Abstract
The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018–December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.
Keywords: Coronavirus disease 2019, Pandemic, Social restriction, Allogeneic hematopoietic stem cell transplantation, Transplant activity and outcome
Introduction
Coronavirus disease 2019 (COVID-19) presents a global health threat and has caused substantial mortality [1]. Since the first outbreak at the end of 2019, COVID-19 has spread worldwide, causing a million deaths [2]. The World Health Organization declared the COVID-19 pandemic on March 11, 2020 [3]. The COVID-19 pandemic also profoundly affected healthcare quality and access worldwide because of restrictions based on social distancing and movement, aiming to mitigate and manage the spread of COVID-19 [4–9]. As a result of the pandemic, the Japanese government declared a state of emergency for the metropolitan areas on April 7, 2020, which subsequently expanded to a nationwide on April 16 and continued until May 25. There were three waves of COVID-19 outbreak in 2020, which peaked in April, August, and December. Japan more successfully controlled the COVID-19 pandemic than Western countries; the number of infected people and deaths in 2020 were 187 per 100,000 and 3492, respectively [2]. Even still, the COVID-19 pandemic affected healthcare quality and access in fields such as cancer and emergency medicine throughout Japan [10–13].
Allogeneic hematopoietic stem cell transplantation (HSCT) is an important treatment option to cure hematological disorders [14]. Patients diagnosed with hematological disorders and having undergone HSCT have been affected by COVID-19 with an initial dramatic mortality rate [15–17]. In addition, there were donor harvest cancellations, donor or patient illness, and operational restrictions [18]. With such concerns, it is expected that transplantation care was also affected to some degree by the COVID-19 pandemic. In the annual activity survey, the European Society for Blood and Marrow Transplantation (EBMT) group revealed that transplant activity decreased in 2020 compared to that of the pre-COVID-19 years [17]. However, there is little available evidence and remaining clinical questions, such as whether transplant activity was decreased in countries where the pandemic was controllable and the extent of change in transplantation outcomes amid the COVID-19 pandemic.
Therefore, we aimed to evaluate the effect of the COVID-19 pandemic on transplant activity and its outcomes in Japan using the Second-Generation Transplant Registry Unified Management Program (TRUMP 2) from the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT).
Methods
Data collection
All data were obtained from the TRUMP2 database, which is a web-based HSCT registry in Japan established to collect clinical outcome data and evaluate the actual situation of HSCT [19]. Patient consent was obtained before the registration of the TRUMP2. This study was approved by the Data Management Committee of the JDCHCT and the Ethics Committee of Kobe City Medical Center General Hospital (#zn220802).
Patient measures
The patient and disease characteristics are summarized in Table 1. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was defined as previously described [20]. The myeloablative conditioning regimen and reduced-intensity conditioning regimen (RIC) were defined as previously described [21, 22]. Human leukocyte antigen (HLA)-matched donor was defined as the same serologically identified HLA-A, HLA-B, and HLA-DRB1 between the donor and the recipient. Haplo-identical donors were defined as related donors mismatched at three HLA antigen levels of HLA-A, HLA-B, and HLA-DRB1. Other donors were defined as mismatched donor. Disease risk was assessed in patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm, and malignant lymphoma. We defined AML and ALL without remission or above third complete remission and malignant lymphoma with stable and progressive disease as high risk and others as low risk.
Table 1.
