Abstract
According to data from the Japanese registry managed by the Transplant Registry Unified Management Program, the number of autologous stem cell transplantations (auto-SCT) in 2018 was approximately 60% of that of allogeneic SCT (allo-SCT). The opposite trend has been reported in the United States. Thus, we hypothesized that auto-SCT is underreported in the registry. We analyzed anonymized aggregated data from the Diagnosis Procedure Combination (DPC) database, a nationwide administrative claims database in Japan. Counts for fiscal years (FY) 2017 and 2018 were obtained for autologous collections, auto-SCT, and allo-SCT by graft source, and summarized by key demographic and clinical characteristics, including disease category and in-hospital outcomes. In FY2018, the DPC data recorded 23 autologous bone marrow transplantations (BMT), 2,590 autologous peripheral blood stem cell transplantations (PBSCT), 1,238 allogeneic BMT, 1,072 allogeneic PBSCT, and 1,353 cord blood transplantations (CBT). Similar findings were observed in FY2017. We identified plasma cell neoplasms (48%) and lymphoma (43%) as the primary indications for autologous PBSCT. Compared with the Japanese transplant registry, allogeneic SCT counts were similar across graft sources, whereas autologous PBSCT counts were approximately 500 higher. However, due to differences in aggregation rules, these findings should be interpreted as approximate rather than precise estimates. Our analysis of nationwide claims-based DPC data indicates potential underreporting of autologous PBSCT in the Japanese registry. Our findings support the complementary use of DPC data with registry data to characterize real-world hematopoietic cell transplantation practice in Japan.
Keywords: diagnosis procedure combination, DPC, administrative claims database, hematopoietic stem cell transplantation, real-world data
Introduction
Hematopoietic stem cell transplantation (HCT) requires specialized techniques and clinical expertise. Although unrelated donor HCT is performed only at facilities that meet institutional standards established by the Japanese Society for Transplantation and Cellular Therapy, no such standards are defined for related donor or autologous HCT. According to the “National Survey of Hematopoietic Cell Transplantation and Cell Therapy" (hereinafter referred to as the national survey) collected using the Transplant Registry Unified Management Program1, approximately 2,100 autologous transplantations were performed in Japan in 2018, representing approximately 60% of the 3,700 allogeneic transplantations. In contrast, the United States reported 11,557 autologous transplantations in 2018, approximately 1.4 times more than the 8,326 allogeneic transplantations that were performed; moreover, in Europe, autologous HCT accounted for 59% of all transplantations in 20191-4. Thus, international studies showed the opposite trend to Japan. In the national survey, the number of unrelated donor transplantations generally matched the publicly reported numbers from the donating bone marrow bank or cord blood banks, suggesting nearly complete data capture. We hypothesized that the registration of autologous transplantations, for which no institutional standards are established, underrepresents the number of transplantations performed.
In addition to patient registries, real-world data research applications using insurance databases and electronic medical records are important sources5. The Diagnosis Procedure Combination (DPC) is a system adopted by the Japanese government to encourage efficient and cost-effective care. It is widely used for classifying inpatients based on their diagnoses and procedures and utilized for payment. Hospitals are paid a fixed amount per day based on the patient's DPC group. In addition, the DPC database is maintained as a nationwide administrative claims database6. Since most HCT are performed at DPC facilities and nearly all procedures are covered by insurance claims, the DPC database is considered to have high completeness for these procedures. We used DPC data to investigate real-world transplantation activity in Japan and to evaluate its utility in the transplantation field. Furthermore, to support safe transplantation practice, we analyzed adverse events and transplantation-related information using real-world data from insurance claims.
Materials and Methods
We obtained anonymized aggregated DPC data from the Ministry of Health, Labour and Welfare (MHLW). The provided data included the number of autologous collections and HCTs (autologous and allogeneic) by graft source for fiscal year (FY) 2017 and FY2018, stratified by region and age/sex. Additional aggregated tables were provided for disease categories based on ICD-10 codes, clinical department, length of hospital stay, days from admission to collection (for autologous collection), discharge outcomes, use of pegfilgrastim or plerixafor in autologous collection, and vasopressor use during hospitalization for autologous collection.
