovery (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.23 to 0.59; P < .001), lower platelet recovery (HR, 0.28; 95% CI, 0.16 to 0.48; P < .001), and a higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (HR, 16.42; 95% CI, 4.11 to 65.54; P < .001), which resulted in higher non-relapse mortality (NRM) (HR, 5.16; 95% CI, 2.62 to 10.15; P < .001) and worse overall survival (HR, 2.81; 95% CI, 1.66 to 4.78; P < .001). Similarly, a maximum body temperature≥40.5°C was significantly associated with lower neutrophil recovery (HR, 0.51; 95% CI, 0.33 to 0.79; P = .002), lower platelet recovery (HR, 0.55; 95% CI, 0.38 to 0.79; P = .001), higher incidence of grades III to IV acute GVHD (HR, 2.93; 95% CI, 1.24 to 6.88; P = .013), and extensive chronic GVHD (HR, 2.47; 95% CI, 1.22 to 4.97; P = .011), which resulted in higher NRM (HR, 3.43; 95% CI, 1.53 to 7.67; P = .002). Maximum CRP level and maximum body temperature during neutropenia were significantly associated with lower hematopoietic recovery and higher NRM following single-unit CBT in adults. Further studies are warranted to explore early intervention strategies aimed at preventing severe inflammation and improving post-transplant outcomes in single-unit CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shohei Andoh
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Konuma T, Hamatani-Asakura M, Monna-Oiwa M, Kato S, Andoh S, Yokoyama K, Nannya Y, Takahashi S. Recipient IL-17A polymorphism rs2275913 is associated with acute graft-versus-host disease after single-unit cord blood transplantation. Transpl Immunol 2024; 86:102096. [PMID: 39067490 DOI: 10.1016/j.trim.2024.102096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Interleukin-17 (IL-17) is elevated in human inflammatory and autoimmune diseases. The polymorphism in the promoter region of the IL-17 A gene is associated with susceptibility to several inflammatory diseases, including acute graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation from adult donors. However, the impacts of IL-17 A polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE The objective of this study was to assess the impact of IL-17 A polymorphism rs2275913 on GVHD, survival, relapse, non-relapse mortality (NRM), and hematopoietic recovery after CBT. STUDY DESIGN We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from January 2005 to March 2023 for whose recipient or donor DNA samples were available. IL-17 A genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2275913. RESULTS A total of 158 recipients and 136 donors were evaluated in this study. Multivariate analysis showed that rs2275913 GA or AA recipients were associated with increased risk of grades II to IV acute GVHD compared to GG recipients (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00-2.13; P = 0.047). Serum IL-17 A levels at eight weeks were significantly higher in rs2275913 GA or AA recipients compared to GG. The rs2275913 polymorphism did not affect survival, relapse, NRM, or hematopoietic recovery after single-unit CBT. CONCLUSION Our data showed recipient IL-17 A polymorphism rs2275913 was associated with the risk of grade II to IV acute GVHD in adults undergoing single-unit CBT. However, the rs2275913 polymorphism in recipients and donors did not affect survival or relapse. Thus, the polymorphism of IL-17 A rs2275913 in recipients might predict the risk of acute GVHD after single-unit CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Megumi Hamatani-Asakura
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shohei Andoh
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuaki Yokoyama
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Konuma T, Monna-Oiwa M, Kato S, Isobe M, Takahashi S, Nannya Y. Prognostic Value of the Pretransplant Fibrosis-4 Index on Non-Relapse and Overall Mortality following Unrelated Single-Unit Cord Blood Transplantation in Adults. Acta Haematol 2024; 148:258-268. [PMID: 39197423 DOI: 10.1159/000541157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024]
Abstract
INTRODUCTION The fibrosis-4 (FIB-4) index is a noninvasive marker of liver fibrosis. The FIB-4 index predicts poor outcomes in patients with hepatic and non-hepatic diseases. However, the association of the FIB-4 index with mortality and liver-related clinical outcomes following cord blood transplantation (CBT) is unclear. METHODS We retrospectively evaluated the impact of the pretransplant FIB-4 index on outcomes in 336 adults following single-unit unrelated CBT at our institution. RESULTS In multivariate analyses, when the FIB-4 index <1.3 group was used as the reference, non-relapse mortality was significantly higher in the FIB-4 index 1.3-2.67 (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.19-5.30) and FIB-4 index >2.67 (HR, 2.34; 95% CI, 1.12-4.90) groups. Overall mortality was significantly higher in the FIB-4 index >2.67 group (HR, 1.66; 95% CI, 1.00-2.73), but with only marginal significance in the FIB-4 index 1.3-2.67 group (HR, 1.59; 95% CI, 0.96-2.64). Hematopoietic recovery, acute and chronic graft-versus-host disease of the liver, and veno-occlusive disease/sinusoidal obstruction syndrome were not associated with the pretransplant FIB-4 index. CONCLUSION The pretransplant FIB-4 index is accurate and useful in predicting mortality in adult patients undergoing single-unit unrelated CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Konuma T, Monna-Oiwa M, Kato S, Isobe M, Nannya Y, Takahashi S. Feasibility and safety of the discontinuation of systemic immunosuppressive treatment after single-unit cord blood transplantation in adults. Bone Marrow Transplant 2024; 59:1127-1136. [PMID: 38740951 PMCID: PMC11296950 DOI: 10.1038/s41409-024-02302-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/16/2024]
Abstract
We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Odutola PO, Olorunyomi PO, Olorunyomi I. Single vs double umbilical cord blood transplantation in acute leukemia: Systematic review and meta-analysis. Leuk Res 2024; 142:107517. [PMID: 38761563 DOI: 10.1016/j.leukres.2024.107517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/29/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND AND AIMS Umbilical cord blood transplantation (UCBT) has emerged as a promising treatment option for patients with acute leukemia needing hematopoietic stem cell transplantation. Both single (sUCBT) and double cord blood units (dUCBT) demonstrate potential benefits, but studies comparing their effectiveness have shown mixed results. This meta-analysis aimed to determine the comparative safety and efficacy of sUCBT versus dUCBT in acute leukemia patients. METHODS Electronic databases were systematically examined to identify relevant studies comparing single vs double UCBT published until November 2023. Nine studies involving 3864 acute leukemia patients undergoing UCBT were included. Outcomes analyzed were acute graft-versus-host disease (GVHD), chronic GVHD, relapse, non-relapse mortality, leukemia-free survival and overall survival. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model. RESULTS The risk of Grade II-IV acute GVHD (RR 1.55, 95% CI 1.19-2.03) and Grade III-IV acute GVHD (RR 1.25, 95% CI 1.07-1.46) were significantly higher with dUCBT. Relapse risk was lower with dUCBT (RR 0.57, 95% CI 0.38-0.88) while overall survival favored sUCBT (RR 1.25, 95% CI 1.06-1.46). No significant differences were observed for chronic GVHD, non-relapse mortality or leukemia-free survival. CONCLUSION Both single and double UCBT have potential as effective treatments for acute leukemia. The choice of treatment should consider various factors, including the risk of GVHD, relapse, and mortality. More research, especially randomized trials, is needed to provide definitive guidance on the optimal use of single and double unit UCBT in patients with acute leukemia.
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Najima Y, Maeda T, Kamiyama Y, Nakao S, Ozaki Y, Nishio H, Tsuchihashi K, Ichihara E, Miumra Y, Endo M, Maruyama D, Yoshinami T, Susumu N, Takekuma M, Motohashi T, Ito M, Baba E, Ochi N, Kubo T, Uchino K, Kimura T, Tamura S, Nishimoto H, Kato Y, Sato A, Takano T, Yano S. Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology. Int J Clin Oncol 2024; 29:899-910. [PMID: 38755516 DOI: 10.1007/s10147-023-02461-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 12/14/2023] [Indexed: 05/18/2024]
Abstract
BACKGROUND The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. METHODS We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. RESULTS Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p = 0.08; I2 = 4%, p = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. CONCLUSIONS G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.