Patient characteristics
| Characteristic | Overall N = 11,194 |
2018 N = 3621 |
2019 N = 3708 |
2020 N = 3865 |
p value1 | p value2 |
|---|---|---|---|---|---|---|
| Age, years | 50 (33, 60) | 50 (33, 60) | 49 (32, 60) | 51 (35, 61) | 0.026 | 0.016 |
| Child (≤ 15 years) | 1262 (11%) | 409 (11%) | 427 (12%) | 426 (11%) | 0.084 | 0.051 |
| Adult (16–59 years) | 7163 (64%) | 2342 (65%) | 2397 (65%) | 2424 (63%) | ||
| Older (60+ years) | 2769 (25%) | 870 (24%) | 884 (24%) | 1015 (26%) | ||
| Sex | 0.914 | 0.439 | ||||
| Female | 4580 (41%) | 1496 (41%) | 1493 (40%) | 1591 (41%) | ||
| Male | 6614 (59%) | 2125 (59%) | 2215 (60%) | 2274 (59%) | ||
| HCT-CI | 0 (0, 2) | 0 (0, 2) | 0 (0, 2) | 0 (0, 2) | 0.381 | 0.118 |
| Missing | 132 | 27 | 27 | 78 | ||
| High (≥ 3) | 1982 (18%) | 644 (18%) | 652 (18%) | 686 (18%) | 0.850 | 0.672 |
| Low (0–2) | 9080 (82%) | 2950 (82%) | 3029 (82%) | 3101 (82%) | ||
| Performance status | 2 (1, 2) | 2 (1, 2) | 2 (1, 2) | 2 (1, 2) | 0.653 | 0.924 |
| Missing | 82 | 13 | 12 | 57 | ||
| High (2–4) | 1146 (10%) | 399 (11%) | 364 (10%) | 383 (10%) | 0.172 | 0.792 |
| Low (0–1) | 9966 (90%) | 3209 (89%) | 3332 (90%) | 3425 (90%) | ||
| Number of HSCT | 0.416 | 0.648 | ||||
| Missing | 111 | 36 | 29 | 46 | ||
| 1st HSCT | 9456 (85%) | 3037 (85%) | 3157 (86%) | 3262 (85%) | ||
| ≥ 2nd HSCT | 1627 (15%) | 548 (15%) | 522 (14%) | 557 (15%) | ||
| Donor source | < 0.001 | < 0.001 | ||||
| Bone marrow | 3544 (32%) | 1241 (34%) | 1237 (33%) | 1066 (28%) | ||
| Peripheral blood | 3522 (31%) | 1089 (30%) | 1118 (30%) | 1,315 (34%) | ||
| Cord blood | 4128 (37%) | 1291 (36%) | 1353 (36%) | 1484 (38%) | ||
| Donor type | 0.046 | 0.003 | ||||
| Related | 3549 (32%) | 1132 (31%) | 1123 (30%) | 1294 (33%) | ||
| Unrelated | 7645 (68%) | 2489 (69%) | 2585 (70%) | 2571 (67%) | ||
| HLA in patients with BM or PB transplant | < 0.001 | 0.002 | ||||
| Missing | 24 | 4 | 3 | 17 | ||
| Matched | 4523 (66%) | 1539 (66%) | 1541 (66%) | 1443 (61%) | ||
| Mismatched | 1842 (25%) | 593 (26%) | 600 (26%) | 649 (28%) | ||
| Haplo-identical | 677 (9%) | 194 (8%) | 211 (9%) | 272 (12%) | ||
| Conditioning | 0.021 | 0.014 | ||||
| Missing | 58 | 5 | 3 | 50 | ||
| Myeloablative | 6050 (54%) | 1996 (55%) | 2051 (55%) | 2003 (53%) | ||
| Reduced intensity | 5086 (46%) | 1620 (45%) | 1654 (45%) | 1812 (47%) | ||
| GVHD prophylaxis | < 0.001 | 0.643 | ||||
| Missing | 329 | 93 | 81 | 155 | ||
| CSA base | 1906 (18%) | 690 (20%) | 609 (17%) | 607 (16%) | ||
| TAC base | 8959 (82%) | 2838 (80%) | 3018 (83%) | 3103 (84%) | ||
| ATG | < 0.001 | < 0.001 | ||||
| Missing | 93 | 19 | 14 | 60 | ||
| Yes | 1824 (16%) | 637 (18%) | 643 (17%) | 544 (14%) | ||
| No | 9277 (84%) | 2965 (82%) | 3051 (83%) | 3261 (86%) | ||
| Disease | 0.222 | 0.255 | ||||
| AML | 4353 (39%) | 1397 (39%) | 1428 (39%) | 1528 (40%) | ||
| MDS/MPN | 1932 (17%) | 600 (17%) | 624 (17%) | 708 (18%) | ||
| ALL | 1921 (17%) | 636 (18%) | 654 (18%) | 631 (16%) | ||
| ML | 1223 (11%) | 399 (11%) | 421 (11%) | 403 (10%) | ||
| Other malignancies | 1088 (10%) | 358 (10%) | 364 (10%) | 366 (10%) | ||
| Non-malignant disease | 677 (6%) | 231 (6%) | 217 (6%) | 229 (6%) | ||
| Disease risk in patients with AML, ALL, MDS and ML | 0.002 | 0.076 | ||||
| Missing | 386 | 124 | 114 | 148 | ||
| High risk | 2979 (33%) | 1013 (35%) | 998 (33%) | 968 (31%) | ||
| Low risk | 6064 (67%) | 1895 (65%) | 2015 (67%) | 2154 (69%) |
