Optimizing Timing and Preparation for Allogeneic Hematopoietic Stem Cell Transplantation in Higher-Risk Myelodysplastic Syndromes

doi:10.21203/rs.3.rs-5313687/v1

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Optimizing Timing and Preparation for Allogeneic Hematopoietic Stem Cell Transplantation in Higher-Risk Myelodysplastic Syndromes

https://doi.org/10.21203/rs.3.rs-5313687/v1

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This retrospective study evaluated allo-HSCT outcomes in 70 higher-risk MDS patients classified by the IPSS-R. Key factors analyzed included the interval from diagnosis to allo-HSCT (early: <6 months vs. late: ≥6 months), number of prior treatment cycles (less: <2 vs. more: ≥2), remission status (CR/PR vs. NR), and donor type (sibling vs. unrelated cord blood [UCB]). The results showed a significantly higher 3-year OS in the early HSCT group (70% vs. 50%, P = 0.05) with lower TRM (22.7% vs. 46.5%, P = 0.0205). Although more pre-transplant treatment cycles were linked to a lower relapse rate (2.3% vs. 15.4%, P = 0.0403), they did not significantly affect OS or TRM. Early HSCT emerged as the only significant factor influencing both OS (HR 2.84, P = 0.01) and TRM (HR 3.21, P = 0.01). While no significant differences were noted between sibling HSCT and UCB for OS and TRM, UCB demonstrated a lower incidence of chronic GVHD (19.0% vs. 52.9%, P = 0.003). Early allo-HSCT is recommended, with UCB as a viable alternative to sibling donors.

Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome

Health sciences/Medical research/Stem-cell research

Myelodysplastic syndromes (MDS) comprise a group of clonal disorders originating from hematopoietic stem cells, characterized by ineffective hematopoiesis that results in refractory cytopenias and an elevated risk of leukemic transformation, particularly in higher-risk patients with poor prognoses(1). Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option(3). Several factors influence post-transplant outcomes, including pre-transplant disease characteristics such as bone marrow blasts, cytogenetic risk, the revised International Prognostic Scoring System (IPSS-R) risk stratification, and disease status, as well as patient-related factors like performance status and comorbidity index(4). Various prognostic scoring systems, such as the IPSS-R, are widely used to guide MDS management and predict survival and disease progression; however, these models do not account for transplant-specific factors(5–7). Sibling donors are generally preferred for transplantation, with alternative donor sources following a hierarchy of matched unrelated donors, haplo/mismatched unrelated donors, and UCB, the latter being less effective overall than sibling(8). However, some pre-transplant issues in higher-risk MDS remain unresolved, including the optimal timing for transplantation, the necessity of achieving CR before transplant, the role of bridging therapy, and the appropriate number of treatment cycles. It is debated whether to wait for CR or proceed with allo-HSCT soon after diagnosis and to what extent blast reduction is required if CR cannot be achieved(9, 10). Previous reports indicate that the 3-year overall survival (OS) for higher-risk MDS patients treated with UCB transplantation (UCBT) approaches 30%, though studies directly comparing UCBT to sibling HSCT (sib-HSCT) are rare(11). As the largest UCBT center in China, our institution has significant experience in using UCBT for MDS patients. This article aims to retrospectively analyze the transplant outcomes of allo-HSCT in higher-risk MDS patients, with a particular focus on the significance of pre-transplant tumor burden and the necessity of multiple cycles of pre-transplant chemotherapy or HMA therapy to achieve remission. It also seeks to explore outcome differences between UCBT and sib-HSCT and assess whether cord blood can serve as a viable alternative donor source for transplantation.