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Affiliation(s)
- Yuho Najima
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-8-22 Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan.
| | - Tomoya Maeda
- Department of Hemato-Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Yutaro Kamiyama
- Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinji Nakao
- Department of Hematology, Faculty of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan
| | - Yukinori Ozaki
- Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroshi Nishio
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kenji Tsuchihashi
- Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan
| | - Eiki Ichihara
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan
| | - Yuji Miumra
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Makoto Endo
- Department of Orthopaedic Surgery, Kyushu University, Fukuoka, Japan
| | - Dai Maruyama
- Department of Hematology Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuhiro Yoshinami
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Nobuyuki Susumu
- Department of Obstetrics and Gynecology, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | | | - Takashi Motohashi
- Department of Obstetrics and Gynecology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Mamoru Ito
- Department of Hematology, Oncology and Cardiovascular Medicine, Fukuoka, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuaki Ochi
- Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan
| | - Toshio Kubo
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Keita Uchino
- Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo, Japan
| | - Takahiro Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinobu Tamura
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Hitomi Nishimoto
- Department of Nursing, Okayama University Hospital, Okayama, Japan
| | - Yasuhisa Kato
- Department of Drug Information, Faculty of Pharmaceutical Sciences, Shonan University of Medical Sciences, Kanagawa, Japan
| | - Atsushi Sato
- Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Toshimi Takano
- Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shingo Yano
- Department of Clinical Oncology/Hematology, The Jikei University School of Medicine, Tokyo, Japan
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Kuwatsuka Y, Kasajima R, Yamaguchi R, Uchida N, Konuma T, Tanaka M, Shingai N, Miyakoshi S, Kozai Y, Uehara Y, Eto T, Toyosaki M, Nishida T, Ishimaru F, Kato K, Fukuda T, Imoto S, Atsuta Y, Takahashi S. Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation. Transplant Cell Ther 2024; 30:444.e1-444.e11. [PMID: 38336299 DOI: 10.1016/j.jtct.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 01/27/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024]
Abstract
Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.
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Affiliation(s)
- Yachiyo Kuwatsuka
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Rika Kasajima
- Division of Health Medical Intelligence, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Rui Yamaguchi
- Division of Health Medical Intelligence, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoyuki Uchida
- Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Naoki Shingai
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shigesaburo Miyakoshi
- Department of Hematology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Yasuji Kozai
- Department of Hematology, Tokyo Metropolitan Tama Medical Center, Fuchu, Japan
| | - Yasufumi Uehara
- Department of Hematology, Kitakyushu City Hospital Organization, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Masako Toyosaki
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Tetsuya Nishida
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Fumihiko Ishimaru
- Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Atsugi, Japan
| | - Koji Kato
- Central Japan Cord Blood Bank, Seto, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan; Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan.
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Takano K, Monna-Oiwa M, Isobe M, Kato S, Takahashi S, Nannya Y, Konuma T. Low urinary sodium-to-potassium ratio in the early phase following single-unit cord blood transplantation is a predictive factor for poor non-relapse mortality in adults. Sci Rep 2024; 14:1413. [PMID: 38228718 DOI: 10.1038/s41598-024-51748-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 01/09/2024] [Indexed: 01/18/2024] Open
Abstract
Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81-12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32-15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15-4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III-IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.
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Affiliation(s)
- Kosuke Takano
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Seiko Kato
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
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Wang H, Berger KN, Miller EL, Fu W, Broglie L, Goldman FD, Konig H, Lim SJ, Berg AS, Talano JA, Comito MA, Farag SS, Pu JJ. The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation. Ther Adv Hematol 2023; 14:20406207231170708. [PMID: 37151808 PMCID: PMC10161310 DOI: 10.1177/20406207231170708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 03/31/2023] [Indexed: 05/09/2023] Open
Abstract
Background Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. Objectives The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. Design This was a multi-institution retrospective study. Methods A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. Results In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. Conclusion In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.
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Affiliation(s)
- Hao Wang
- Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Kristin N. Berger
- Penn State Hershey Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Elizabeth L. Miller
- Penn State Hershey Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Wei Fu
- Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Larisa Broglie
- Division of Hematology and Oncology - Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Frederick D. Goldman
- Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AB, USA
| | - Heiko Konig
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Su Jin Lim
- Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Arthur S. Berg
- Penn State Hershey Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Julie-An Talano
- Division of Hematology and Oncology - Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Melanie A. Comito
- Penn State Hershey Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Sherif S. Farag
- Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA
| | - Jeffrey J. Pu
- Cancer Center, The University of Arizona, 1515 N Campbell Avenue, Room#1968C, Tucson, AZ 85724, USA
- Penn State Hershey Cancer Institute, College of Medicine, Pennsylvania State University, Hershey, PA, USA
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10
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Sugita J, Atsuta Y, Nakamae H, Maruyama Y, Ishiyama K, Shiratori S, Fukuda T, Kurata M, Shingai N, Ozawa Y, Masuko M, Nagafuji K, Uchida N, Tanaka M, Onizuka M, Kanda J, Kimura T, Ichinohe T, Teshima T. Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation. Bone Marrow Transplant 2022; 57:1681-1688. [DOI: 10.1038/s41409-022-01770-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 11/12/2022]
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11
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Chen DP, Jaing TH, Hour AL, Lin WT, Hsu FP. Single-Nucleotide Polymorphisms Within Non-HLA Regions Are Associated With Engraftment Effectiveness for Patients With Unrelated Cord Blood Transplantation. Front Immunol 2022; 13:888204. [PMID: 35769457 PMCID: PMC9234117 DOI: 10.3389/fimmu.2022.888204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/28/2022] [Indexed: 11/18/2022] Open
Abstract
Clinically, stem cells with matched human leukocyte antigens (HLAs) must be selected for allogeneic transplantation to avoid graft rejection. However, adverse reactions still occur after cord blood transplantation (CBT). It was inferred that the HLA system is not the only regulatory factor that may influence CBT outcomes. Therefore, we plan to investigate whether the single-nucleotide polymorphisms (SNPs) located in non-HLA genes are associated with the effectiveness of CBT. In this study, the samples of 65 donors from CBT cases were collected for testing. DNA sequencing was focused on the SNPs of non-HLA genes, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1), which were selected in regard to the literatures published in 2017 and 2018, which indicated that they were related to stem cell transplantation. Then, in combination with the detailed follow-up transplantation tracking database, these SNPs were analyzed with the risk of mortality, relapse, cytomegalovirus (CMV) infection, and graft-versus-host disease (GVHD). We found that there were 2 SNPs of CTLA4, 1 SNP of TNFSF4, and 2 SNPs of PDCD1 associated with the effectiveness of unrelated CBT. These statistically significant SNPs and haplotypes would be used in clinical to choose the best donor for the patient receiving CBT. Moreover, the polygenic risk scores (PRSs) with these SNPs could be used to predict the risk of CBT adverse reactions with an area under the receiver operating characteristic curve (AUC) of 0.7692. Furthermore, these SNPs were associated with several immune-related diseases or cancer susceptibility, which implied that SNPs play an important role in immune regulation.
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Affiliation(s)
- Ding-Ping Chen
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- *Correspondence: Ding-Ping Chen,
| | - Tang-Her Jaing
- Department of Pediatrics, Division of Hematology/Oncology, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan, Taiwan
| | - Ai-Ling Hour
- Department of Life Science, Fu Jen Catholic University, Taipei, Taiwan
| | - Wei-Tzu Lin
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Fang-Ping Hsu
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
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12
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Abudayyeh A, Wanchoo R. Kidney Disease Following Hematopoietic Stem Cell Transplantation. Adv Chronic Kidney Dis 2022; 29:103-115.e1. [PMID: 35817518 DOI: 10.1053/j.ackd.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/07/2021] [Accepted: 11/15/2021] [Indexed: 11/11/2022]
Abstract
Hematopoietic stem cell transplantation (SCT) provides a curative option for the treatment of several malignancies. Its growing use is associated with an increased burden of kidney disease. Acute kidney injury is usually seen within the first 100 days of transplantation and has an incidence ranging between 12 and 73%, with the highest rate in myeloablative allogeneic SCT. A large subset of patients after SCT develop chronic kidney disease. They can be broadly classified into thrombotic microangiopathy, nephrotic syndrome, and calcineurin toxicity. Dialysis requirement after SCT is associated with mortality exceeding 80%. Given the higher morbidity and mortality related to development kidney disease, nephrologists need to be aware of the various causes and best treatment options.
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Affiliation(s)
- Ala Abudayyeh
- Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Rimda Wanchoo
- Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY.