Continuous variables are summarized as medians and interquartile ranges (quartiles 1–3), and categorical variables are summarized as numbers and percentages
AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, ATG antithymocyte globulin, CsA cyclosporine A, GVHD graft-versus-host disease, HCT-CI hematopoietic cell transplant comorbidity index, HSCT hematopoietic stem cell transplantation, MDS myelodysplastic syndrome, ML malignant lymphoma, MPN myeloproliferative neoplasm, Tac tacrolimus
1P value compared 2020 and 2018
2P value compared 2020 and 2019
Endpoints and statistical analyses
To assess the difference in the total number of allogeneic HSCTs between 2020 and both 2018 and 2019, we showed the absolute number of patients who received HSCT and the relative ratio (RR), which was calculated considering the number of hematopoietic disorder cases per year as the denominator. Similarly, we showed the absolute number of HSCTs and RR per month to evaluate the effect of the waves of the COVID-19 pandemic and state of emergency.
Continuous variables were summarized using medians and interquartile ranges (quartiles 1–3), and categorical variables were summarized as numbers and percentages. Data were compared using the Mann–Whitney U test for continuous variables and chi-square tests for categorical variables.
We excluded patients without information on outcomes (n = 244) in the analysis of outcomes after HSCT. Then, we evaluated the following endpoints in regard to HSCT outcomes: 1-year overall survival rate (OS), 1-year cumulative incidence of relapse, and 1-year cumulative incidence of non-relapse mortality (NRM). If patients did not achieve complete remission after allogeneic HSCT, relapse was considered immediately after the allogeneic HSCT. Relapse was analyzed considering NRM as a competing risk factor. NRM was defined as death without relapse and analyzed considering relapse as a competing risk. Event rates were estimated with 95% confidence intervals (CI) using the Kaplan–Meier or Gray’s method for the OS and other endpoints. Gray’s method was employed to consider the competing risks. We also performed a univariate Cox proportional-hazards model for the OS and the Fine-Gray method for other endpoints. The endpoints were described as adjusted hazard ratios (HRs) and 95% CIs. The Fine-Gray method was employed to consider the competing risks.
Statistical significance was set at P < 0.05. All the statistical analyses were performed using the R software package (version 4.0.2; R Development Core Team).
Results
HSCT activity
The present study included 11,194 patients who received allogeneic HSCT between January 2018 and December 2020. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020 (Fig. 1, Table 1). There were no significant differences in the monthly numbers of HSCT between 2020 and 2018 or 2019 in corresponding months except for February, October, and December in 2018 (Fig. 1).
Fig. 1.
Number of hematopoietic stem cell transplantation in 2018, 2019, and 2020. In the upper panel, the points indicate relative risk, whereas the vertical lines indicate 95% confidence intervals. In the lower panel, the monthly numbers of overall patients who underwent hematopoietic stem cell transplantation are shown. *Indicates significant difference. **Total indicated average monthly number of patients who underwent hematopoietic stem cell transplantation.