Study Design and procedures

This retrospective study included higher-risk MDS patients who underwent their first allo-HSCT at the First Affiliated Hospital of the University of Science and Technology of China between February 2015 and December 2021. Diagnosis and classification of MDS were based on the 2016 World Health Organization criteria(12). Only patients classified as higher-risk (high or very high) according to the IPSS-R at diagnosis were included. Exclusion criteria were: lower-risk IPSS-R categories (very low, low, or intermediate), missing data, prior HSCT, bone marrow or peripheral blood blasts ≥ 20% at any point, or loss to follow-up. To minimize donor heterogeneity, cases of haplo-identical HSCT (n = 4) were also excluded. Donor selection was based on the availability of a suitable HLA-matched sibling. If unavailable or if rapid disease progression precluded finding a matched unrelated donor, a single-unit UCBT was considered. Cord blood units were matched at 4/6 to 6/6 loci using high-resolution DNA typing. Units with donor-specific antibodies positive against recipient HLA antigens were discarded. Follow-up data were collected up to March 1, 2024. Informed consent was obtained from all participants or their legal guardians, and the study was conducted in accordance with the Declaration of Helsinki.

Statistical analysis

The primary outcomes of this study were 3-year OS, 3-year transplant-related mortality (NRM), and 3-year relapse rate. The secondary outcome was graft-versus-host disease (GVHD) relapse-free survival (GRFS). OS was measured from the date of stem cell infusion to the date of death or last follow-up. NRM was defined as death resulting from factors related to the conditioning regimen, bone marrow aplasia, infections prior to immune recovery, or complications associated with GVHD in the absence of disease relapse. GRFS was defined as the time from allo-HSCT to the occurrence of grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic treatment, relapse or disease progression, or death, whichever occurred first.

Statistical analysis was conducted using SPSS version 25. Survival times were reported as medians (range). OS and GRFS were estimated using the Kaplan–Meier method, with group differences analyzed by the log-rank test. Univariate analysis was performed using logistic regression. Neutrophil and platelet engraftment rates, along with the incidence of aGVHD, TRM, and relapse, were analyzed using a competing risks model with EZR version 1.36. Cumulative incidence rates were compared using the Gray test in R software. A P-value of less than 0.05 was considered statistically significant.

Patient characteristics

A total of 70 higher-risk MDS patients who underwent allo-HSCT were identified from the database. Patient demographics and disease characteristics are summarized in Table 1. The median age was 33 years (range: 2–63 years). 15 patients (21.4%) had a genetic karyotype of monosomy or complex karyotype at diagnosis. The median time from diagnosis to transplantation was 5 months (range: 1–110 months). Twenty-one patients (30%) achieved partial remission or CR following prior chemotherapy or HMA induction, while 18 patients underwent direct transplantation without prior induction treatment. 43 patients (48.6%) were long-term transfusion-dependent before transplantation. Most patients were diagnosed with RAEB-1 or RAEB-2, had received fewer than two treatment cycles (chemotherapy or HMA), underwent HSCT within 6 months of diagnosis, received UCBT, followed a myeloablative conditioning regimen, and used combined GVHD prophylaxis with cyclosporine A and mycophenolate mofetil. 10 patients (14.3%) received four or more cycles of chemotherapy/HMA before transplantation, of whom 6 (60%) achieved CR. The UCBT group had significantly lower counts of total nucleated cells and CD34 + cells infused compared to the sibling-HSCT group (p < 0.001). None of the patients received anti-thymocyte globulin during the whole period. All patients were primarily analyzed within three subgroups: (1) based on whether HSCT was performed early after diagnosis (“early HSCT” < 6 months) or later (“late HSCT” ≥ 6 months); (2) based on the number of chemotherapy/HMA treatments prior to HSCT, categorized as “less treatment” (< 2 cycles) or “more treatment” (≥ 2 cycles) groups; and (3) based on pre-transplant remission status, categorized as “remission” (CR/PR) or “non-remission” (NR) groups.