The dataset contained aggregated counts and did not include individual-level patient data. Transplant procedure counts were extracted for procedures performed in each FY. Disease was classified by ICD-10 codes. FY2017-FY2018 was used as the extraction period. However, due to the government's aggregation policy for DPC data, some tables were compiled for cases that underwent transplantation in FY2017 or FY2018 and were discharged in FY2018. Disease categories were assigned by hematology specialists using ICD-10 codes to ensure correspondence with the disease categories defined in the Japanese registry. Department-level counts for autologous collection and transplantation were compiled as single-FY totals. Length of stay and discharge outcomes were extracted using the same FY2017–FY2018 discharge-based criteria as the disease-classification table. Use of pegfilgrastim/plerixafor was summarized separately for FY2017 and FY2018. Vasopressor use during hospitalization for autologous collection was also summarized separately for FY2017 and FY2018. For the Japanese national transplant registry, we used publicly available annual survey report data, which are summarized by calendar year (January–December).
Research was conducted in accordance with MHLW guidelines governing the use of anonymized medical care-related information7, after submitting a detailed application to the MHLW specifying the extraction conditions. In accordance with these guidelines, aggregated values of 1-9 cases or values from which 1-9 cases could be inferred were masked. Only aggregated results approved for publication by the MHLW are presented herein. The statistics used in this study were independently generated by the authors using the provided anonymized medical care-related information. Thus, these statistics may differ from MHLW-published ones. Data were managed at Nagoya University Hospital in accordance with the relevant guidelines. This study was conducted under the Ethical Guidelines for Medical and Biological Research Involving Human Subjects after receiving Ethical Review Board approval from Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital (IRB number, 11000028; approval number, 2020-454) and Nagoya University Hospital (IRB number 15000226; approval number, 2020-0537). Informed consent was waived due to the use of anonymized aggregated data.
Results
Number of hematopoietic cell transplantations performed
Table 1 summarizes procedure counts in the DPC data by FY and the corresponding counts from the national registry survey by calendar year. Table 2 and Supplementary Tables/Figures are based on cases transplanted in FY2017–2018 and discharged in FY2018 due to the MHLW aggregation policy. In the DPC data, the number of autologous transplantations in Japan was: 19 autologous bone marrow transplantations (BMTs) and 2,612 autologous peripheral blood stem cell transplantations (PBSCTs) in FY2017, and 23 autologous BMTs and 2,590 autologous PBSCTs in FY2018. The nationwide number of allogeneic transplantations was: 1,302 BMTs, 1,156 PBSCTs, and 1,329 cord blood transplantations (CBTs) in FY2017; and 1,238 BMTs, 1,072 PBSCTs, and 1,353 CBTs in FY2018 (Table 1).
Table 1.
Number of transplants reported in DPC data and the Japanese registry
| (a) Number of Auto-SCT cases | ||||
| Auto-SCT | Year | BMT | PBSCT | Auto-SCT |
| DPC data | FY2017 | 19 | 2,612 | NA |
| FY2018 | 23 | 2,590 | NA | |
| National registry | 2017 | NA | NA | 2,116 |
| 2018 | NA | NA | 2,107 | |
| (b) Number of Allo-SCT cases | ||||
| Allo-SCT | Year | BMT | PBSCT | CBT |
| DPC data | FY2017 | 1,302 | 1,156 | 1,329 |
| FY2018 | 1,238 | 1,072 | 1,353 | |
| National registry | 2017 | 1,348 | 1,121 | 1,359 |
| 2018 | 1,255 | 1,095 | 1,317 | |
Auto, autologous; Allo, allogeneic; SCT, stem cell transplantation; BMT, bone marrow transplantation; PBSCT, peripheral blood stem cell transplantation; CBT, cord blood transplantation; NA, not available; FY, fiscal year
Years for DPC data refer to Japanese fiscal years (i.e. April to March). National registry data are summarized by calendar year (January–December). National registry data are referenced from JDCHCT/JSHCT http://www.jdchct.or.jp/data/report/2020/
Table 2.