Patient characteristics
Patient characteristics are shown in Table 1. The median age of patients was 50 years (interquartile range, 33–60 years), with 59% (n = 6614) being male. The median HCT-CI was zero (interquartile range, 0–2). Eighty-five percent of patients (n = 9456) received first allogeneic HSCT. Regarding the donor source, 32% (n = 3544), 31% (n = 3522), and 37% (n = 4128) of patients received bone marrow transplantation, peripheral blood transplantation, and cord blood transplantation, respectively. Among patients that received bone marrow or peripheral blood transplantation, 66% (n = 4523), 25% (n = 1842), and 9% (n = 677) of patients received transplants from HLA-matched donor, mismatched donor, and haploidentical donor, respectively. The majority of diseases requiring HSCT were acute myeloid leukemia (n = 4353, 39%), acute lymphoblastic leukemia (n = 1921, 17%), myelodysplastic syndrome/myeloproliferative neoplasm (n = 1932, 17%), and malignant lymphoma (n = 1223, 11%). The patient characteristics differed between patients who received HSCT in 2020 versus those in 2018 or 2019; the patient group transplanted in 2020 included more elderly patients, less patients who received bone marrow transplantation, fewer patients transplanted from unrelated and matched donors, more patients who received RIC, and less patients who received antithymocyte globulin compared with the patient groups transplanted in 2019 and 2018.
Outcomes after HSCT
In total, 10,950 patients were included in the outcome analysis after HSCT. The 1-year OS was 65.8% (95% CI 64.0–67.5%) in patients transplanted in 2020 versus 66.5% (95% CI 64.9–68.1%) and 66.4% (95% CI 64.8–67.9%) in patients transplanted in 2019 and 2018, respectively (P = 0.926) (Fig. 2A). The HR of OS in patients transplanted in 2020 was 1.02 (95% CI 0.93–1.11) compared with that in patients transplanted in 2019 (p = 0.639) and 1.00 (95% CI 0.96–1.05) compared with that in patients transplanted in 2018 (p = 0.900). The 1-year cumulative incidence of relapse was 27.1% (95% CI 25.6–28.7%) in patients transplanted in 2020 vs. 24.6% (95% CI 23.2–26.0%) and 24.9% (95% CI 23.5–26.4%) in patients transplanted in 2019 and 2018, respectively (p = 0.037) (Fig. 2B). The HR of relapse in patients transplanted in 2020 was significantly higher than that of patients transplanted in 2019 (HR 1.10, 95% CI 1.08–1.21, p = 0.033); it also tended to be higher than that of patients transplanted in 2018 (HR 1.04, 95% CI 1.00–1.09, p = 0.076). We performed the ad-hoc stratified analysis considering disease risk, which was a significant factor for relapse. The 1-year cumulative incidence of relapse was not significant among low-risk patients. In high-risk patients, the HR of relapse in patients that underwent transplantation in 2020 was significantly higher than that of patients who received transplants in 2019 (HR 1.26, 95% CI 1.09–1.46, p = 0.002) and in 2018 (HR 1.33, 95% CI 1.15–1.55, p < 0.001). In contrast, the cumulative incidence of NRM was not significantly different among the three groups (16.4% [95% CI 15.1–17.8] in 2020 vs. 17.1% [95% CI 15.9–18.4] in 2019 vs. 17.0% [95% CI 15.8–18.3] in 2018, p = 0.648) (Fig. 2C).
Fig. 2.
Transplant outcomes compared 2018, 2019 and 2020. A Overall survival, B cumulative incidence of relapse, and C cumulative incidence of non-relapse mortality
Discussion
Using the Japanese multicenter HSCT registry, we revealed that the total transplant activity in 2020 did not decrease compared with the previous two years. In a detailed comparison between 2020 and the previous two years, there were changes in the method of allogeneic HSCT, such as selection of donor and conditioning regimens. The transplant outcomes were similar in 2020 compared with the previous two years, except for a slight increase of cumulative incidence of relapse (HR 1.04–1.10). It can be inferred that the activity and outcomes were maintained as usual by modification of HSCT methods. Possessing several modifiable methods may maximize patient benefit in the event of a contingency. These findings are influenced by the fact that the pandemic was more successfully controlled in Japan than in Western countries [2]. Our results also suggest that we may be able to maintain transplant care as usual by controlling the pandemic to some degree.