Table 1

Patient and Transplantation Characteristics
	N = 70
Age at HSCT, median (range) year	33(2–63)
Sex, n (%)
Male	38 (54.3)
Time from diagnosis to HSCT, n (%)
≥ 6 months	30 (42.8)
< 6m months	40 (57.2)
2016 WHO classification at HCT, n (%)
RCMD	12 (17.2)
EB-1	15 (21.4)
EB-2	42 (60)
MDS- U	1 (1.4)
IPSS-R cytogenetic score values
Good	35 (50)
Int-1	14 (20)
poor	11 (15.7)
Very poor	4 (5.7)
Missing data	6 (8.6)
BM blasts at diagnosis, %
≤ 10	30 (42.8)
> 10	40 (57.2)
IPSS-R at diagnosis, n (%)
High	43 (61.4)
Very-high	27 (38.6)
Prior therapy of HSCT, n (%)
No	18 (25.7)
HMA	39 (55.7)
Chemotherapy	3 (4.3)
Immunotherapy	9 (12.9)
Others	1 (1.4)
Pre-transplant chemo/HMA cycles, n (%)
≤ 1	44 (62.9)
> 1	26 (37.1)
Disease status before HCT, n (%)
CR/PR	21 (30)
NR	49 (70)
HSCT type
sib-HSCT	17 (24.3)
UCBT	53 (75.7)
Conditioning regimen, n (%)
MAC without HMA	37 (52.9)
MAC + HMA	29 (41.4)
RIC without HMA	3 (4.3)
RIC + HMA	1 (1.4)
HLA matched, n (%)
3/6	6 (8.6)
4/6	26 (37.2)
5/6	19 (27.1)
6/6	19 (27.1)
ABO incompatibility, n (%)
Match	27 (38.6)
Major mismatch	14 (20)
Minor mismatch	21 (30)
Bidirectional mismatch	8 (11.4)
GVHD prophylaxis, n (%)
CSA + MMF	66 (94.3)
CSA + MMF + MTX	3 (4.3)
CSA + MMF + Cy	1 (1.4)
TNC, median (range) ×10⁸/kg
Sib-HSCT	9.43(6.24–14.29)
UCBT	0.29(0.08–0.99)
CD34 + cells, median (range) × 10⁶/kg
Sib-HSCT	5.19(1.41–8.95)
UCBT	0.17(0.03–0.66)
Year of HCT, n (%)
2015–2018	21 (30)
2019–2021	49 (70)
Follow-up, median (range) day	892(18-3222)
Abbreviations: Sib-HSCT, sibling hematopoietic stem cell transplantation; UCBT, umbilical cord blood transplantation; HCT,hematopoietic cell transplantation; WHO, World Health Organization;EB, excess blasts; IPSS-R, international prognostic scoring system revised; HMA, hypomethylating agents; CR, complete remission; NR, non-remission; PR, partial remission; CB, cord blood; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; HLA, human leukocyte antigen; GVHD, graft‐versus‐host disease; CSA, cyclosporin a; MMF, mycophenolate mofetil; MTX, methotrexate; Cy, cyclophosphamide; TNC, Total nucleated cell count.

3-year OS and 3-year TRM

The 3-year OS rate was significantly higher in the "early HSCT" group compared to the "late HSCT" group (70% vs. 50%, P = 0.05, see Fig. 1A). However, no significant difference in 3-year OS was observed between the "less treatment" (< 2 cycles) and "more treatment" (≥ 2 cycles) groups (57.2% vs. 63.6%, P = 0.666, see Fig. 1D), nor between the "CR/PR" and "NR" groups (66.0% vs. 59.2%, P = 0.387, see Fig. 1G). Similarly, the 3-year TRM rate was significantly lower in the "early HSCT" group than in the "late HSCT" group (22.7% vs. 46.5%, P = 0.0205, see Fig. 1B). No significant differences in 3-year TRM were found between the other subgroups (34.1% vs. 38.2%, P = 0.802, and 23.8% vs. 36.7%, P = 0.209, see Figs. 1E and 1H, respectively). Additionally, no significant differences were observed in 3-year OS or TRM between the sibling-HSCT and UCBT groups (see Supplementary Figs. 1A and 1B). Multivariate analysis identified the time from diagnosis to HSCT as the only factor significantly influencing both 3-year OS and TRM (HR, 2.84 [1.22–6.63], P = 0.01, and HR, 3.21 [1.29–7.94], P = 0.01, see Table 2).

