Upfront versus Delayed Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Acquired Aplastic Anemia: A Multicenter Retrospective Study

Upfront versus Delayed Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Acquired Aplastic Anemia: A Multicenter Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Upfront versus Delayed Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Acquired Aplastic Anemia: A Multicenter Retrospective Study Hawk Kim, Byung Woo Yoon, Yunsuk Choi, Sung-Soo Yoon, Soo Mee Bang, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6873313/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The role of allogeneic hematopoietic cell transplantation (alloHCT) as first-line therapy in elderly patients with acquired aplastic anemia (AA) remains uncertain. While immunosuppressive therapy (IST) is the standard initial treatment for patients aged ≥40 years, recent evidence suggests that upfront alloHCT may offer improved outcomes. We conducted a retrospective multicenter study of 173 Korean patients aged ≥40 years who underwent alloHCT between 1999 and 2017. Patients received either upfront alloHCT without prior IST (n=66) or delayed alloHCT following IST failure or relapse (n=107). The upfront group had a higher rate of matched sibling donors (78.8% vs. 50.5%, p<0.001) and shorter time to transplant (median, 3.4 vs. 8.3 months; p=0.046). Rates of engraftment, hematopoietic recovery, and acute and chronic graft-versus-host disease were comparable. Five-year overall survival was higher in the upfront group (73.5% vs. 56.4%, p=0.059). In multivariate analysis, upfront alloHCT (hazard ratio [HR], 2.476; p=0.004) and ECOG performance status ≤1 (HR, 4.736; p<0.001) were independently associated with improved survival. These findings suggest that upfront alloHCT may be a viable first-line option for selected elderly AA patients and support re-evaluation of treatment algorithms that currently prioritize IST. Health sciences/Medical research/Stem-cell research Biological sciences/Stem cells/Haematopoietic stem cells Figures Figure 1 Figure 2 Figure 3 Introduction Immunosuppressive therapy (IST) remains the standard first-line treatment for severe acquired aplastic anemia (AA) in elderly patients, typically those over 40 or 50 years of age. 1 – 3 However, emerging evidence suggests that selected elderly patients, particularly those with a matched related donor (MRD), may achieve favorable outcomes with upfront allogeneic hematopoietic cell transplantation (alloHCT). In fact, outcomes in these patients may exceed those of younger individuals undergoing delayed alloHCT from alternative donors (AD), such as matched unrelated donors (MUD). 4 With advancements in transplant techniques and supportive care, an increasing number of elderly patients—previously excluded from alloHCT— are now successfully transplanted from both MRD and AD sources. This challenges traditional age cutoffs, which may no longer reflect current clinical realities. MRDs are available in only 20–30% of AA cases. For patients without an MRD, current treatment algorithms recommend postponing AD alloHCT until IST failure, largely due to historically lower survival rates with AD alloHCT (5-year overall survival [OS], 39–61%). 5–7 However, many of these outcomes are based on older publications. Recent improvements in transplant outcomes—including better complication management and high-resolution HLA typing—have significantly increased survival with AD alloHCT. 8 , 9 Recent studies report 2- to 4-year overall survival rates of 73–89% with AD alloHCT, suggesting that it can be safely and effectively performed even in the first-line setting of AA. 10 – 15 Our recent study (Kim et al.) demonstrated comparable outcomes between AD and MRD alloHCT. 16 This is due to the use of triple immunosuppression regimen of cyclophosphamide, procarbazine, and anti-thymocyte globulin (ATG) in alloHCT. 17 However, outcomes with IST in Korea remain suboptimal, with a response rate of only 47% and a 6-year OS of 69 Historically, many centers have hesitated to pursue AD alloHCT due to early negative experiences. Nevertheless, accumulating evidence now supports its consideration as a first-line option, even in the absence of a suitable MRD. In light of these developments, a reevaluation of donor strategy (MRD vs. AD) in elderly patients with AA is warranted. Additionally, multiple prognostic factors—such as age, transfusion history, donor-recipient sex match, stem cell source, conditioning intensity, GvHD prophylaxis, and timing of transplantation—require reassessment. This study aims to evaluate the outcomes of upfront versus delayed alloHCT in elderly AA patients in Korea, with a focus on donor source and prognostic factors influencing transplant success. Methods Study design This was a retrospective, multicenter study conducted to evaluate the outcomes of alloHCT in patients with acquired AA aged 40 years or over, using either MRD or AD. The study initially aimed to enroll approximately 300 patients, based on national alloHCT volume in Korea. Study enrollment closed once all participating institutions completed case report form submissions. Eligibility Eligible patients met the following criteria: (1) a confirmed diagnosis of acquired aplastic anemia, regardless of etiology; (2) receipt of alloHCT from either an MRD or AD; and (3) age ≥ 40 years at the time of transplantation. Patients with congenital bone marrow failure syndromes—including Fanconi anemia, dyskeratosis congenita, and Diamond-Blackfan anemia—were excluded. Definitions of variables Upfront alloHCT was defined as transplantation administered as first-line therapy without prior IST. Delayed alloHCT was defined as transplantation administered as second-line or later, following IST failure or relapse. Acute and chronic GvHD were diagnosed and graded according to the Glucksberg and Shulman criteria, respectively. 18 , 19 Hepatic sinusoidal obstruction syndrome (SOS) was defined and graded using the modified Seattle criteria. 