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13
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Wada F, Watanabe M, Konuma T, Okabe M, Kobayashi S, Uchida N, Ikegame K, Tanaka M, Sugio Y, Mukae J, Onizuka M, Kawakita T, Kuriyama T, Takahashi S, Fukuda T, Nakano N, Sawa M, Kimura T, Ichinohe T, Atsuta Y, Kanda J. HLA 1-3 antigen-mismatched related peripheral blood stem cells transplantation using low-dose antithymocyte globulin versus unrelated cord blood transplantation. Am J Hematol 2022; 97:311-321. [PMID: 34978726 DOI: 10.1002/ajh.26446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 11/08/2022]
Abstract
Little information is available regarding whether unrelated cord blood transplantation (CBT) or an HLA 1-3 antigen-mismatched related donor peripheral blood stem-cell transplantation (PBSCT) using low-dose anti-thymocyte globulin (ATG) is superior as an alternative transplantation for patients who lack an HLA-matched sibling or unrelated donor. Therefore, we evaluated 7861 patients with hematologic malignancies (aged 0 to 70 years) who received either a CBT without ATG (CBT-no ATG, n = 7034) or an HLA 1-3 antigen-mismatched related donor PBSCT using low-dose ATG (PBSCT-ATG, n = 827). CBT-no ATG was associated with significantly better overall survival (OS) than the use of a PBSCT-ATG (hazard ratio [HR], 0.77; p < .001), although PBSCT-ATG patients with an HLA 1 antigen-mismatch showed OS comparable to that in the CBT-no ATG group. Neutrophil and platelet engraftment was significantly delayed, whereas the incidences of nonrelapse mortality, and severe graft-versus-host disease (GVHD) were significantly lower in the CBT-no ATG group. The incidences of relapse and chronic GVHD were comparable between these donors. In conclusion, CBT-no ATG may be a better alternative than HLA-mismatched related donor PBSCT using low-dose ATG. Notably, HLA 2-3 antigen mismatch-related transplantation with low-dose ATG had significant adverse effects on transplantation outcomes.
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Affiliation(s)
- Fumiya Wada
- Department of Hematology and Oncology, Graduate School of Medicine Kyoto University Kyoto Japan
- Department of Hematology Kobe City Medical Center General Hospital Kobe Japan
| | - Mizuki Watanabe
- Department of Hematology and Oncology, Graduate School of Medicine Kyoto University Kyoto Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science The University of Tokyo Tokyo Japan
| | - Motohito Okabe
- Department of Hematology/Oncology, The Institute of Medical Science The University of Tokyo Tokyo Japan
| | - Shinichi Kobayashi
- Division of Hematology, Department of Internal Medicine National Defense Medical College Saitama Japan
| | - Naoyuki Uchida
- Department of Hematology Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital Tokyo Japan
| | - Kazuhiro Ikegame
- Department of Hematology Hyogo College of Medicine Hospital Nishinomiya Japan
| | | | - Yasuhiro Sugio
- Department of Hematology Kitakyushu City Hospital Organization, Kitakyushu Municipal Medical Center Kitakyushu Japan
| | - Junichi Mukae
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Tokyo Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology Tokai University School of Medicine Isehara‐shi Japan
| | - Toshiro Kawakita
- Department of Hematology National Hospital Organization Kumamoto Medical Center Kumamoto Japan
| | | | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science The University of Tokyo Tokyo Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation National Cancer Center Hospital Tokyo Japan
| | - Nobuaki Nakano
- Department of Hematology Imamura General Hospital Kagoshima Japan
| | - Masashi Sawa
- Department of Hematology and Oncology Anjo Kosei Hospital Anjo Japan
| | - Takafumi Kimura
- Preparation Department Japanese Red Cross Kinki Block Blood Center Osaka Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan
| | - Yoshiko Atsuta
- Department of Healthcare Administration, Japanese Data Center for Hematopoietic Cell Transplantation Nagoya University Graduate School of Medicine Nagoya Japan
| | - Junya Kanda
- Department of Hematology and Oncology, Graduate School of Medicine Kyoto University Kyoto Japan
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14
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Konuma T, Ooi J, Monna-Oiwa M, Isobe M, Tomonari A, Kato S, Iseki T, Nannya Y, Tojo A, Takahashi S. Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults. Leuk Lymphoma 2021; 63:1191-1201. [PMID: 34949127 DOI: 10.1080/10428194.2021.2018583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III-IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Jun Ooi
- Department of Health and Nutrition, University of Human Arts and Sciences, Saitama, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Akira Tomonari
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology, Yokohama Minami Kyousai Hospital, Yokohama, Japan
| | - Tohru Iseki
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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15
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Konuma T, Ooi J, Nagayama H, Tomonari A, Tsukada N, Kato S, Kawakita T, Isobe M, Monna-Oiwa M, Tojo A, Iseki T, Takahashi S. Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies. Ann Hematol 2021; 101:177-189. [PMID: 34591162 DOI: 10.1007/s00277-021-04676-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/21/2021] [Indexed: 10/20/2022]
Abstract
An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
| | - Jun Ooi
- Department of Health and Nutrition, University of Human Arts and Sciences, Saitama, Japan
| | - Hitomi Nagayama
- International Research Center for Medical Science, Kumamoto University, Kumamoto, Japan
| | - Akira Tomonari
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,Eisai Co., Ltd., Tokyo, Japan
| | - Nobuhiro Tsukada
- Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology, Yokohama Minami Kyousai Hospital, Kanagawa, Japan
| | - Toshiro Kawakita
- Department of Hematology, National Hospital Organisation Kumamoto Medical Center, Kumamoto, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tohru Iseki
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.,Division of Molecular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.,Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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16
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Isobe M, Konuma T, Monna-Oiwa M, Okabe M, Kato S, Takahashi S, Tojo A. Momentum of neutrophil recovery using an exponential growth model predicts the prognosis of single cord blood transplantation. Int J Lab Hematol 2021; 43:1465-1471. [PMID: 34185959 DOI: 10.1111/ijlh.13636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/22/2021] [Accepted: 06/03/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION After the first appearance of peripheral blood neutrophils, recipients from adult donor sources have a rapid increase in neutrophil recovery, whereas cord blood transplantation (CBT) recipients have a slow increase. However, the momentum of neutrophil recovery after CBT varies widely among individuals, but optimal methods to evaluate the momentum of neutrophil recovery and their clinical impacts are yet to be clarified. METHODS We retrospectively examined the prognostic effect of the momentum of neutrophil recovery in the last 7 days until neutrophil engraftment, which was calculated by an exponential growth model, after single CBT following myeloablative conditioning for 207 adults. RESULTS Among patients who achieved each hematopoietic lineage recovery by day 100, the momentum of neutrophil recovery, which was represented as a growth constant, was associated with the day of neutrophil engraftment (P < .0001), red blood cell engraftment (P < .0001), and platelet engraftment (P < .0001) using the Spearman's rank correlation coefficient test. More importantly, overall survival was superior with a higher growth constant compared with a lower growth constant (P < .001). In the multivariate analysis, a higher growth constant showed a lower overall mortality compared with a lower growth constant (hazard ratio: 0.48, P = .014). CONCLUSION Our data demonstrated that the momentum of neutrophil recovery during the last 7 days before neutrophil engraftment, which was measured using an exponential growth model, was associated not only with hematopoietic recovery but also with a better prognosis after single CBT.
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Affiliation(s)
- Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Monna-Oiwa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Motohito Okabe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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17
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Intrabone transplantation of CD34+ cells with optimized delivery does not enhance engraftment in a rhesus macaque model. Blood Adv 2021; 4:6148-6156. [PMID: 33351110 DOI: 10.1182/bloodadvances.2020003040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/21/2020] [Indexed: 12/25/2022] Open
Abstract
Intrabone (IB) injection of umbilical cord blood has been proposed as a potential mechanism to improve transplant engraftment and prevent graft failure. However, conventional IB techniques produce low retention of transplanted cells in the marrow. To overcome this barrier, we developed an optimized IB (OIB) injection method using low-volume, computer-controlled slow infusion that promotes cellular retention in the marrow. Here, we compare engraftment of CD34+ cells transplanted in a myeloablative rhesus macaque (RM) model using the OIB method compared with IV delivery. RM CD34+ cells obtained by apheresis were split equally for transduction with lentiviral vectors encoding either green fluorescent protein or yellow fluorescent protein reporters. Following conditioning, one marked autologous population of CD34+ cells was injected directly IB using the OIB method and the other was injected via slow IV push into the same animal (n = 3). Daily flow cytometry of blood quantified the proportion of engrafting cells deriving from each source. Marrow retention was examined using positron emission tomography/computed tomography imaging of 89Zirconium (89Zr)-oxine-labeled CD34+ cells. CD34+ cells injected via the OIB method were retained in the marrow and engrafted in all 3 animals. However, OIB-transplanted progenitor cells did not engraft any faster than those delivered IV and contributed significantly less to hematopoiesis than IV-delivered cells at all time points. Rigorous testing of our OIB delivery system in a competitive RM myeloablative transplant model showed no engraftment advantage over conventional IV infusion. Given the increased complexity and potential risks of IB vs IV approaches, our data do not support IB transplantation as a strategy to improve hematopoietic engraftment.