In the annual activity survey, the EBMT group revealed that the transplant activity was down 6.5% in 2020 compared with that of 2019 [17]. Regarding the methods of allogeneic HSCT, a change to a RIC regimen and a decrease in transplants from unrelated donors were observed due to restrictions associated with successive waves of COVID-19, including lockdown. In our study, the total transplant activity in 2020 was not decreased compared with that of the previous two years, which was inconsistent with the study from the EBMT. Similarly, the monthly trend of allogeneic HSCT did not decrease even after declaration of a state of emergency and outbreak waves. Social reasons for the decreased transplant activity in the COVID-19 pandemic year include lax restrictions, national success in infection control, and good access to medical facilities [23]. Additionally, cord blood, which is commonly used as a transplant source in Japan, was easy to use even within social restrictions and may have complemented the decrease of other donor sources [24, 25]. Similarly, cryopreservation of donor grafts from the Japan Marrow Donor Program might be another reason for maintenance of the transplant activity during the COVID-19 pandemic [26, 27]. The trend of changes in transplantation methods are similar to those reported by the EBMT, such as donor and conditioning selection [17]. The results indicate that the COVID-19 pandemic influenced transplant medicine even in Japan, although the total activity was maintained.
There is little available evidence regarding the changes in transplant outcomes in the COVID-19 pandemic. Although it was expected to have a negative effect as in the results of other studies, the COVID-19 pandemic in Japan did not affect the OS and NRM of patients undergoing allogeneic HSCT in our study [28, 29]. The results indicate that there was no need to postpone transplantation out of concern for worsening patient outcomes, although it should be noted that only short-term outcomes could be evaluated. Conversely, the cumulative relapse incidence was slightly higher in 2020 than in 2018 and 2019 with a HR of 1.04–1.10. The increased relapse rate was remarkable in patients with a high-risk disease status. The increased relapse rate was due to changes in patient characteristics. More patients with poor disease conditions might have undergone allogeneic HSCT during the COVID-19 pandemic. Additionally, delayed diagnosis in the COVID-19 pandemic may be a contributing factor for the result.
It is important to note this study is not without limitations. First, our study was conducted in Japan, one of the most successful countries in controlling the COVID-19 pandemic; therefore, researchers need to be careful regarding the extrapolation of the results. Second, there is currently no data regarding long-term outcomes. The COVID-19 pandemic may not only affect the early post-HSCT period; we need to collect and analyze long-term data to understand the holistic effects of the pandemic on HSCT outcomes. Third, we could not understand the reason behind some changes such as the increased number of elderly patients undergoing transplantation. Finally, we had no data regarding COVID-19 in study patients. Consecutive studies are needed to clarify the effect of the COVID-19 pandemic on transplant activity in other contexts, long-term prognosis, and effect of COVID-19 in pre- or post-HSCT patients.
In conclusion, the findings of our study show that transplant activity was not decreased, and outcome of HSCT was not influenced, in the COVID-19 pandemic year compared with that of the two years prior.
Acknowledgements
The authors thank all the physicians and data managers of the centers who contributed to the collection of data on transplantation to the Japanese Data Center for Hematopoietic Cell Transplantation and the Second-Generation Transplant Registry Unified Management Program. We would like to express our gratitude to the Japan Society of Clinical Research for their support.
Author contributions
YS: designed the study, analyzed the data, performed the statistical analysis, and wrote the first draft of the manuscript. MN, TK, and TS: contributed to the critical review of the data analysis and the manuscript. All other authors contributed to data collection. All authors approved the final version of the manuscript.
Funding
None.
Data availability
The data used in this study are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
The authors have no conflicts of interest to declare.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study are available from the corresponding author upon reasonable request.