20 The start date for survival analyses was the date of stem cell infusion. Relapse-free survival was measured only in patients who achieved successful engraftment and transfusion independence, and was calculated from the start of conditioning to relapse or death. Patients without relapse or death were censored at last follow-up. Time to relapse was defined as the interval from stem cell infusion to treatment failure due to adverse events, progressive disease, death, or loss to follow-up. Overall survival (OS) was defined as the time from the start of conditioning to death or last known date alive. All analyses were performed on an intent-to-treat basis, and comparisons between MRD and AD groups were predefined. Study conduction The study protocol was reviewed and approved by the Clinical Study Committee of the Korean Society of Hematology Stem Cell Transplantation and the institutional review boards of all participating centers. Informed consent was waived due to the retrospective nature of the study. Data were collected through standardized case report forms, and all queries were resolved by the principal investigator. Final data analysis was conducted by the principal investigator. Manuscripts and presentations derived from this study required consensus from all participating investigators. All manuscripts were reviewed by all participating investigators before publication, and any form of presentation required agreement from all participating investigators. Statistical analysis Categorical variables were compared using the chi-square test, and continuous variables using Student’s t-test. For comparisons involving three or more groups, one-way ANOVA was applied. Survival outcomes were estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. A Cox proportional hazards regression model was used for multivariate analysis of factors affecting survival. The primary endpoint was the difference in overall survival between MRD and AD alloHCT recipients. Prognostic variables evaluated included age, donor-recipient sex match, transfusion history, use of irradiated blood products, time from diagnosis to transplantation, stem cell source, radiation dose, HLA matching, GvHD prophylaxis, prior IST, and anti-thymocyte globulin (ATG) use. A two-sided p-value < 0.05 was considered statistically significant. Results Patient characteristics The study included patients diagnosed with AA between December 12, 1987, and April 28, 2017, who subsequently underwent alloHCT between September 15, 1999, and August 10, 2017. Patients were classified into two groups based on treatment sequence: the upfront alloHCT group (no prior IST) and the delayed alloHCT group (alloHCT following IST failure or recur). The patient enrollment process is detailed in Fig. 1 . The AAWP2017-01 study initially aimed to enroll 300 elderly patients (aged 40 years or above) to assess alloHCT outcomes in this population. A total of 143 patients were enrolled before data were merged with 80 additional patients aged 40 years or above from the KSBMT2007-01 registry (total N = 268). After excluding duplicates (n = 46) and patients with hypocellular myelodysplastic syndrome (n = 4), 173 patients remained for final analysis: 66 in the upfront alloHCT group and 107 in the delayed alloHCT group. Baseline demographic and clinical characteristics are presented in Table 1 . The upfront group comprised 32 males (48.5%) and 34 females (51.5%), while the delayed group included 62 males (57.9%) and 45 females (42.1%) (p = 0.272). As per study definition, all patients in the delayed alloHCT group received prior IST, whereas none in the upfront alloHCT group had IST. Table 1 Patients’ characteristics Characteristics Upfront Delayed p-value Gender, Male/Female, n (%) 32(48.5)/34(51.5) 62(57.9)/45(42.1) 0.272 Prior IST 0 (0) 107 (100) < 0.001 alloHCT from MSD 52 (78.8) 54 (50.5) < 0.001 HLA full match 56 (84.8) 78 (72.9) 0.091 Haplo-identical alloHCT 3 (4.5) 4 (3.7) 1.000 Female donor to male recipient 13 (19.7) 21 (19.6) 1.000 Compatible ABO typing 37 (56.1) 64 (59.8) 0.637 Classical Cy-ATG conditioning 29 (43.9) 26 (24.3) 0.011 Fludarabine-containing regimen 32 (48.5) 77 (72.0) 0.002 TBI as a conditioning regimen 3 (4.5) 3 (2.8) 0.417 ATG/ALG as a conditioning regimen 54 (81.8) 90 (84.1) 0.682 BM as a stem cell source 36 (54.5) 37 (34.6) 0.012 Median (Range) Age, years 48.4 (40.1–64.9) 50.5 (40.0–69.0) 0.079 Time to alloHCT, months 3.4 (0.7-173.2) 8.3 (0.7-234.1) 0.046 Units of PRC transfusion 13 (1–93) 21 (0-500) 0.093 Units of PC transfusion 87 (0-960) 127 (0-1000) 0.007 Infused CD34 + cells, ⅹ10 6 /kg 4.0 (0.6–70.0) 4.2 (0.2–41.0) 0.964 Abbreviations: IST, immune suppression therapy; alloHCT, allogeneic hematopoietic cell transplantation; MSD, matched sibling donor; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; ALG, anti-lymphocte globulin; BM, bone marrow; PRC, packed red cell; PC, platelet concentrate A significantly higher proportion of patients in the upfront group underwent transplantation from a MSD compared to the delayed group (78.8% vs. 50.5%, p < 0.001). Full HLA matching was more common in the upfront group (84.8% vs. 72.9%), though this difference did not reach statistical significance (p = 0.091). The median age at transplant was slightly lower in the upfront group (48.4 years [range, 40.1–64.9]) than in the delayed group (50.5 years [range, 40.0–69.0]), but this difference was not statistically significant (p = 0.079). The median time from diagnosis to alloHCT was significantly shorter in the upfront group (3.4 months [range, 0.7–173.2]) compared to the delayed group (8.3 months [range, 0.7–234.1], p = 0.046). Additionally, patients in the upfront group required significantly fewer platelet concentrate (PC) transfusions (median 87 units [range, 0–960]) than those in the delayed group (median 127 units [range, 0–1000], p = 0.007). No significant differences were observed between groups in the number of packed red cell transfusions, CD34 + cell dose, or use of conditioning regimens, including cyclophosphamide combined with anti-thymocyte globulin (Cy-ATG), fludarabine-based regimens, and total body irradiation (TBI). Transplantation outcomes Table 2 compares key transplantation outcomes. Engraftment failure occurred in 21.2% of the upfront group and 29.9% of the delayed group (p = 0.209). Neutrophil engraftment failure occurred in 7.6% vs. 15.0% (p = 0.149), and platelet engraftment failure in 16.7% vs. 23.4% (p = 0.292), respectively. The incidence of SOS was low and comparable (4.5% vs. 5.6%, p = 1.000). Rates of acute and chronic GvHD were also similar between groups: aGvHD occurred in 24.2% vs. 29.0% (p = 0.497) and cGvHD in 18.2% vs. 19.6% (p = 0.814). Table 2 Transplant outcomes Characteristics Upfront Delayed p-value Engraft failure, n (%) Any 14 (21.2) 32 (29.9) 0.209 Neutrophil 5 (7.6) 16 (15.0) 0.149 Platelet 11 (16.7) 25 (23.4) 0.292 Hepatic SOS, n (%) 3 (4.5) 6 (5.6) 1.000 aGvHD, n (%) 16 (24.2) 31 (29.0) 0.497 cGvHD, n (%) 12 (18.2) 21 (19.6) 0.814 Extensive cGvHD, n (%) 4 (6.1) 6 (5.6) 1.000 Causes of death 17 (25.8) 45 (42.1) 0.030 Unknown, n (%) 1 (6.3) 2 (4.4) Infection, n (%) 9 (56.3) 23 (51.1) GvHD, n (%) 3 (18.8) 5 (11.1) Engraftment failure, n (%) 1 (6.3) 4 (8.9) Hemorrhage, n (%) 0 (0) 4 (8.9) Secondary malignancies, n (%) 0 (0) 2 (4.4) Pulmonary complications, n (%) 0 (0) 1 (2.2) Thrombotic microangiopathy, n (%) 1 (6.3) 0 (0) Hemochromatosis, n (%) 0 (0) 1 (2.2) PTLD, n (%) 0 (0) 2 (4.4) Cardiac complications, n (%) 1 (6.3) 0 (0) Hepatic SOS 0 (0) 1 (2.2) Abbreviations: SOS, sinusoidal obstruction syndrome; aGvHD, acute graft versus host disease; cGvHD, chronic graft versus host disease; PTLD, post-transplant lymphoproliferative disease Hematopoietic cell recovery The cumulative incidence of hematopoietic recovery is shown in Table 3 and Fig. 2 . The median time to absolute neutrophil count > 500/µL was 14 days (range, 11–22) in the upfront group and 11 days (range, 13–24) in the delayed group (p = 0.611). The median time to platelet recovery > 20,000/µL was 24 days (range, 19–39) and 19 days (range, 13–29), respectively (p = 0.129), with no significant difference in cumulative recovery between groups. Table 3 Cumulative incidence of transplant outcomes Characteristics Upfront Delayed p-value Cumulative Incidences, Median (Range) Time to ANC > 500/µL, days 14 (11–22) 15 (13–24) 0.611§ Time to platelet > 20K/µL, days 24 (19–39) 19 (13–29) 0.129§ Time to aGvHD, days 41.5 (9-2577) 47 (9-3963) 0.470§ aGvHD, G3/4 0.838§ Time to cGvHD, months 38.5 (0.6-119.6) 4.4 (1.2-121.7) 0.334§ cGvHD, extensive 0.771§ Abbreviations: ANC, absolute neutrophil count; aGvHD, acute graft versus host disease; cGvHD, chronic graft versus host disease §Cumulative incidence of competing events and Grey’s test Graft versus host disease The median time to aGvHD onset was 41.5 days (range, 9–2577) in the upfront group and 47 days (range, 9–3963) in the delayed group (p = 0.469). The cumulative incidence of grade 3–4 aGvHD was comparable (p = 0.838). Chronic GvHD developed at a median of 38.5 months (range, 0.6–119.6) in the upfront group and 4.4 months (range, 1.2–121.7) in the delayed group (p = 0.334). The cumulative incidence of extensive cGvHD was also similar (p = 0.771). Survival Univariate and multivariate survival analyses are presented in Table 4 and Fig. 3 . The 5-year OS was higher in the upfront group (73.5%) compared to the delayed group (56.4%), with a trend toward significance (p = 0.059), though the difference was attenuated when calculated from diagnosis (p = 0.155). Patients with ECOG performance status ≤ 1 had significantly higher 5-year OS compared to those with ECOG > 1 (66.9% vs. 30.3%, p < 0.001). Table 4 Prognostic factors for overall survival Factor n Univariate analysis Multivariate analysis 5-year survival rate (%) p-value HR 95% CI p-value Female vs. male 94 vs. 79 63.5 vs. 62.2 0.890 - - - Upfront vs. Delayed alloHCT after IST 66 vs. 107 73.5 vs. 56.4 0.059 2.476 1.337–4.586 0.004 Age at alloHCT ≤60 years vs. >60 years 155 vs. 18 63.9 vs. 53.8 0.259 1.934 0.883–4.237 0.099 Time from Dx to alloHCT ≤ 6 months vs. >6 months 94 vs. 79 63.7 vs. 62.1 0.590 - - - Matched related donor vs. Unrelated donor 79 vs. 50 64.7 vs. 57.9 0.517 - - - ABO compatible vs. incompatible 101 vs. 72 62.0 vs. 64.0 0.951 - - - HLA full match vs. mismatch 134 vs. 39 63.4 vs. 60.8 0.475 - - - Others vs. female donor-to-male recipient 139 vs. 34 62.8 vs. 63.4 0.909 - - - ECOG performance status at HCT; ≤1 vs. >1 154 vs. 17 66.9 vs. 30.3 < 0.001 4.736 2.336–9.602 < 0.001 Prior PRC transfusion < 15 U vs. ≥15 U 81 vs. 92 68.4 vs. 60.8 0.490 - - - Prior PC transfusion < 100 U vs. ≥100 U 82 vs. 91 71.5 vs. 58.0 0.231 1.103 0.639–1.906 0.724 Conditioning with vs. without fludarabine 109 vs. 64 65.2 vs. 58.3 0.170 2.090 0.830–5.264 0.118 Conditioning with vs. without ATG/ALG 144 vs. 29 61.8 vs. 67.6 0.571 - - - Cy-ATG conditioning vs. other 55 vs. 118 58.9 vs. 64.4 0.251 1.042 0.402–2.697 0.933 BM as a stem cell source vs. Others 73 vs. 100 60.1 vs. 64.9 0.334 - - - Infused CD34 + cells > 4 vs. ≤4 (×10 6 /kg) 120 vs. 53 62.2 vs. 63.6 0.933 - - - Abbreviations: HCT, allogeneic hematopoietic cell transplantation; IST, immune suppression therapy; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate; Cy-ATG, cyclophosphamide-antithymocyte globulin; BM, bone marrow Causes of death Overall mortality was significantly lower in the upfront group (25.8%) than in the delayed group (42.1%, p = 0.030). Infection was the leading cause of death in both groups, accounting for 56.3% and 51.1% of deaths, respectively. GvHD was the second most common cause (18.8% vs. 11.1%). Other causes (e.g., engraftment failure, hemorrhage, secondary malignancy, pulmonary complications, thrombotic microangiopathy, post-transplant lymphoproliferative disease, cardiac events, and hepatic SOS were rare and did not differ significantly between groups. Prognostic factors on survival In multivariate analysis, upfront alloHCT was independently associated with improved 5-year survival (HR, 2.476; 95% CI, 1.337–4.586; p = 0.004). ECOG > 1 was strongly associated with increased mortality (HR, 4.736; 95% CI, 2.336–9.602; p < 0.001). Other factors—including age at transplant, time from diagnosis to HCT, donor type, ABO compatibility, HLA matching, and conditioning regimen—were not statistically significant. Fludarabine use in conditioning showed a non-significant trend toward improved survival in univariate analysis (65.2% vs. 58.3%, p = 0.170), which was not confirmed in multivariate analysis (HR, 2.090; 95% CI, 0.830–5.264; p = 0.118). The use of bone marrow as a stem cell source was also not predictive of survival. Discussion The crude incidence of acquired AA in Korea is approximately 71.8 cases per million, significantly higher than reported in Western countries. The number of alloHCT for AA has steadily increased, with more than 60 procedures performed annually. 21 Despite this upward trend, published Korean data remain limited, emphasizing the need for national-level analyses. Ethnic differences may influence disease characteristics, treatment responses, and transplant outcomes, highlighting the importance of region-specific evidence. AlloHCT from a MRD is the standard and potentially curative treatment for severe AA, taking precedence over IST when a MRD is available. 22 Large-scale studies have reported 5-year overall survival (OS) rates exceeding 80% with MRD alloHCT. 