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18
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Okabe M, Konuma T, Oiwa-Monna M, Kato S, Isobe M, Takahashi S, Tojo A. Impact of a prior history of cancer on prognosis after myeloablative single-unit cord blood transplantation. Jpn J Clin Oncol 2021; 51:657-660. [PMID: 33395483 DOI: 10.1093/jjco/hyaa250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 11/24/2020] [Indexed: 11/14/2022] Open
Abstract
A prior history of cancer was associated with higher non-relapse mortality or overall mortality in patients undergoing allogeneic haematopoietic cell transplantation. Because it is unclear whether the outcomes after cord blood transplantation are influenced by a prior history of cancer, we retrospectively assessed the prevalence and prognostic impact of a prior history of cancer in adult patients undergoing myeloablative single-unit cord blood transplantation in our institute between 2004 and 2020. The univariate analysis showed that a prior history of cancer did not affect the probability of overall survival; the cumulative incidence of relapse; or non-relapse mortality. In the multivariate analysis, prior history of cancer was not associated with overall mortality, relapse or non-relapse mortality. No patients with a prior history of cancer had experienced prior cancer relapse. A prior history of cancer was not associated with non-relapse mortality or overall mortality following single-unit cord blood transplantation.
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Affiliation(s)
- Motohito Okabe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Oiwa-Monna
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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19
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Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia. Int J Hematol 2021; 113:840-850. [PMID: 33611725 DOI: 10.1007/s12185-021-03097-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 10/22/2022]
Abstract
To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX15-10-10, 415; MTX10-7-7, 294; MTX5-5-5, 71; MMF, 108) were included. In multivariate analyses with MTX15-10-10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX10-7-7 group, and similarly better in MMF group compared with MTX15-10-10. All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX15-10-10 or Tac plus MMF.
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Terakura S, Konuma T, Tanaka M, Ozawa Y, Onizuka M, Nanno S, Onishi Y, Aotsuka N, Kondo T, Kawakita T, Kato J, Kobayashi T, Nishida T, Yamaguchi T, Kuwatsuka Y, Takahashi S. Randomised controlled trial of conditioning regimen for cord blood transplantation for adult myeloid malignancies comparing high-dose cytarabine/cyclophosphamide/total body irradiation with versus without G-CSF priming: G-CONCORD study protocol. BMJ Open 2020; 10:e040467. [PMID: 33277285 PMCID: PMC7722372 DOI: 10.1136/bmjopen-2020-040467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION A better long-term quality of life after umbilical cord blood transplantation (CBT) is observed compared with transplants from other alternative donors, whereas graft failure and relapses after CBT are still major issues. To minimise graft failure and relapse after CBT, intensification of conditioning by the addition of high-dose cytosine arabinoside (CA) and concomitant continuous use of granulocyte-colony stimulating factor (G-CSF) are reported to convey a significantly better survival after CBT in some retrospective studies. To confirm the effect of G-CSF plus CA combination, in addition to the standard conditioning regimen, cyclophosphamide (CY)/total body irradiation (TBI), we design a randomised controlled study comparing CA/CY/TBI with versus without G-CSF priming (G-CSF combined conditioned cord blood transplantation [G-CONCORD] study). METHODS AND ANALYSIS This is a multicentre, open-label, randomised phase III study that aimed to compare G-CSF+CA/CY/TBI as a conditioning regimen for CBT with CA/CY/TBI. Patients with acute myeloid leukaemia or myelodysplastic syndrome, aged 16-55 years, are eligible. The target sample size is 160 and the registration period is 4 years. The primary endpoint is the 2-year disease-free survival rate after CBT. The secondary endpoints are overall survival, relapse, non-relapse mortality, acute and chronic graft-versus-host disease, engraftment rate, time to neutrophil recovery, short-term adverse events, incidence of infections and causes of death.This study employs a single one-to-one web-based randomisation between the with-G-CSF versus without-G-CSF groups after patient registration. Combination of high-dose CA and CY/TBI in both groups is used for conditioning. ETHICS AND DISSEMINATION The study protocol was approved by the central review board, Nagoya University Certified Review Board, after the enforcement of the Clinical Trials Act in Japan. The manuscripts presenting data from this study will be submitted for publication in quality peer-reviewed medical journals. Study findings will be disseminated via presentations at national/international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBERS UMIN000029947 and jRCTs041180059.
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Affiliation(s)
- Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science The University of Tokyo, Tokyo, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yukiyasu Ozawa
- Department of Hematology and Oncology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
| | - Makoto Onizuka
- Department of Hematology and Oncology, Tokai University School of Medicine Graduate School of Medicine, Isehara, Japan
| | - Satoshi Nanno
- Department of Hematology, Osaka City University Graduate School of Medicine School of Medicine, Osaka, Japan
| | - Yasushi Onishi
- Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan
| | - Nobuyuki Aotsuka
- Division of Hematology-Oncology, Japanese Red Cross Society Narita Hospital, Narita, Japan
| | - Tadakazu Kondo
- Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshiro Kawakita
- Department of Hematology, National Hospital Organisation Kumamoto Medical Center, Kumamoto, Japan
| | - Jun Kato
- Division of Hematology, Keio University School of Medicine, Tokyo, Japan
| | - Takeshi Kobayashi
- Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Tetsuya Nishida
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takuhiro Yamaguchi
- Department of Biostatistics, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Yachiyo Kuwatsuka
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science The University of Tokyo, Tokyo, Japan
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21
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Miyao K, Terakura S, Kimura F, Konuma T, Miyamura K, Yanada M, Kako S, Morhishima S, Uchida N, Toya T, Ozawa Y, Fukuda T, Tanaka M, Sawa M, Takada S, Yoshida S, Kimura T, Ichinohe T, Atsuta Y, Kanda J. Updated Comparison of 7/8 HLA Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Umbilical Cord Blood Transplantation as Alternative Donors in Adults with Acute Leukemia. Biol Blood Marrow Transplant 2020; 26:2105-2114. [PMID: 32784070 DOI: 10.1016/j.bbmt.2020.08.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/23/2020] [Accepted: 08/01/2020] [Indexed: 12/18/2022]
Abstract
The outcomes of 7/8 allele-matched unrelated bone marrow transplantation (7/8 UBMT) and umbilical cord blood transplantation (UCBT) have been improving. We retrospectively analyzed adults with acute leukemia who underwent their first 7/8 UBMT or UCBT in Japan. Between January 2008 and December 2017, a total of 4150 patients were recorded, including 488 who underwent 7/8 UBMT and 3662 who underwent UCBT. Only 32 patients with 7/8 UBMT had graft-versus-host-disease (GVHD) high-risk HLA mismatched pairs. Overall survival at 3 years was 54% for 7/8 the UBMT group and 46% for the UCBT group, a nonsignificant difference in multivariate analysis (hazard ratio [HR], 1.01; 95% confidence interval [CI], .88 to 1.17; P = .89). The 7/8 UBMT and UCBT groups showed a similar nonrelapse mortality rate (HR, 1.16; 95% CI, .96 to 1.45; P = .16) and relapse rate (HR, .85; 95% CI, .71 to 1.02; P = .08). However, the UCBT group had a lower risk of grade II-IV acute GVHD (HR, .76; 95% CI, .65 to .88; P < .001) and chronic GVHD (HR, .77; 95% CI, .66- .91; P = .002) compared with the 7/8 UBMT group. In stratified analyses combining disease risk with conditioning intensity, 7/8 UBMT showed superior overall survival to UCBT in standard risk and myeloablative conditioning (HR, .72; 95% CI, .56 to .93; P = .014). Both 7/8 UBMT and UCBT are appropriate alternative donor procedures. The stem cell source can be selected on the basis of disease risk, patient tolerability, or concerns regarding GVHD.
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Affiliation(s)
- Kotaro Miyao
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan.