Number of transplants performed by disease category
| Disease | Auto-SCT | Allo-SCT | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| BM | (%) | PBSC | (%) | BM | (%) | PBSC | (%) | CB | (%) | |
| Leukemia/MPD | # | # | 53 | (2) | 945 | (78) | 879 | (83) | 1,057 | (83) |
| Lymphoma | # | # | 1,076 | (43) | 131 | (11) | 139 | (13) | 135 | (11) |
| Plasma cell neoplasms | # | # | 1,195 | (48) | 23 | (2) | 13 | (1) | # | # |
| Solid tumor | 13 | (62) | 184 | (7) | # | # | # | # | 27 | (2) |
| Aplastic anemia | # | # | # | # | 82 | (7) | 13 | (1) | 20 | (2) |
| Congenital hematopoietic disorder | # | # | # | # | # | # | # | # | # | # |
| Others | # | # | # | # | 36 | (3) | # | # | 17 | (1) |
| Total | 21 | 2,510 | 1,218 | 1,055 | 1,266 | |||||
# 0-9 cases
Auto, autologous; Allo, allogeneic; SCT, stem cell transplantation; BM, bone marrow; PBSC, peripheral blood stem cell; CB, cord blood; MPD, myeloproliferative disorders
Numbers 1 through 9 must be masked according to the provisions of the Guideline of Ministry of Health, Labour and Welfare. Zeros are also masked in this table as it enables to analogize the masked numbers of 1 through 9.
Numbers are applicable to cases transplanted in FY 2017 or FY 2018 and discharged in FY 2018.
Regarding age distribution (extracted from FY2017-2018, i.e., cases transplanted in FY2017 or 2018 and discharged in FY2018), the most frequent age groups by 5-year intervals were identified for each procedure (Supplementary Table 1). The peak age group was 0-4 years for autologous BMT (less than 10 cases) and 65-69 years for autologous PBSCT (558 cases). For allogeneic transplantation, the most frequent age groups were 60-64 years for BMT, 55-59 years for PBSCT (154 cases), and 60-64 years for CBT (181 cases).
The number of transplantations performed by disease classification is shown in Table 2. The proportions of cases by underlying disease for autologous PBSCT were as follows: leukemia/myeloproliferative disorders 2%, lymphoma 43%, plasma cell neoplasms 48%, and solid tumors 7%. Plasma cell neoplasms accounted for 20.3% of all allogeneic and autologous transplantations, representing a higher proportion than the 17.8% reported in the national survey3. Among autologous PBSCTs for solid tumors, frequent indications included malignant neoplasms of the mesothelium and soft tissue. Frequent indications also included malignant neoplasms of the eye, brain, and other parts of the central nervous system, as well as malignant neoplasms of the thyroid and other endocrine glands (Supplementary Table 2). Department-level counts were available as single-FY totals. Table 3 summarizes the results for FY2017. In the analysis of HCT by department, autologous PBSCTs performed by specialized departments other than internal medicine, pediatrics, and hematology, including oncology and respiratory medicine, were also included (Table 3).
Table 3.
Number of autologous collection and transplantation by department for 2017
| Department | Harvest | Auto-SCT | Allo-SCT | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BM | (%) | PBSC | (%) | BM | (%) | PBSC | (%) | BM | (%) | PBSC | (%) | CB | (%) | |
| Internal medicine | * | * | 794 | (27) | 0 | (0) | 741 | (28) | 368 | (28) | 342 | (30) | 311 | (23) |
| Pediatric | 11 | (38) | 179 | (6) | * | * | 183 | (7) | 190 | (15) | 72 | (6) | 139 | (10) |
| Hematology | 13 | (45) | 1,839 | (62) | * | * | 1,612 | (62) | 732 | (56) | 729 | (63) | 863 | (65) |
| Oncology | 0 | (0) | 15 | (1) | 0 | (0) | 19 | (1) | 0 | (0) | 0 | (0) | 0 | (0) |
| #### | 0 | (0) | 10 | (0) | 0 | (0) | 14 | (1) | * | * | * | * | 0 | (0) |
| Neurosurgery | 0 | (0) | 19 | (1) | 0 | (0) | * | * | 0 | (0) | 0 | (0) | 0 | (0) |
| Pulmonary medicine | 0 | (0) | 15 | (1) | 0 | (0) | 12 | (0) | * | * | * | * | 10 | (1) |
| Nephrology | 0 | (0) | 39 | (1) | 0 | (0) | * | * | * | * | 0 | (0) | * | * |
| Others | *** | *** | *** | *** | *** | *** | *** | *** | *** | *** | *** | *** | *** | *** |
| Total | 29 | (100) | 2,955 | (100) | 19 | (100) | 2,612 | (100) | 1,302 | (100) | 1,156 | (100) | 1,329 | (100) |