8 , 17 , 23 , 24 Outcomes are particularly favorable in younger patients and those with limited transfusion histories. In the absence of an MRD, IST remains the first-line alternative, with initial response rates ranging from 61–77%. However, relapse remains a challenge, with rates between 12% and 37%. 25–28 . Cy-ATG is widely used as the standard conditioning regimen for MRD alloHCT, although the role of ATG in this setting remains debated. 29 TBI is generally avoided in MRD alloHCT due to concerns over long-term toxicity. In contrast, TBI has traditionally been considered essential in conditioning regimens for alloHCT using AD, particularly MUD. 6 , 30 – 32 However, data from the Japan Marrow Donor Program and other recent studies suggest that regimens with minimal irradiation can yield survival outcomes comparable to MRD alloHCT. 7 , 15 , 33 Moreover, several investigators have explored non-irradiation-based conditioning regimens for AD alloHCT and reported promising results. 12 , 34 Korean studies have also demonstrated excellent outcomes with non-TBI regimens in unrelated donor transplantation. 10 , 14 These findings collectively suggest that non-TBI conditioning may be a viable and effective option for unrelated donor alloHCT. In our recent study comparing Cy-ATG with a fludarabine-based regimen (Cy-Flu-ATG), the latter was associated with reduced toxicity, indicating it may be a more favorable conditioning strategy. 35 Based on these data, conditioning regimen was included as a key variable in our analysis. Comparison of upfront versus delayed alloHCT revealed similar outcomes in terms of engraftment failure, neutrophil and platelet recovery, SOS, and both acute and chronic GvHD. The comparable time to neutrophil and platelet engraftment suggests that delaying transplantation does not compromise hematopoietic recovery, which is a critical determinant of post-transplant success. These findings support the flexibility of transplant timing and allow clinicians to tailor alloHCT based on individual patient characteristics without adversely impacting engraftment. Additionally, the incidence and severity of grade 3/4 acute GvHD and chronic extensive GvHD were not significantly different between groups, indicating that delayed alloHCT does not increase the risk of GvHD. This reinforces the safety of deferring alloHCT when clinically appropriate and supports a more individualized, patient-centered approach to transplantation planning. Importantly, upfront alloHCT was associated with significantly improved 5-year overall survival compared to delayed alloHCT, suggesting that early transplantation may offer a survival advantage. Furthermore, performance status, particularly ECOG scores, was a strong predictor of survival, highlighting the importance of functional assessment and patient selection in optimizing transplant outcomes. An analysis of causes of death revealed that infection and GvHD were the most frequent causes of mortality in both groups. However, the delayed alloHCT group experienced higher overall mortality, largely due to transplant-related complications. These findings underscore the importance of timely transplantation and effective prophylactic strategies to mitigate post-transplant complications. Notably, other causes of death were infrequent and did not differ significantly between groups, suggesting that upfront alloHCT does not increase non-transplant-related mortality risks. Thrombopoietin receptor agonists (TPO-RAs) have emerged as effective agents in both first- and second-line settings. 36 – 39 TPO-RAs have been shown to enhance the efficacy of IST, both in initial treatment and in refractory cases, which may shift treatment strategies toward delaying alloHCT until after IST and TPO-RA failure. 40 However, our results indicate that alloHCT from AD does not lead to significantly inferior outcomes compared to MRD, supporting consideration of upfront transplantation even in the absence of a matched sibling donor. As such, treatment decisions must now account for donor availability, TPO-RA response, and individual patient risk profiles. In conclusion, our findings suggest that upfront alloHCT offers superior survival compared to delayed transplantation in elderly AA patients. With the increasing availability of TPO-RAs and evolving donor options, continued investigation is needed to optimize treatment sequencing and transplant timing. 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Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 2006; 108(8): 2509–2519. Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood 2000; 95(6): 1931–1934. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003; 101(4): 1236–1242. Kojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood 2000; 96(6): 2049–2054. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol 2006; 133(6): 606–611. Champlin RE, Perez WS, Passweg JR, Klein JP, Camitta BM, Gluckman E et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood 2007; 109(10): 4582–4585. Wagner JL, Deeg HJ, Seidel K, Anasetti C, Doney K, Sanders J et al. Bone marrow transplantation for severe aplastic anemia from genotypically HLA-nonidentical relatives. An update of the Seattle experience. Transplantation 1996; 61(1): 54–61. Kojima S, Inaba J, Yoshimi A, Takahashi Y, Watanabe N, Kudo K et al. Unrelated donor marrow transplantation in children with severe aplastic anaemia using cyclophosphamide, anti-thymocyte globulin and total body irradiation. Br J Haematol 2001; 114(3): 706–711. Yagasaki H, Takahashi Y, Kudo K, Ohashi H, Hama A, Yamamoto T et al. Feasibility and results of bone marrow transplantation from an HLA-mismatched unrelated donor for children and young adults with acquired severe aplastic anemia. Int J Hematol 2007; 85(5): 437–442. Deeg HJ, Amylon ID, Harris RE, Collins R, Beatty PG, Feig S et al. Marrow transplants from unrelated donors for patients with aplastic anemia: minimum effective dose of total body irradiation. Biol Blood Marrow Transplant 2001; 7(4): 208–215. Mao P, Wang S, Wang S, Zhu Z, Liv Q, Xuv Y et al. Umbilical cord blood transplant for adult patients with severe aplastic anemia using anti-lymphocyte globulin and cyclophosphamide as conditioning therapy. Bone Marrow Transplant 2004; 33(1): 33–38. Kim H, Lee JH, Joo YD, Bae SH, Hyun MS, Kim DY et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol 2012; 91(9): 1459–1469. Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014; 123(12): 1818–1825. e-pub ahead of print 2013/12/19; doi: 10.1182/blood-2013-10-534743 Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 2012; 367(1): 11–19. e-pub ahead of print 2012/07/06; doi: 10.1056/NEJMoa1200931 Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood 2022; 139(1): 34–43. doi: 10.1182/blood.2021012130 Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med 2017; 376(16): 1540–1550. doi: 10.1056/NEJMoa1613878 Young NS. Aplastic Anemia. N Engl J Med 2018; 379(17): 1643–1656. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6873313","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":473271235,"identity":"81d541f7-d2fd-48b8-b286-cbbc8e628942","order_by":0,"name":"Hawk Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACCWYGNiCVwMBwvAFIG1iQouXMAZAWCSK0MMC03EiA8gkByXbutAc/29Ki+W4+v7rhR4EEA397dwJeLdLMvNsNe9tycmfezim72QN0mMSZsxvwapFj5t0mwbutInfD7Zy0GzxALQYSuYS1SP4Fabl5Ju3mH2K0AB22TZp3W07uhhvsx24TZYtkM1CL7L+03JlncthuyxhI8BD0i8T5s9sk35xJzu07fvzZzTd/bOT423vxa0ECPAZgkljlIMD+gBTVo2AUjIJRMIIAALn0Sjb+V46IAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-2036-1466","institution":"Ulsan University Hospital, University of Ulsan College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hawk","middleName":"","lastName":"Kim","suffix":""},{"id":473271236,"identity":"350b5282-0532-48ac-827b-dfb3565eefaf","order_by":1,"name":"Byung Woo Yoon","email":"","orcid":"https://orcid.org/0000-0003-1391-6344","institution":"Gachon University Gil Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Byung","middleName":"Woo","lastName":"Yoon","suffix":""},{"id":473271237,"identity":"92856b70-73a0-4aa7-8d02-9923ab522232","order_by":2,"name":"Yunsuk Choi","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yunsuk","middleName":"","lastName":"Choi","suffix":""},{"id":473271238,"identity":"a57a711b-4fbe-410a-9402-92938f393118","order_by":3,"name":"Sung-Soo Yoon","email":"","orcid":"https://orcid.org/0000-0003-2591-7459","institution":"Department of Internal Medicine, Seoul National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sung-Soo","middleName":"","lastName":"Yoon","suffix":""},{"id":473271239,"identity":"21f70104-ff25-4c6e-b255-912d5124285e","order_by":4,"name":"Soo Mee Bang","email":"","orcid":"","institution":"Seoul National University Bundang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Soo","middleName":"Mee","lastName":"Bang","suffix":""},{"id":473271240,"identity":"5b61687f-1520-425b-a5d4-07975a0b26cd","order_by":5,"name":"Hyeoung-Joon Kim","email":"","orcid":"https://orcid.org/0000-0002-0998-1090","institution":"Chonnam National University Hwasun Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hyeoung-Joon","middleName":"","lastName":"Kim","suffix":""},{"id":473271241,"identity":"a6099ae7-a649-4a84-9477-7496dcafd3d7","order_by":6,"name":"Sang Kyun Sohn","email":"","orcid":"https://orcid.org/0000-0003-1932-0429","institution":"Kyungpook National University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sang","middleName":"Kyun","lastName":"Sohn","suffix":""},{"id":473271242,"identity":"a70ec122-8e11-42e0-bd58-31ea44c6b000","order_by":7,"name":"Yeung-Chul Mun","email":"","orcid":"https://orcid.org/0000-0002-1882-3983","institution":"Ewha Womans University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yeung-Chul","middleName":"","lastName":"Mun","suffix":""},{"id":473271243,"identity":"6884042e-96f6-4836-810e-11e1aae17533","order_by":8,"name":"Young Rok Do","email":"","orcid":"","institution":"Dongsan Medical Center, Keimyung University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Young","middleName":"Rok","lastName":"Do","suffix":""},{"id":473271244,"identity":"01bd60d3-5c01-4390-b52f-29932a908402","order_by":9,"name":"Yong Park","email":"","orcid":"","institution":"Korea University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Park","suffix":""},{"id":473271245,"identity":"10d0d590-8f88-4a28-930a-de9a6987ec9d","order_by":10,"name":"Ji Hyun Lee","email":"","orcid":"https://orcid.org/0000-0003-2341-4911","institution":"Dong-A Medical Center, Dong-A University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ji","middleName":"Hyun","lastName":"Lee","suffix":""},{"id":473271246,"identity":"8a6866d8-fcff-42d9-a1d8-1b1d9be1dda2","order_by":11,"name":"Sung Hwa Bae","email":"","orcid":"","institution":"Daegu Catholic University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sung","middleName":"Hwa","lastName":"Bae","suffix":""},{"id":473271247,"identity":"fbef2dec-232f-4a12-b72e-1e5cd3729776","order_by":12,"name":"Ho-Seop Lee","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ho-Seop","middleName":"","lastName":"Lee","suffix":""},{"id":473271248,"identity":"176f534e-cd5d-47d9-a8e8-fa3e00112a05","order_by":13,"name":"Min Kyoung Kim","email":"","orcid":"","institution":"Yeungnam University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"Kyoung","lastName":"Kim","suffix":""},{"id":473271249,"identity":"b0b50663-63df-4d64-80e2-a0e4cd1a07b5","order_by":14,"name":"Won Sik Lee","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Won","middleName":"Sik","lastName":"Lee","suffix":""},{"id":473271250,"identity":"9c525abb-6ecd-4424-b438-06d9c0455540","order_by":15,"name":"Jeong-Yeal Ahn","email":"","orcid":"","institution":"Gachon University Gil Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeong-Yeal","middleName":"","lastName":"Ahn","suffix":""},{"id":473271251,"identity":"96511719-5121-462b-9d99-f88c076b0969","order_by":16,"name":"Kyoo-Hyung Lee","email":"","orcid":"https://orcid.org/0000-0002-2841-0779","institution":"Ewha University Medical Center, Mokdong Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kyoo-Hyung","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-06-11 15:25:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6873313/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6873313/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85389733,"identity":"d9db716f-a6a4-4183-a9b8-acd8292b52b1","added_by":"auto","created_at":"2025-06-25 10:23:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1278732,"visible":true,"origin":"","legend":"\u003cp\u003ePatient enrollment flowchart\u003c/p\u003e\n\u003cp\u003eFlow diagram showing the enrollment process for the study population. Patients aged ≥40 years with acquired aplastic anemia who underwent allogeneic hematopoietic cell transplantation (alloHCT) between 1999 and 2017 were screened. After excluding duplicates and patients with hypocellular myelodysplastic syndrome, 173 patients were included in the final analysis: 66 in the upfront alloHCT group and 107 in the delayed alloHCT group.