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumihiko Kimura
- Division of Hematology, National Defense Medical College, Tokorozawa, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Miyamura
- Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
| | - Masamitsu Yanada
- Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan
| | - Shinichi Kako
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Satoko Morhishima
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Takashi Toya
- Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Yukiyasu Ozawa
- Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
| | - Takahiro Fukuda
- Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Masatsugu Tanaka
- Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Satoru Takada
- Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Shuro Yoshida
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | | | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junya Kanda
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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22
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Byun JM, Hong J, Oh D, Yhim HY, Do YR, Park JS, Jung CW, Yang DH, Won JH, Lee HG, Moon JH, Mun YC, Jo DY, Han JJ, Lee JH, Lee JH, Lee J, Yoon SS. Optimizing Preparative Regimen for Umbilical Cord Blood Transplantation in Adult Acute Leukemia Patients: Acute Lymphoblastic Leukemia Requires Myeloablative Conditioning but Not Acute Myeloid Leukemia. J Clin Med 2020; 9:jcm9072310. [PMID: 32708168 PMCID: PMC7408460 DOI: 10.3390/jcm9072310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/07/2020] [Accepted: 07/17/2020] [Indexed: 11/16/2022] Open
Abstract
Cord blood transplantation (CBT) is a valuable alternative to bone marrow transplantation in adults without readily available donors. We conducted this study to investigate the feasibility of CBT for adult patients with acute leukemia with regards to impact of different conditioning and graft-versus-host disease (GVHD) prophylaxis regimens on clinical outcomes. From 16 centers in Korea, 41 acute myeloid leukemia (AML) and 29 ALL (acute lymphoblastic leukemia) patients undergoing CBT were enrolled. For AML patients, the neutrophil engraftment was observed in 87.5% of reduced intensity conditioning (RIC) and 72.0% of myeloablative conditioning (MAC) (p = 0.242). The median RFS was 5 months and OS 7 months. Conditioning regimen did not affect relapse free survival (RFS) or overall survival (OS). GVHD prophylaxis using calcineurin inhibitors (CNI) plus methotrexate was associated with better RFS compared to CNI plus ATG (p = 0.032). For ALL patients, neutrophil engraftment was observed in 55.6% of RIC and 90.0% of MAC (p = 0.034). The median RFS was 5 months and OS 19 months. MAC regimens, especially total body irradiation (TBI)-based regimen, were associated with both longer RFS and OS compared to other conditioning regimens. In conclusion, individualized conditioning regimens will add value in terms of enhancing safety and efficacy of CBT.
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Affiliation(s)
- Ja Min Byun
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongro-gu, Seoul 03080, Korea; (J.M.B.); (J.H.)
| | - Junshik Hong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongro-gu, Seoul 03080, Korea; (J.M.B.); (J.H.)
| | - Doyeun Oh
- Department of Internal Medicine, CHA University School of Medicine, Seongnam 13496, Korea;
| | - Ho-Young Yhim
- Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju 54907, Korea;
| | - Young Rok Do
- Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Joon Seong Park
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon 16499, Korea;
| | - Chul Won Jung
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Deok-Hwan Yang
- Division of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun 58128, Korea;
| | - Jong-Ho Won
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea;
| | - Hong Ghi Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Konkuk University Medical Center, Seoul 05030, Korea;
| | - Joon Ho Moon
- Department of Hematology and Oncology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Yeung-Chul Mun
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 07985, Korea;
| | - Deog-Yeon Jo
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Korea;
| | - Jae Joon Han
- Department of Hematology and Medical Oncology, College of Medicine, Kyung Hee University, Seoul 02447, Korea;
| | - Je-Hwan Lee
- Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Jae Hoon Lee
- Division of Hematology, Department of Internal Medicine, Gachon University College of Medicine Gil Medical Center, Incheon 21565, Korea;
| | - Junglim Lee
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Daegu Fatima Hospital, 99, Ayang-ro, Dong-gu, Daegu 41199, Korea
- Correspondence: (J.L.); (S.-S.Y.); Tel.: +82-10-2726-0325 (J.L.); +82-2-2072-3079 (S.-S.Y.); Fax: +82-53-940-7416 (J.L.); +82-2-762-9662 (S.-S.Y.)
| | - Sung-Soo Yoon
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongro-gu, Seoul 03080, Korea; (J.M.B.); (J.H.)
- Correspondence: (J.L.); (S.-S.Y.); Tel.: +82-10-2726-0325 (J.L.); +82-2-2072-3079 (S.-S.Y.); Fax: +82-53-940-7416 (J.L.); +82-2-762-9662 (S.-S.Y.)
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Abstract
INTRODUCTION Umbilical cord blood transplantation (UCBT) is a suitable alternative for patients with acute leukemia (AL) in need of an allograft and who lack an HLA-matched donor. Single-institution and registry studies have shown that, in both children and adults with AL, the outcome of UCBT is comparable to that of matched unrelated donor. At the same time, these studies have highlighted some limitations of UCBT, such as increased early mortality and delayed recovery of both hematopoietic and immune compartment, which hamper a more widespread adoption of this approach. AREAS COVERED In this review, we will analyze the current results of UCBT in children and adults with AL, including comparisons with other hematopoietic stem cell sources and transplant strategies. We will also discuss important factors to be considered when selecting UCB units, as well as future strategies to further improve the outcome of UCBT recipients. EXPERT OPINION The utilization of UCBT for the treatment of AL patients has decreased in recent years. However, recent clinical data suggesting that UCBT might offer better results in patients with minimal residual disease, as well as innovative strategies to facilitate engraftment, reduce transplant-related mortality, and optimize anti-leukemic activity, may pave the way toward a second youth for use of UCB cells.
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Affiliation(s)
- Mattia Algeri
- Department of Pediatric Hematology and Oncology, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Children's Hospital , Rome, Italy
| | - Stefania Gaspari
- Department of Pediatric Hematology and Oncology, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Children's Hospital , Rome, Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Children's Hospital , Rome, Italy.,Sapienza University of Rome , Rome, Italy
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24
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Yasu T, Konuma T, Oiwa-Monna M, Mizusawa M, Isobe M, Kato S, Takahashi S, Tojo A. Efficacy and safety of micafungin in unrelated cord blood transplant recipients. Ann Hematol 2019; 98:2593-2600. [PMID: 31494737 DOI: 10.1007/s00277-019-03790-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 08/29/2019] [Indexed: 10/26/2022]
Abstract
Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT.
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Affiliation(s)
- Takeo Yasu
- Department of Pharmacy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
| | - Maki Oiwa-Monna
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Mai Mizusawa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
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25
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Kanda J, Hayashi H, Ruggeri A, Kimura F, Volt F, Takahashi S, Labopin M, Kako S, Tozatto-Maio K, Yano S, Sanz G, Uchida N, Van Lint MT, Kato S, Mohty M, Forcade E, Kanamori H, Sierra J, Ohno Y, Saccardi R, Fukuda T, Ichinohe T, Takanashi M, Rocha V, Okamoto S, Nagler A, Atsuta Y, Gluckman E. Prognostic factors for adult single cord blood transplantation among European and Japanese populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study. Leukemia 2019; 34:128-137. [DOI: 10.1038/s41375-019-0534-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 11/09/2022]
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26
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Yamamoto H. Single cord blood transplantation in Japan; expanding the possibilities of CBT. Int J Hematol 2019; 110:39-49. [PMID: 31152417 DOI: 10.1007/s12185-019-02672-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022]
Abstract
Cord blood (CB) has been an alternative stem cell source for patients with a wide variety of hematological diseases. Cord blood confers the advantages of rapid availability and higher tolerance to two HLA antigen mismatches compared with unrelated donors, and this has increased opportunities for patients who do not have suitable donors or require urgent transplantation. Although the higher rate of engraftment failure remains a serious concern after cord blood transplantation (CBT), the mechanisms underlying this risk have gradually been clarified, which has helped to improve engraftment. Recent studies of CBT and other alternatives have reported comparable outcomes. Moreover, CBT shows promise even when patients are in a non-remission status, which may reflect the potent graft-versus-leukemia effect of CB. Here we compare the most recent outcomes of CBT with those of other stem cell sources and discuss the potential of CB and several outstanding issues that require resolution.
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Affiliation(s)
- Hisashi Yamamoto
- Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.
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27
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Red blood cell transfusion burden by day 30 predicts mortality in adults after single-unit cord blood transplantation. Bone Marrow Transplant 2019; 54:1836-1846. [DOI: 10.1038/s41409-019-0555-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/12/2019] [Accepted: 04/17/2019] [Indexed: 11/08/2022]
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28
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Konuma T, Kato S, Isobe M, Mizusawa M, Oiwa-Monna M, Takahashi S, Tojo A. Reduced-Toxicity Myeloablative Conditioning Consisting of Fludarabine/Busulfan/Low-Dose Total Body Irradiation/Granulocyte Colony-Stimulating Factor–Combined Cytarabine in Single Cord Blood Transplantation for Elderly Patients with Nonremission Myeloid Malignancies. Biol Blood Marrow Transplant 2019; 25:764-770. [DOI: 10.1016/j.bbmt.2018.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/05/2018] [Indexed: 11/26/2022]
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29
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Isobe M, Konuma T, Kato S, Tanoue S, Mizusawa M, Oiwa-Monna M, Takahashi S, Tojo A. Development of Pre-Engraftment Syndrome, but Not Acute Graft-versus-Host Disease, Reduces Relapse Rate of Acute Myelogenous Leukemia after Single Cord Blood Transplantation. Biol Blood Marrow Transplant 2019; 25:1187-1196. [PMID: 30771495 DOI: 10.1016/j.bbmt.2019.02.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/06/2019] [Indexed: 01/08/2023]
Abstract
The different effects of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on outcomes after cord blood transplantation (CBT) are unclear. We retrospectively evaluated the impact of PES and aGVHD on relapse and survival after single-unit CBT in 138 adult patients with hematologic malignancies at our institution between 2004 and 2016. Multivariate analysis demonstrated that development of grade III-IV aGVHD, particularly with gut or liver involvement, significantly contributed to higher nonrelapse mortality (P < .001), but PES and grade II-IV aGVHD did not. In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (P = .032) and better disease-free survival (DFS) (P = .046) in patients with acute myelogenous leukemia (AML). These data suggest that PES is associated with a reduced relapse rate and better DFS in AML, indicating that the early immune reaction before neutrophil engraftment may provide a unique graft-versus-leukemia effect after single-unit CBT.