Table 2

Multivariate analysis of 3-year OS, 3-year DFS and 3-year relapse.
	3-year OS		3-year TRM		3-year relapse
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
UCB vs sib-HSCT	1.98(0.65–5.98)	0.22	1.91(0.57–6.42)	0.29	3.02(0.24–37.38)	0.39
BM blasts at diagnosis: <10% vs ≥ 10%	1.55(0.57–4.23)	0.39	2.09(0.62–7.02)	0.23	6.35(0.31–129.8)	0.22
Prior chemo/HMA: <2 vs ≥ 2 cycles	1.37(0.43–4.32)	0.59	0.90(0.26–3.14)	0.87	35.32(0.47–2658)	0.11
remission state prior HSCT: CR/PR vs NR	2.42(0.84–6.97)	0.10	2.24(0.69–7.21)	0.17	11.4(0.36–358)	0.17
Cytogenetics: poor/very poor vs good/int	1.70(0.49–5.94)	0.41	1.00(0.24–4.14)	0.99	0.00(0.00-inf)	0.99
Prior treatment of therapy: yes vs no	0.54(0.16–1.84)	0.33	0.57(0.16–2.05)	0.39	0.00(0.00-inf)	0.99
interval from diagnosis to HSCT: <6m vs ≥ 6m	2.84(1.22–6.63)	0.01	3.21(1.29–7.94)	0.01	0.89(0.02–29.9)	0.94
Year of HCT 2015–2018 versus 2019–2021	0.53(0.20–1.41)	0.20	0.73(0.25–2.13)	0.57	0.09(0.00-1.9)	0.12
P values in bold are statistically significant (< .05).
Abbreviations: Sib-HSCT, sibling hematopoietic stem cell transplantation; UCBT, umbilical cord blood transplantation; HSCT, hematopoietic stem cell transplantation; HMA, hypomethylating agents; CR, complete remission; NR, non-remission; PR, partial remission; BM, bone marrow; TRM: transplant-related mortality; OS, overall survival.

In multivariate analysis, parameters such as bone marrow blasts ≥ 10% and poor or worse cytogenetic status were not significant predictors of 3-year OS, TRM, or relapse. Likewise, variables including HSCT type, bone marrow blasts at diagnosis, number of prior chemotherapy/HMA cycles, pre-transplant remission status, cytogenetic risk, time from diagnosis to HSCT, and HSCT year did not significantly impact 3-year OS or graft-versus-host disease relapse-free survival (GRFS).

3-year relapse rate

The 3-year relapse rate was significantly higher in the "more treatment" group the "less treatment" group (15.4% vs. 2.3%, P = 0.0403, see Fig. 1F). No significant differences were observed in the other subgroup analyses or between the two types of HSCT. In the multivariate analysis, none of the parameters showed a significant association with the 3-year relapse rate.

Sib-HSCT vs. UCBT subgroups

In the UCBT group, 88.7% (47/53) of patients achieved neutrophil engraftment, with a median engraftment time of 17 days (range: 11–41 days), compared to 100% in the sib-HSCT group with a median of 12 days (range: 9–20 days) (p < 0.001). 69.8% (37/53) of UCBT patients achieved platelet engraftment, with a median time of 38 days (range: 14–134 days), while 100% of the sib-HSCT group with a median of 14 days (range: 11–26 days) (p < 0.001). Five patients in the UCBT group who experienced engraftment failure were rescued through second transplantation (4 haplo and 1 UCBT). Additionally, the incidence of grade III-IV aGVHD within 100 days was higher in the UCBT group compared to the sib-HSCT group, but the difference was not statistically significant (17.0% vs. 0%, P = 0.717). However, the 3-year incidence of cGVHD was significantly lower in the UCBT group compared to the sibling-HSCT group and the 3-year GRFS was comparable for both subgroups (see Supplementary Figs. 1A-F).

Causes of death

During the follow-up period, a total of 30 patients passed away, including 7 cases (41.2%) in the sib-HSCT group and 23 cases (43.4%) in the UCBT group. The primary cause of death was infection, which accounted for 11 cases (36.7% of all deaths), multi-organ failure in 8 patients (26.6%), and relapse and GVHD, which caused 5 (16.7%) and 4 (13.3%) deaths, respectively. Early deaths occurred in 18 patients within 180 days post-transplant, with 14 cases (77.8%) resulting from infection or organ failure.