\u003c/p\u003e","description":"","filename":"Fig1StudyPopulation.png","url":"https://assets-eu.researchsquare.com/files/rs-6873313/v1/aa70d355a98697ecea34c0d9.png"},{"id":85391589,"identity":"f08a2ea6-5aaf-49d9-bc72-1846afa9ca5d","added_by":"auto","created_at":"2025-06-25 10:31:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1794299,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of hematopoietic recovery\u003c/p\u003e\n\u003cp\u003e(A) Time to neutrophil engraftment (ANC \u0026gt;500/μL). (B) Time to platelet recovery (\u0026gt;20,000/μL). (C) Cumulative incidence of acute GvHD (grades 1–4 and grades 3–4). (D) Cumulative incidence of chronic GvHD (overall and extensive). No significant differences were observed between upfront alloHCT and delayed alloHCT groups in neutrophil engraftment (p=0.611), platelet engraftment (p=0.129), acute GvHD (p=0.470 for grades 1–4; p=0.838 for grades 3–4), or chronic GvHD (p=0.334 for overall; p=0.771 for extensive).\u003c/p\u003e","description":"","filename":"Fig2EngraftGvHD.png","url":"https://assets-eu.researchsquare.com/files/rs-6873313/v1/1c4c616d9ec85a2932449c93.png"},{"id":85389738,"identity":"5c5601e2-35ba-40bb-9ac8-2574d5b4d6ed","added_by":"auto","created_at":"2025-06-25 10:23:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1429147,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival\u003c/p\u003e\n\u003cp\u003e(A) Overall survival for the entire cohort. (B) Overall survival calculated from the time of alloHCT. (C) Overall survival calculated from the time of initial diagnosis. (D) Overall survival stratified by ECOG performance status (PS ≤1 vs. \u0026gt;1). (E) Overall survival stratified by donor type (matched sibling donor vs. alternative donor). (F) Overall survival stratified by age group.\u003c/p\u003e","description":"","filename":"Fig3OS.png","url":"https://assets-eu.researchsquare.com/files/rs-6873313/v1/9c1731c26bf5d6912da20f78.png"},{"id":87207294,"identity":"1570209d-ecba-4945-b372-6c9cd1f1c5b4","added_by":"auto","created_at":"2025-07-21 14:19:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8200333,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6873313/v1/0bf43ae4-2a9c-484a-853f-5d2beedd9dca.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Upfront versus Delayed Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Acquired Aplastic Anemia: A Multicenter Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmunosuppressive therapy (IST) remains the standard first-line treatment for severe acquired aplastic anemia (AA) in elderly patients, typically those over 40 or 50 years of age.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, emerging evidence suggests that selected elderly patients, particularly those with a matched related donor (MRD), may achieve favorable outcomes with upfront allogeneic hematopoietic cell transplantation (alloHCT). In fact, outcomes in these patients may exceed those of younger individuals undergoing delayed alloHCT from alternative donors (AD), such as matched unrelated donors (MUD).\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWith advancements in transplant techniques and supportive care, an increasing number of elderly patients\u0026mdash;previously excluded from alloHCT\u0026mdash; are now successfully transplanted from both MRD and AD sources. This challenges traditional age cutoffs, which may no longer reflect current clinical realities.\u003c/p\u003e \u003cp\u003eMRDs are available in only 20\u0026ndash;30% of AA cases. For patients without an MRD, current treatment algorithms recommend postponing AD alloHCT until IST failure, largely due to historically lower survival rates with AD alloHCT (5-year overall survival [OS], 39\u0026ndash;61%).\u003csup\u003e5\u0026ndash;7\u003c/sup\u003e However, many of these outcomes are based on older publications. Recent improvements in transplant outcomes\u0026mdash;including better complication management and high-resolution HLA typing\u0026mdash;have significantly increased survival with AD alloHCT.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Recent studies report 2- to 4-year overall survival rates of 73\u0026ndash;89% with AD alloHCT, suggesting that it can be safely and effectively performed even in the first-line setting of AA.\u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur recent study (Kim et al.) demonstrated comparable outcomes between AD and MRD alloHCT.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e This is due to the use of triple immunosuppression regimen of cyclophosphamide, procarbazine, and anti-thymocyte globulin (ATG) in alloHCT.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e However, outcomes with IST in Korea remain suboptimal, with a response rate of only 47% and a 6-year OS of 69\u003c/p\u003e \u003cp\u003eHistorically, many centers have hesitated to pursue AD alloHCT due to early negative experiences. Nevertheless, accumulating evidence now supports its consideration as a first-line option, even in the absence of a suitable MRD. In light of these developments, a reevaluation of donor strategy (MRD vs. AD) in elderly patients with AA is warranted. Additionally, multiple prognostic factors\u0026mdash;such as age, transfusion history, donor-recipient sex match, stem cell source, conditioning intensity, GvHD prophylaxis, and timing of transplantation\u0026mdash;require reassessment.\u003c/p\u003e \u003cp\u003eThis study aims to evaluate the outcomes of upfront versus delayed alloHCT in elderly AA patients in Korea, with a focus on donor source and prognostic factors influencing transplant success.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis was a retrospective, multicenter study conducted to evaluate the outcomes of alloHCT in patients with acquired AA aged 40 years or over, using either MRD or AD. The study initially aimed to enroll approximately 300 patients, based on national alloHCT volume in Korea. Study enrollment closed once all participating institutions completed case report form submissions.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility\u003c/h3\u003e\n\u003cp\u003eEligible patients met the following criteria: (1) a confirmed diagnosis of acquired aplastic anemia, regardless of etiology; (2) receipt of alloHCT from either an MRD or AD; and (3) age\u0026thinsp;\u0026ge;\u0026thinsp;40 years at the time of transplantation. Patients with congenital bone marrow failure syndromes\u0026mdash;including Fanconi anemia, dyskeratosis congenita, and Diamond-Blackfan anemia\u0026mdash;were excluded.