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Affiliation(s)
- Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Susumu Tanoue
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mai Mizusawa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Oiwa-Monna
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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30
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Optimal dosage of methotrexate for GVHD prophylaxis in umbilical cord blood transplantation. Int J Hematol 2019; 109:440-450. [DOI: 10.1007/s12185-019-02598-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 12/28/2018] [Accepted: 01/16/2019] [Indexed: 12/30/2022]
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Miyashita E, Konuma T, Kataoka J, Oiwa-Monna M, Mizusawa M, Isobe M, Kato S, Sato T, Takahashi S, Tojo A. The Prognostic Impact of Pretransplantation Inflammatory and Nutritional Status in Adult Patients after Myeloablative Single Cord Blood Transplantation. Biol Blood Marrow Transplant 2019; 25:981-988. [PMID: 30639818 DOI: 10.1016/j.bbmt.2019.01.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022]
Abstract
Markers of inflammatory and nutritional status, such as the Controlling Nutritional Status (CONUT) score, Prognostic Nutritional Index, Glasgow Prognostic Score, and C-reactive protein-albumin ratio (CAR) has been demonstrated to be associated with poor prognosis in patients with various cancers. Although the relatively low cell dose of a single cord blood unit restricts the indication for cord blood transplantation (CBT) to pediatric and relatively smaller and lighter adult patients, the impact of malnutrition on outcomes after CBT is unclear. We retrospectively analyzed 165 adult patients who underwent myeloablative single-unit CBT in our institute. In multivariate analysis, a higher CONUT score, which is indicative of poor inflammatory and nutritional status, was significantly associated with poor outcomes, including low neutrophil engraftment and development of extensive chronic graft-versus-host disease. A higher CAR, which is also suggestive of poor inflammatory and nutritional status, was significantly associated with poor neutrophil engraftment and higher overall mortality. Body mass index (BMI) was not associated with transplantation outcomes. These data suggest that poor pretransplantation inflammatory and nutritional status might be a more practical parameter than lower BMI, for predicting transplantation outcomes after single CBT for adults.
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Affiliation(s)
- Eita Miyashita
- Department of Nursing, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Jun Kataoka
- Department of Nursing, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Maki Oiwa-Monna
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mai Mizusawa
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiko Kato
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomoko Sato
- Department of Nursing, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Efficacy and Safety of Low-Dose Liposomal Amphotericin B in Adult Patients Undergoing Unrelated Cord Blood Transplantation. Antimicrob Agents Chemother 2018; 62:AAC.01205-18. [PMID: 30104271 DOI: 10.1128/aac.01205-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/07/2018] [Indexed: 11/20/2022] Open
Abstract
Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute. Within the entire cohort, 42 patients (88%) received L-AMB as empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62 to 2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7 to 241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1 to 313 days). A documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 patients (90%) survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patient developed an increase in serum creatinine levels of grade 3 or higher. In univariate analyses using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB of more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.
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Risk factors and survival impact of readmission after single-unit cord blood transplantation for adults. Int J Hematol 2018; 109:115-124. [PMID: 30302739 DOI: 10.1007/s12185-018-2539-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/19/2018] [Accepted: 09/19/2018] [Indexed: 12/31/2022]
Abstract
Hospital readmissions have been used as a prognostic indicator for patients receiving allogeneic hematopoietic cell transplantation (HCT). However, the impact of readmission during early and mid-phase of cord blood transplantation (CBT) on long-term outcomes has not been fully investigated. We retrospectively analyzed 156 adult patients who received single-unit CBT in our institute. Among this cohort, thirteen patients (8%) were readmitted within 30 days after discharge, and 27 (17%) were readmitted within 90 days after discharge. The most common causes for readmission within 30 and 90 days of discharge were infection, chronic graft-versus-host disease, and relapse. Higher cryopreserved cord blood CD34+ cell count was only significantly associated with lower readmission within 90 days after discharge. The probabilities of overall survival were significantly lower in patients readmitted within 90 days after discharge compared with those who were not readmitted within 90 days after discharge in univariate and multivariate analysis. These data suggest that readmission within 90 days after discharge may have a significant impact on long-term mortality after single-unit CBT.
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Chen DP, Chang SW, Jaing TH, Wang WT, Hus FP, Tseng CP. Single nucleotide polymorphisms within HLA region are associated with disease relapse for patients with unrelated cord blood transplantation. PeerJ 2018; 6:e5228. [PMID: 30083439 PMCID: PMC6076982 DOI: 10.7717/peerj.5228] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 06/21/2018] [Indexed: 12/13/2022] Open
Abstract
Disease relapse occurs in unrelated cord blood transplantation (CBT) even when the alleles of human leukocyte antigen (HLA) are fully matched between donor and recipient. This is similar to that observed in other types of hematopoietic stem cell transplantation. Fourteen single nucleotide polymorphisms (SNPs) within the HLA region have been reported previously by Petersdorf et al. and Piras et al. as transplantation determinants in unrelated hematopoietic cell transplantation. In this study, the genomic sequences within 500 base pairs upstream and downstream of the fourteen transplantation-related SNPs from 53 patients and their HLA-matched unrelated donors were analyzed for determining whether or not genetic variants, conferred by either recipient or donor SNP genotype or by recipient-donor SNP mismatching, were associated with the risk of relapse. Seven SNPs were associated with the risk of relapse in unrelated CBT. These included the donor genotype with the SNPs of rs2523675 and rs2518028 at the telomeric end of HCP5 gene, rs2071479 in the intron of the HLA-DOB gene, and rs2523958 in the MICD gene; and the recipient genotype with SNPs of rs9276982 in the HLA-DOA gene, and rs435766 and rs380924 in the MICD gene. As measured by pair-wise linkage disequilibrium (LD) with D′ as the parameter for normalized standard measurement of LD which compares the observed and expected frequencies of one haplotype comprised by alleles at different loci, rs2523675 had high LD with rs4713466 (D′ = 0.86) and rs2523676 (D′ = 0.91) in the HCP5 gene. The rs2518028 had no LD with all other SNPs except rs2523675 (D′ = 0.76). This study provides the basis for developing a method or algorithm for selecting better unrelated CBT candidate donors.
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Affiliation(s)
- Ding-Ping Chen
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Su-Wei Chang
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tang-Her Jaing
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan
| | - Wei-Ting Wang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Fang-Ping Hus
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ching-Ping Tseng
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Matsuoka Y, Nakamura F, Hatanaka K, Fujioka T, Otani S, Kimura T, Fujimura Y, Asano H, Sonoda Y. The number of CD34 +CD133 + hematopoietic stem cells residing in umbilical cord blood (UCB) units is not correlated with the numbers of total nucleated cells and CD34 + cells: a possible new indicator for quality evaluation of UCB units. Int J Hematol 2018; 108:571-579. [PMID: 30046987 DOI: 10.1007/s12185-018-2502-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 07/13/2018] [Accepted: 07/18/2018] [Indexed: 10/28/2022]
Abstract
Umbilical cord blood transplantation (UCBT) is often associated with delayed neutrophil and platelet recovery. Engraftment failure is another major obstacle. Several factors influence these serious complications, including the numbers of total nucleated cells (TNCs) and CD34+ cells which have been used as reliable factors for selecting UCB units for transplantation. However, whether both factors are reliable indices of the hematopoietic stem cell (HSC) activity of UCB units remains unknown. To evaluate the quality of UCB units, we quantified the actual number of transplantable CD34+CD133+ HSCs (tHSCs) residing in UCB units. The number of tHSCs was not correlated with the numbers of TNCs or CD34+ cells. These results strongly suggest that neither factor reflects the numbers of tHSCs residing in UCB units. To validate the significance of the number of tHSCs, further analysis is required to determine whether the number of tHSCs residing in UCB units is useful as a new indicator for the quality assessment of UCB units.