Consistent with findings from numerous retrospective studies, our results suggest that higher-risk MDS patients should undergo allo-HSCT as early as possible after diagnosis. Attempts to achieve CR or multiple pre-transplant treatments did not confer additional benefits; in fact, patients who underwent multiple treatment cycles exhibited a higher relapse rate. Some studies indicate that reducing blasts prior to HSCT may correlate with improved prognosis. For instance, Warlick et al. reported that MDS patients who achieved CR or had bone marrow blasts < 5% before transplantation experienced a lower 1-year cumulative relapse rate compared to those with 5%-20% blasts (18% vs. 35%, P = 0.07) (13). Ryotaro et al. analyzed newly diagnosed intermediate-2 or high-risk MDS patients, revealing that the HSCT group had significantly superior 3-year OS and leukemia-free survival compared to those who did not undergo HSCT (increased by 21.3%, P < 0.001, and 15.2%, P = 0.003, respectively). This survival advantage in the HSCT group was consistent across all subgroups, including age (< 65 vs. ≥65 years), performance status, IPSS score, IPSS-R score, disease duration (< 3 vs. ≥3 months), and response to HMAs (any vs. no response) (14). Gregory et al. conducted a prospective observational study on advanced MDS patients and found that "early HSCT" (< 5 months post-diagnosis) significantly reduced mortality compared to those who did not undergo HSCT (HR = 0.53, P = 0.006). In contrast, "delayed HSCT" (≥ 5 months post-diagnosis) did not demonstrate a significant difference in mortality (HR = 1.17, P = 0.49). The OS for patients undergoing early HSCT or HSCT at CR was significantly better than for those in the non-HSCT group or those who underwent delayed HSCT without achieving CR (P = 0.01). Both early HSCT and delayed HSCT with CR were associated with a lower risk of mortality (HR = 0.52, P = 0.004). Subgroup analyses indicated that patients with high-risk cytogenetics, intermediate-2 or high IPSS scores, and poor-risk MDS derived significant benefits from HSCT(15). Alzahrani et al. found that patients with < 5% blasts before HSCT had a relapse rate of 23%, compared to 69% for those with 5%-20% blasts and 66% for those with > 20% blasts (P = 0.0004)(16). Similarly, Schroeder et al. compared outcomes of advanced MDS or secondary acute myeloid leukemia patients who were untreated, underwent chemotherapy (CTX), or HMA treatment before HSCT, finding no significant differences in 5-year OS, relapse-free survival, or relapse rates. For patients who proceeded directly to HSCT, blast levels prior to HSCT (> 10% vs. <10%) did not significantly impact OS or RFS (17). Overall, these findings support the notion that for high-risk MDS patients, the advantages of early HSCT or achieving CR prior to transplantation are considerable.

In our study, the low relapse rate observed is attributed to the fact that most patients (94.3%) received myeloablative conditioning without antithymocyte globulin. This approach enhanced the graft-versus-leukemia effect following UCBT, facilitating earlier and more sustained clearance of residual tumor cells(18). Furthermore, the incidence of cGVHD was lower in the UCBT group, which is critical for improving patients' quality of life and facilitating better reintegration into society. We conducted a retrospective analysis of immune profiles in 1,945 post-transplant patients, utilizing six parameters—neutrophil, total lymphocyte, natural killer (NK), total T, CD4 + T, and B cell counts in peripheral blood—to predict early mortality (within 91–180 days after allo-HSCT). This analysis led to the development of a Composite Immune Risk Score, which demonstrated a significant correlation between higher scores and increased early mortality risk. Notably, we observed that NK, CD4 + T, and B cell counts reached significantly higher levels in the UCBT group compared to other transplant types, while CD8 + T cell counts did not show significant differences. NK cell levels in the UCBT group rapidly reconstituted during the early post-transplant period (within 30 days), potentially explaining the reduced incidence of cGVHD observed in these patients(19). Both mouse and human allo-HSCT studies have confirmed that donor NK cells can modulate GVHD by exerting cytotoxic functions against activated alloreactive T cells (20, 21). Anushruti et al. demonstrated that cord blood contains a high abundance of regulatory B cells (Bregs) after UCBT, with a robust recovery of Bregs observed in UCBT patients. This recovery included higher frequencies and absolute numbers of Bregs, which displayed strong inhibitory activity against allogeneic CD4 + T cells in vitro, a response not seen in cGVHD patients (22). Additionally, we found that the absolute counts and proportions of B cells and Breg cells in the UCBT group were higher than in patients receiving peripheral blood HSCT. Notably, Breg cells in the non-cGVHD group consistently exceeded those in the moderate to severe cGVHD group, suggesting that Bregs may reduce the occurrence of cGVHD (23). Together, these findings highlight a rich source of Bregs and suggest a protective role for CB-derived Bregs against the development of cGVHD in cord blood recipients. Our retrospective study demonstrated that post-transplant bone marrow recovery does not require a specific CD34 + cell threshold. We found a nearly linear correlation between log2 (CD34+/blood volume) and neutrophil recovery time (24). Additionally, in cases where HLA mismatches were ≤ 3/10, a CD34 + cell dosage of less than 0.83 × 10^5/kg was still acceptable without negatively impacting survival outcomes (25). These findings offer crucial insights for clinicians, providing greater confidence in selecting suitable cord blood units for transplantation.