* 1-9 cases
*** Other masked numbers
#### Department information missing.
Auto, autologous; Allo, allogeneic; SCT, stem cell transplantation; BM, bone marrow; PBSC, peripheral blood stem cell; CB, cord blood
Values from 1 to 9 are masked in accordance with the guidelines of the Ministry of Health, Labour and Welfare. Numbers for Others are also masked, as their inclusion could allow inference of the masked values.
Duration of hospital stay
The distribution of hospital stay duration for transplantation differed by graft source (Supplementary Figure 1). The highest frequency categories were 29-35 days for autologous PBSCT, 78-84 days for allogeneic BMT, and 64-70 days for allogeneic PBSCT. CBT peaked at 85-91 and 92-98 days, indicating longer hospital stays. In terms of discharge outcomes, CBT showed a relatively high number of deaths due to both disease-related and other causes (Supplementary Table 3).
Autologous collection
In the DPC data, the number of autologous collections in Japan was 29 autologous bone marrow collections and 2,955 autologous peripheral blood stem cell collections in FY2017, and 43 autologous bone marrow collections and 2,854 autologous peripheral blood stem cell collections in FY2018. The most frequent age groups by 5-year intervals (extracted from FY2017-2018) were 0-4 years (less than 10 cases) and 65-69 years (less than 10 cases) for autologous bone marrow collection, and 65-69 years (624 cases) for autologous peripheral blood stem cell collection. In the number of autologous collections by department, implementation by oncology, neurosurgery, respiratory medicine, and nephrology was reported (Table 3).
In autologous peripheral blood stem cell collection, pegfilgrastim was used in 59 cases in FY2017 and 63 cases in FY2018, whereas plerixafor was used in 1,373 cases and 1,579 cases, respectively. The number of cases requiring vasopressor use during hospitalization for autologous peripheral blood stem cell collection was 29 in FY2017 and 13 in FY2018. Less than 10 cases of vasopressor use were also observed during the hospitalization period for autologous bone marrow collection in FY2018.
Discussion
Our analysis of the anonymized DPC data found that the number of autologous transplantations was higher than that reported in the Japanese transplant registry. Regarding overseas transplant cohorts, the possibility of underreporting in registries has been suggested8. In the United States, the Center for International Blood and Marrow Transplant Research also collects data for most (> 85%) autologous HCTs performed, although data submission is not required4. On the other hand, although registration with the data center is strongly recommended in Japan's national survey, it remains voluntary, and there may be cases, particularly autologous transplantation cases, that were not registered. Plasma cell disorders represented a smaller proportion of transplantations in the national survey than in DPC data. A nationwide prospective cohort study in Japan also reported that approximately 25% of newly diagnosed symptomatic patients with plasma cell disorders received upfront autologous HCT9, suggesting a substantial number of autologous transplantations in this category. Thus, the low volume of autologous transplantations in non-hematology departments argues against underreporting from those settings. Instead, the underrepresentation of plasma cell disorders in the national survey relative to DPC data suggests that unregistered plasma cell disorder cases account for the discrepancy in autologous transplantation numbers.
Several limitations of the data sources warrant mention. DPC data are compiled by FY (defined as April-March in Japan), whereas the national registry survey reports use the calendar year (January-December). Therefore, comparisons between the two sources (e.g., Table 1) should be interpreted as approximate rather than direct one-to-one comparisons. Additionally, since DPC data are recorded at discharge, some items required aggregation across FY, limiting analysis to frequency distributions where annual event count could not be strictly determined. As DPC represents claims-based aggregates, figures likely reflect procedures or hospitalizations rather than unique patients.
Vasopressor use during hospitalization was used as a safety indicator for autologous collection. Since this is a compilation of anonymized DPC data without clinical judgment, the causal relationship and temporal association between vasopressor use and collection were not investigated. In addition, vasopressor use may reflect clinical deterioration unrelated to stem cell collection or transplantation such as that associated with sepsis. However, assuming that vasopressor use was appropriately entered into DPC, the number of reports of serious events requiring vasopressor use during hospitalization was small.