\u003c/p\u003e\n\u003ch3\u003eDefinitions of variables\u003c/h3\u003e\n\u003cp\u003eUpfront alloHCT was defined as transplantation administered as first-line therapy without prior IST. Delayed alloHCT was defined as transplantation administered as second-line or later, following IST failure or relapse.\u003c/p\u003e \u003cp\u003eAcute and chronic GvHD were diagnosed and graded according to the Glucksberg and Shulman criteria, respectively.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Hepatic sinusoidal obstruction syndrome (SOS) was defined and graded using the modified Seattle criteria.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe start date for survival analyses was the date of stem cell infusion. Relapse-free survival was measured only in patients who achieved successful engraftment and transfusion independence, and was calculated from the start of conditioning to relapse or death. Patients without relapse or death were censored at last follow-up.\u003c/p\u003e \u003cp\u003eTime to relapse was defined as the interval from stem cell infusion to treatment failure due to adverse events, progressive disease, death, or loss to follow-up. Overall survival (OS) was defined as the time from the start of conditioning to death or last known date alive. All analyses were performed on an intent-to-treat basis, and comparisons between MRD and AD groups were predefined.\u003c/p\u003e\n\u003ch3\u003eStudy conduction\u003c/h3\u003e\n\u003cp\u003e The study protocol was reviewed and approved by the Clinical Study Committee of the Korean Society of Hematology Stem Cell Transplantation and the institutional review boards of all participating centers. Informed consent was waived due to the retrospective nature of the study. Data were collected through standardized case report forms, and all queries were resolved by the principal investigator. Final data analysis was conducted by the principal investigator. Manuscripts and presentations derived from this study required consensus from all participating investigators. All manuscripts were reviewed by all participating investigators before publication, and any form of presentation required agreement from all participating investigators.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using the chi-square test, and continuous variables using Student\u0026rsquo;s t-test. For comparisons involving three or more groups, one-way ANOVA was applied. Survival outcomes were estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. A Cox proportional hazards regression model was used for multivariate analysis of factors affecting survival.\u003c/p\u003e \u003cp\u003eThe primary endpoint was the difference in overall survival between MRD and AD alloHCT recipients. Prognostic variables evaluated included age, donor-recipient sex match, transfusion history, use of irradiated blood products, time from diagnosis to transplantation, stem cell source, radiation dose, HLA matching, GvHD prophylaxis, prior IST, and anti-thymocyte globulin (ATG) use. A two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eThe study included patients diagnosed with AA between December 12, 1987, and April 28, 2017, who subsequently underwent alloHCT between September 15, 1999, and August 10, 2017. Patients were classified into two groups based on treatment sequence: the upfront alloHCT group (no prior IST) and the delayed alloHCT group (alloHCT following IST failure or recur). The patient enrollment process is detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe AAWP2017-01 study initially aimed to enroll 300 elderly patients (aged 40 years or above) to assess alloHCT outcomes in this population. A total of 143 patients were enrolled before data were merged with 80 additional patients aged 40 years or above from the KSBMT2007-01 registry (total N\u0026thinsp;=\u0026thinsp;268). After excluding duplicates (n\u0026thinsp;=\u0026thinsp;46) and patients with hypocellular myelodysplastic syndrome (n\u0026thinsp;=\u0026thinsp;4), 173 patients remained for final analysis: 66 in the upfront alloHCT group and 107 in the delayed alloHCT group.\u003c/p\u003e \u003cp\u003eBaseline demographic and clinical characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The upfront group comprised 32 males (48.5%) and 34 females (51.5%), while the delayed group included 62 males (57.9%) and 45 females (42.1%) (p\u0026thinsp;=\u0026thinsp;0.272). As per study definition, all patients in the delayed alloHCT group received prior IST, whereas none in the upfront alloHCT group had IST.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpfront\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelayed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, Male/Female, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32(48.5)/34(51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62(57.9)/45(42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior IST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ealloHCT from MSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLA full match\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (72.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaplo-identical alloHCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale donor to male recipient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (19.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompatible ABO typing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (56.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (59.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.637\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClassical Cy-ATG conditioning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (43.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFludarabine-containing regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (48.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77 (72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBI as a conditioning regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.417\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATG/ALG as a conditioning regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (81.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (84.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.682\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM as a stem cell source\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eMedian (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.4 (40.1\u0026ndash;64.