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Affiliation(s)
- Yoshikazu Matsuoka
- Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Fumiaki Nakamura
- Clinical Development and Operations, Product Development Department, Bayer Yakuhin, Ltd, Osaka, Japan
| | - Kazuo Hatanaka
- Department of Hematology, Osaka Red Cross Hospital, Osaka, Japan
| | - Tatsuya Fujioka
- Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Satoshi Otani
- Japanese Red Cross Kinki Block Blood Center, Osaka, Japan
| | | | | | - Hiroaki Asano
- Graduate School of Nursing for Health Care Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshiaki Sonoda
- Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan.
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Tanoue S, Konuma T, Kato S, Oiwa-Monna M, Isobe M, Jimbo K, Takahashi S, Tojo A. Platelet Transfusion Refractoriness in Single-Unit Cord Blood Transplantation for Adults: Risk Factors and Clinical Outcomes. Biol Blood Marrow Transplant 2018; 24:1873-1880. [PMID: 29753839 DOI: 10.1016/j.bbmt.2018.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/06/2018] [Indexed: 12/16/2022]
Abstract
Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5 × 109/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34+ cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10 mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults.
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Affiliation(s)
- Susumu Tanoue
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Takaaki Konuma
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
| | - Seiko Kato
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Maki Oiwa-Monna
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Masamichi Isobe
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Koji Jimbo
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Satoshi Takahashi
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Arinobu Tojo
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Aoyama T, Imataki O, Arai H, Kume T, Shiozaki H, Katsumata N, Mori M, Ishide K, Ikeda T. Comparison of Nutrition-Related Adverse Events and Clinical Outcomes Between ICE (Ifosfamide, Carboplatin, and Etoposide) and MCEC (Ranimustine, Carboplatin, Etoposide, and Cyclophosphamide) Therapies as Pretreatment for Autologous Peripheral Blood Stem Cell Transplantation in Patients with Malignant Lymphoma. Med Sci Monit Basic Res 2018; 24:31-39. [PMID: 29398693 PMCID: PMC5810616 DOI: 10.12659/msmbr.908113] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 01/11/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. MATERIAL AND METHODS We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. RESULTS Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=-0.73, P=0.003; r=-0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). CONCLUSIONS Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition-related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation.
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Affiliation(s)
- Takashi Aoyama
- Division of Nutrition, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Osamu Imataki
- Division of Hematology and Stem Cell Transplantation, Kagawa University Hospital, Miki, Kagawa, Japan
| | - Hidekazu Arai
- Division of Laboratory of Clinical Nutrition and Management, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, The University of Shizuoka, Naga-izumi, Shizuoka, Japan
| | - Tetsuo Kume
- Department of Pharmacy, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Hitomi Shiozaki
- Division of Nutrition, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Naomi Katsumata
- Division of Nutrition, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Mariko Mori
- Division of Nutrition, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Keiko Ishide
- Division of Nursing in Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
| | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Naga-izumi, Shizuoka, Japan
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Clinical outcomes of allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in the tyrosine kinase inhibitor era. ACTA ACUST UNITED AC 2018. [DOI: 10.7889/hct-17-002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan. Biol Blood Marrow Transplant 2017; 24:840-848. [PMID: 29196081 DOI: 10.1016/j.bbmt.2017.11.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 11/13/2017] [Indexed: 11/22/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P = .008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P < .001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P < .001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P = .010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.
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Tong J, Xuan L, Sun Y, Huang D, Liu H, Zheng C, Zhu X, Tang B, Song K, Zhang X, Zhang L, Yao W, Lin D, Liu Q, Sun Z. Umbilical Cord Blood Transplantation without Antithymocyte Globulin Results in Similar Survival but Better Quality of Life Compared with Unrelated Peripheral Blood Stem Cell Transplantation for the Treatment of Acute Leukemia—A Retrospective Study in China. Biol Blood Marrow Transplant 2017; 23:1541-1548. [DOI: 10.1016/j.bbmt.2017.05.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 05/02/2017] [Indexed: 12/26/2022]
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Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, Tojo A, Takahashi S. Cryopreserved CD34 + Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients. Biol Blood Marrow Transplant 2017; 23:1142-1150. [DOI: 10.1016/j.bbmt.2017.03.036] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 03/23/2017] [Indexed: 01/08/2023]
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GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transplant 2017; 52:1261-1267. [PMID: 28604665 DOI: 10.1038/bmt.2017.116] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/04/2017] [Accepted: 05/02/2017] [Indexed: 11/08/2022]
Abstract
To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.
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Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant 2016; 52:423-430. [PMID: 27941766 DOI: 10.1038/bmt.2016.255] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/16/2016] [Accepted: 08/18/2016] [Indexed: 01/04/2023]
Abstract
In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.
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Juric MK, Ghimire S, Ogonek J, Weissinger EM, Holler E, van Rood JJ, Oudshoorn M, Dickinson A, Greinix HT. Milestones of Hematopoietic Stem Cell Transplantation - From First Human Studies to Current Developments. Front Immunol 2016; 7:470. [PMID: 27881982 PMCID: PMC5101209 DOI: 10.3389/fimmu.2016.00470] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 10/19/2016] [Indexed: 12/21/2022] Open
Abstract
Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA) system allowed improved donor selection, including HLA-identical related and unrelated donors. Besides bone marrow, other stem cell sources like granulocyte-colony stimulating-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from GvL or antitumor effects. Whereas in the early years, malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal; nowadays, allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity. This chapter will summarize the key milestones of HSCT and introduce current developments.
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Affiliation(s)
- Mateja Kralj Juric
- BMT, Department of Internal Medicine I, Medical University of Vienna , Vienna , Austria
| | - Sakhila Ghimire
- Department of Internal Medicine III, University Hospital of Regensburg , Regensburg , Germany
| | - Justyna Ogonek
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School , Hannover , Germany
| | - Eva M Weissinger
- Transplantation Biology, Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School , Hannover , Germany
| | - Ernst Holler
- Department of Internal Medicine III, University Hospital of Regensburg , Regensburg , Germany
| | - Jon J van Rood
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands
| | - Machteld Oudshoorn
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands
| | - Anne Dickinson
- Hematological Sciences, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK
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Infectious Complications after Umbilical Cord-Blood Transplantation from Unrelated Donors. Mediterr J Hematol Infect Dis 2016; 8:e2016051. [PMID: 27872731 PMCID: PMC5111514 DOI: 10.4084/mjhid.2016.051] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/03/2016] [Indexed: 12/23/2022] Open
Abstract
Umbilical cord-blood (UCB) is a well-recognized alternative source of stem cells for unrelated donor hematopoietic stem cell transplantation (HSCT). As compared with other stem cell sources from adult donors, it has the advantages of immediate availability of cells, absence of risk to the donor and reduced risk of graft-versus-host disease despite donor-recipient HLA disparity. However, the use of UCB is limited by the delayed post-transplant hematologic recovery due, at least in part, to the reduced number of hematopoietic cells in the graft and the delayed or incomplete immune reconstitution. As a result, severe infectious complications continue to be a leading cause of morbidity and mortality following UCB transplantation (UCBT). We will address the complex differences in the immune properties of UCB and review the incidence, characteristics, risk factors, and severity of bacterial, fungal and viral infectious complications in patients undergoing UCBT.
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46
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Chen DP, Chang SW, Jaing TH, Tseng CP, Chen SH, Wang WT. Effect of HLA mismatching at HLA-A, -B, and -DRB1 for umbilical-cord blood transplantation in Taiwan. Clin Chim Acta 2016; 462:162-165. [PMID: 27693078 DOI: 10.1016/j.cca.2016.09.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 07/28/2016] [Accepted: 09/26/2016] [Indexed: 10/20/2022]
Abstract
Unrelated cord blood transplantation has become a reliable alternative therapy for children and adults owing to that one or two antigen/allele mismatches between a patient and the cord blood donor are acceptable without occurrence of graft-versus-host disease. To investigate the relationship between the number and types of mismatches and relapse, we compared the number of mismatched and non-mismatched donor-recipient pairs, number of mismatched alleles, and number of mismatched antigens at each of the Human Leukocyte Antigen (HLA) -A, -B, and -DR loci, respectively. The result indicates that the number of mismatched antigens at the HLA-A locus was significantly associated with occurrence of relapse (X2P-value=0.0243; RR=1.49, 95% CI: 1.04-2.13). Additionally, the number of mismatched donor-recipient pairs and the number of mismatched alleles at the HLA-DR locus was negatively associated with risks of relapse (X2P-value=0.0028; RR=0.52, 95% CI: 0.31-0.89). In this study, we found that the mismatch at the HLA-A locus is associated with increased risk of relapse; while the mismatch at the HLA-DR locus is innocuous. Hence, we suggest that the well-matched HLA-A alleles were most critical for matching HLA alleles between umbilical-cord blood transplantation donors and recipients. In other words, cord blood transplantation requires less stringent HLA matching, if there are two 5/6 or 4/6 HLA matched donors, it's better to choose HLA-A matched donor at least.