However, we observed a notable incidence of early mortality, largely attributed to infections and organ failure. Many patients had transfusion dependence before transplantation, leading to significantly elevated serum ferritin levels (> 1000 ng/ml) and insufficient iron chelation therapy. Iron overload has been linked to complications such as organ dysfunction, secondary infections, and transplant failure (26, 27). Hence, we recommend maintaining iron chelation therapy for higher-risk MDS patients with iron overload both before and after transplantation to mitigate these risks.

Our study does have certain limitations, including being a single-center investigation with a relatively small sample size, lacking data on patients' performance status and specific genetic mutations. Moreover, we did not collect comprehensive data on pre-transplant blasts and newly acquired somatic mutations, all of which are essential for prognostic assessment. The applicability of UCBT in elderly high-risk MDS patients also warrants further exploration. Future studies should focus on larger, multi-center cohorts and diverse transplant approaches to address these gaps.

In conclusion, our findings emphasize the importance of early transplantation after diagnosis in improving outcomes for high-risk MDS patients. Prolonged pre-transplant treatment may offer little benefit, often resulting in suboptimal efficacy and delayed transplantation. When HLA-matched sibling or unrelated donors are unavailable, UCBT serves as a viable alternative.

ACKNOWLEDGMENTS

We thank all the patients who gave consent to disclose their medical records and answered our review calls.

Acknowledgements: This study was approved by the ethical committee of the Anhui Provincial Hospital Affiliated to University of Science and Technology of China. This work was supported in part by grants from the National Natural Science Foundation of China (grant number: 81470350), the Fundamental Research Funds for the Central Universities (grant number: WK9110000001).

Author Contributions: L.G., E.C andY.J. collected and analyzed data and wrote the original paper. H.L. participated in patient care and contributed to data interpretation. Z.S. designed the research, performed the research, analyzed and interpreted data, critically reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Competing Interests: We declare that there is no competing financial interest in relation to the work described.

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The authors have declared there is NO conflict of interest to disclose.

Supplementfigure1.tif
Supplement Figure 1. Accoroding to HSCT type:(A-C) CuI of 3-year OS, 3-year TRM, and 3-year relapse ; (D-F) CuI of 100-day grade II-IV aGVHD, 3-year cGVHD and 3-year GRFS.

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Review #2 received at journal
17 Nov, 2024
Review #1 received at journal
07 Nov, 2024
Reviewer #2 agreed at journal
27 Oct, 2024
Reviewer #1 agreed at journal
23 Oct, 2024
Reviewers invited by journal
23 Oct, 2024
Submission checks completed at journal
23 Oct, 2024
Editor assigned by journal
22 Oct, 2024
First submitted to journal
22 Oct, 2024

You are reading this latest preprint version

Optimizing Timing and Preparation for Allogeneic Hematopoietic Stem Cell Transplantation in Higher-Risk Myelodysplastic Syndromes

Status:

Version 1

Abstract

Figures

Introduction

Patients and methods

Study Design and procedures

Statistical analysis

Results

Patient characteristics

3-year OS and 3-year TRM

3-year relapse rate

Sib-HSCT vs. UCBT subgroups

Causes of death

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1