Pegfilgrastim was approved in 2014, and its indication was expanded in 2022 to include hematopoietic stem cell mobilization in allogeneic PBSCT donors. Because the study period predates this expansion, pegfilgrastim use in the aggregated DPC tables may reflect off-label use or use for other clinical purposes; thus, it should not be interpreted as use for mobilization. Japanese real-world data also support the use of plerixafor for routine peripheral blood stem cell mobilization10. Since aggregated DPC data do not capture the indication for pegfilgrastim, its use cannot be directly linked to a specific mobilization setting; however, such data may still be useful for monitoring real-world utilization of agents with more specific indications such as plerixafor.
Inherent limitations of claims-based data should be considered when interpreting the findings of this study. Diagnoses and procedures in the DPC database are recorded primarily for reimbursement purposes; consequently, outcomes and complications identified using administrative codes may be subject to missing information or misclassification. Furthermore, clinical severity, timing, and causality are often difficult to ascertain, because key clinical details may not be consistently captured, resulting in limited clinical granularity5.
Conclusion
Anonymous medical care-related information can be used to understand real-world practice in HCT. Such data can provide national-level estimates, such as the number of autologous PBSCT cases, which are difficult for individual researchers to obtain. In addition, these data may support surveillance and registry validation by enabling nationwide cross-source comparisons in HCT and related settings.
Author Contributions
Research planning: YK, KS, YA, TN, YO, MH, KM. Data compilation: YK. Result interpretation: YK, KS, YA, TN, YO, MH, KM.
Conflicts of Interest
YA reports consulting fees from Novartis Pharma KK and honoraria from Otsuka Pharmaceutical Co., Ltd., CHUGAI PHARMACEUTICAL Co., Ltd., Novartis Pharma KK, Gilead Sciences, Inc., Janssen Pharmaceutical K.K., and JCR Pharmaceuticals Co., Ltd. TN reports consulting fees from Kyowa Kirin Co., Ltd., and honoraria from Kyowa Kirin Co., Ltd., and Sanofi K.K. MH reports funding from the Ministry of Health, Labor and Welfare of Japan; grants or contracts from Chugai Pharmaceutical Co., Ltd., Asahi KASEI Co., Ltd., Nippon Kayaku Co., Ltd., JCR Pharmaceuticals Co., Ltd., Kyowa Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., TAIHO PHARMACEUTICAL Co., Ltd., and Japan Blood Products Organization; and honoraria from NIPPON SHINYAKU Co., Ltd., ONO PHARMACEUTICAL Co., Ltd., AstraZeneca Co., Ltd., Chugai Pharmaceutical Co., Ltd., Novartis Pharma Co., Ltd., Abbott Japan LLC, Meiji Seika Pharma Co., Ltd., AbbVie LLC, Kyowa Kirin Co., Ltd., Bristol-Myers Squibb Co., Ltd., BeOne Medicines LLC, Mallinckrodt Pharma Co., Ltd., PharmaEssentia Japan Co., Ltd., Astellas Pharma Inc, MSD Co., Ltd., Pfizer Inc, Argenx Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd., Gilead Sciences, Inc., Janssen Pharmaceutical Co., Ltd., MOCHIDA PHARMACEUTICAL Co., Ltd., Alexion Pharma LLC, Sanofi Co., Ltd., Nippon Kayaku Co., Ltd., Daiichi Sankyo Co., Ltd., and Amgen Inc. The other authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website.
TN is one of the editors of Blood Cell Therapy. He was not involved in the editorial evaluation and the decision to accept this article for publication.
Supplementary Material
Acknowledgments
We express our deep gratitude to all DPC target facilities nationwide that perform hematopoietic cell transplantation, and to Dr. Akitaka Sugishita and Dr. Masahiko Ando from Department of Advanced Medicine of Nagoya University Hospital, and Dr. Yoshimune Shiratori from the Medical IT Center for their dedicated efforts in IT/operational management infrastructure development. We also thank Dr. Naomichi Nishikimi from Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital and Dr. Masaya Saito from Inuyama Chuo General Hospital for their valuable contributions.
Funding Statement
This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS KAKENHI grant numbers 17K08911 and 22K10360, YK), and by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan (grant number 20FF1002, MH).
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