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Affiliation(s)
- Ding-Ping Chen
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan County, Taiwan.
| | - Su-Wei Chang
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tang-Her Jaing
- Department of Pediatrics, Division of Hematology/Oncology, Chang Gung Children's Hospital, Chang Gung University, Taoyuan County, Taiwan
| | - Ching-Ping Tseng
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan County, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan County, Taiwan
| | - Shih-Hsiang Chen
- Department of Pediatrics, Division of Hematology/Oncology, Chang Gung Children's Hospital, Chang Gung University, Taoyuan County, Taiwan
| | - Wei-Ting Wang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan County, Taiwan
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Rocha V. Umbilical cord blood cells from unrelated donor as an alternative source of hematopoietic stem cells for transplantation in children and adults. Semin Hematol 2016; 53:237-245. [PMID: 27788761 DOI: 10.1053/j.seminhematol.2016.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 08/09/2016] [Indexed: 01/13/2023]
Abstract
Umbilical cord blood (CB) is an alternative source of hematopoietic stem cells (HSC) for patients requiring allogeneic HSC transplantation but lacking a suitable human leukocyte antigen (HLA)-matched donor. Using CB has many advantages, including lower HLA-matching requirements, increased donor availability, and low rates of graft-versus-host disease. Furthermore, with over 630,000 cryopreserved volunteer CB units currently stored in international CB banks worldwide, CB is rapidly available for those patients requiring urgent transplantation. However, concern remains over the low HSC doses available in CB grafts, resulting in delayed engraftment and poor immune reconstitution. This article reviews the current use and future developments of unrelated allogeneic CB transplantation (CBT). An overview of the encouraging results of CBT and the comparisons with other HSC sources and transplant strategies both in children and adults with malignant and non-malignant diseases are shown. We will discuss important factors that need to be considered when selecting CB units for transplantation to further improve the results of CBT.
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Affiliation(s)
- Vanderson Rocha
- Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom; NHS Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Oxford, United Kingdom; Eurocord, Hôpital Saint Louis APHP, University Paris VII IUH Paris, France; Department of Hematology, University of São Paulo, São Paulo, Brazil.
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48
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Ishida T, Takahashi S, Lai CY, Nojima M, Yamamoto R, Takeuchi E, Takeuchi Y, Higashihara M, Nakauchi H, Otsu M. Multiple allogeneic progenitors in combination function as a unit to support early transient hematopoiesis in transplantation. J Exp Med 2016; 213:1865-80. [PMID: 27503070 PMCID: PMC4995077 DOI: 10.1084/jem.20151493] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 06/06/2016] [Indexed: 12/23/2022] Open
Abstract
Cord blood (CB) is a valuable donor source in hematopoietic cell transplantation. However, the initial time to engraftment in CB transplantation (CBT) is often delayed because of low graft cell numbers. This limits the use of CB. To overcome this cell dose barrier, we modeled an insufficient dose CBT setting in lethally irradiated mice and then added hematopoietic stem/progenitor cells (HSCs/HPCs; HSPCs) derived from four mouse allogeneic strains. The mixture of HSPCs rescued recipients and significantly accelerated hematopoietic recovery. Including T cells from one strain favored single-donor chimerism through graft versus graft reactions, with early hematopoietic recovery unaffected. Furthermore, using clinically relevant procedures, we successfully isolated a mixture of CD34(+) cells from multiple frozen CB units at one time regardless of HLA-type disparities. These CD34(+) cells in combination proved transplantable into immunodeficient mice. This work provides proof of concept that when circumstances require support of hematopoiesis, combined multiple units of allogeneic HSPCs are capable of early hematopoietic reconstitution while allowing single-donor hematopoiesis by a principal graft.
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Affiliation(s)
- Takashi Ishida
- Department of Hematology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
| | - Satoshi Takahashi
- Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
| | - Chen-Yi Lai
- Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
| | - Masanori Nojima
- Division of Advanced Medicine Promotion, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
| | - Ryo Yamamoto
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Emiko Takeuchi
- Department of Immunology, Kitasato University Graduate School of Medical Science, Kanagawa 252-0374, Japan
| | - Yasuo Takeuchi
- Department of Nephrology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Masaaki Higashihara
- Department of Hematology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
| | - Hiromitsu Nakauchi
- Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305
| | - Makoto Otsu
- Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan Division of Stem Cell Processing, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
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49
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Ishii H, Konuma T, Kato S, Oiwa-Monna M, Tojo A, Takahashi S. Impact of hematogones on the long-term outcomes of single-unit cord blood transplantation for adult patients. Leuk Lymphoma 2016; 58:118-126. [DOI: 10.1080/10428194.2016.1180687] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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50
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Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, Kanamori H, Hidaka M, Sakura T, Onizuka M, Kobayashi N, Sawa M, Eto T, Matsuhashi Y, Kato K, Ichinohe T, Atsuta Y, Miyamura K. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol 2016; 91:E284-92. [PMID: 26910296 DOI: 10.1002/ajh.24340] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 02/02/2016] [Accepted: 02/17/2016] [Indexed: 12/16/2022]
Abstract
Older recipient and donor age were associated with higher incidences of severe graft-versus-host disease (GVHD) and mortality after allogeneic hematopoietic stem cell transplantation from matched sibling donors (MSDs) and matched unrelated donors. Since a lower incidence of severe GVHD is advantageous in unrelated cord blood transplantation (CBT), a higher incidence of GVHD using older MSDs could be overcome using cord blood for older patients. We retrospectively analyzed Japanese registration data of 2,091 patients with acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome aged 50 years or older who underwent MSD bone marrow transplantation (BMT) (n = 319), MSD peripheral blood stem cell transplantation (PBSCT) (n = 462), or unrelated CBT (n = 1,310) between 2007 and 2012. Median age of MSD was 56 (range, 38-74) years. Compared with CBT, the risk of developing extensive chronic GVHD was higher after BMT (hazard ratio [HR], 2.00; P = 0.001) or PBSCT (HR, 2.38; P < 0.001), and transplant-related mortality was lower after BMT (HR, 0.61; P < 0.001) or PBSCT (HR, 0.63; P < 0.001). Relapse rates were not significant difference between three groups. Although overall mortality was lower after BMT (HR, 0.67; P < 0.001) or PBSCT (HR, 0.75; P = 0.002) compared with CBT, the rates of a composite endpoint of GVHD-free, relapse-free survival (GRFS) were not significant difference between three groups. These data showed that MSDs remain the best donor source for older patients, but CBT led to similar GRFS to BMT and PBSCT.
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Affiliation(s)
- Takaaki Konuma
- Department of Hematology/Oncology; the Institute of Medical Science, the University of Tokyo; Tokyo Japan
| | - Nobuhiro Tsukada
- Division of Hematology; Japanese Red Cross Medical Center; Tokyo Japan
| | - Junya Kanda
- Division of Hematology; Jichi Medical University, Saitama Medical Center; Saitama Japan
| | - Naoyuki Uchida
- Department of Hematology; Toranomon Hospital; Tokyo Japan
| | - Yuju Ohno
- Department of Internal Medicine; Kitakyushu Municipal Medical Center; Kitakyushu Japan
| | | | - Heiwa Kanamori
- Department of Hematology; Kanagawa Cancer Center; Yokohama Japan
| | - Michihiro Hidaka
- Department of Hematology; National Hospital Organization Kumamoto Medical Center; Kumamoto Japan
| | - Toru Sakura
- Saiseikai Maebashi Hospital; Leukemia Research Center; Gunma Japan
| | - Makoto Onizuka
- Department of Hematology and Oncology; Tokai University School of Medicine; Isehara Japan
| | - Naoki Kobayashi
- Department of Hematology; Sapporo Hokuyu Hospital; Sapporo Japan
| | - Masashi Sawa
- Department of Hematology and Oncology; Anjo Kosei Hospital; Anjo Japan
| | - Tetsuya Eto
- Department of Hematology; Hamanomachi Hospital; Fukuoka Japan
| | | | - Koji Kato
- Department of Hematology and Oncology; Children's Medical Center, Japanese Red Cross Nagoya First Hospital; Nagoya Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology; Research Institute for Radiation Biology and Medicine, Hiroshima University; Hiroshima Japan
| | - Yoshiko Atsuta
- Department of Healthcare Administration; Nagoya University Graduate School of Medicine; Nagoya Japan
- Japanese Data Center for Hematopoietic Cell Transplantation; Nagoya Japan
| | - Koichi Miyamura
- Department of Hematology; Japanese Red Cross Nagoya First Hospital; Nagoya Japan
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