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.5 (40.0\u0026ndash;69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to alloHCT, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.4 (0.7-173.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3 (0.7-234.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnits of PRC transfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (1\u0026ndash;93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (0-500)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnits of PC transfusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (0-960)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127 (0-1000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfused CD34\u0026thinsp;+\u0026thinsp;cells, ⅹ10\u003csup\u003e6\u003c/sup\u003e/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 (0.6\u0026ndash;70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2 (0.2\u0026ndash;41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.964\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: IST, immune suppression therapy; alloHCT, allogeneic hematopoietic cell transplantation; MSD, matched sibling donor; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; ALG, anti-lymphocte globulin; BM, bone marrow; PRC, packed red cell; PC, platelet concentrate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA significantly higher proportion of patients in the upfront group underwent transplantation from a MSD compared to the delayed group (78.8% vs. 50.5%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Full HLA matching was more common in the upfront group (84.8% vs. 72.9%), though this difference did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.091). The median age at transplant was slightly lower in the upfront group (48.4 years [range, 40.1\u0026ndash;64.9]) than in the delayed group (50.5 years [range, 40.0\u0026ndash;69.0]), but this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.079).\u003c/p\u003e \u003cp\u003eThe median time from diagnosis to alloHCT was significantly shorter in the upfront group (3.4 months [range, 0.7\u0026ndash;173.2]) compared to the delayed group (8.3 months [range, 0.7\u0026ndash;234.1], p\u0026thinsp;=\u0026thinsp;0.046). Additionally, patients in the upfront group required significantly fewer platelet concentrate (PC) transfusions (median 87 units [range, 0\u0026ndash;960]) than those in the delayed group (median 127 units [range, 0\u0026ndash;1000], p\u0026thinsp;=\u0026thinsp;0.007). No significant differences were observed between groups in the number of packed red cell transfusions, CD34\u0026thinsp;+\u0026thinsp;cell dose, or use of conditioning regimens, including cyclophosphamide combined with anti-thymocyte globulin (Cy-ATG), fludarabine-based regimens, and total body irradiation (TBI).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTransplantation outcomes\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e compares key transplantation outcomes. Engraftment failure occurred in 21.2% of the upfront group and 29.9% of the delayed group (p\u0026thinsp;=\u0026thinsp;0.209). Neutrophil engraftment failure occurred in 7.6% vs. 15.0% (p\u0026thinsp;=\u0026thinsp;0.149), and platelet engraftment failure in 16.7% vs. 23.4% (p\u0026thinsp;=\u0026thinsp;0.292), respectively. The incidence of SOS was low and comparable (4.5% vs. 5.6%, p\u0026thinsp;=\u0026thinsp;1.000). Rates of acute and chronic GvHD were also similar between groups: aGvHD occurred in 24.2% vs. 29.0% (p\u0026thinsp;=\u0026thinsp;0.497) and cGvHD in 18.2% vs. 19.6% (p\u0026thinsp;=\u0026thinsp;0.814).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTransplant outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpfront\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelayed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEngraft failure, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (29.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.149\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (23.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.292\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic SOS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGvHD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (29.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.497\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecGvHD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtensive cGvHD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCauses of death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (56.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (51.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGvHD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEngraftment failure, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemorrhage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary malignancies, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary complications, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombotic microangiopathy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemochromatosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTLD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac complications, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic SOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: SOS, sinusoidal obstruction syndrome; aGvHD, acute graft versus host disease; cGvHD, chronic graft versus host disease; PTLD, post-transplant lymphoproliferative disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eHematopoietic cell recovery\u003c/h2\u003e \u003cp\u003eThe cumulative incidence of hematopoietic recovery is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The median time to absolute neutrophil count\u0026thinsp;\u0026gt;\u0026thinsp;500/\u0026micro;L was 14 days (range, 11\u0026ndash;22) in the upfront group and 11 days (range, 13\u0026ndash;24) in the delayed group (p\u0026thinsp;=\u0026thinsp;0.611). The median time to platelet recovery\u0026thinsp;\u0026gt;\u0026thinsp;20,000/\u0026micro;L was 24 days (range, 19\u0026ndash;39) and 19 days (range, 13\u0026ndash;29), respectively (p\u0026thinsp;=\u0026thinsp;0.129), with no significant difference in cumulative recovery between groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCumulative incidence of transplant outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpfront\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDelayed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eCumulative Incidences, Median (Range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to ANC\u0026thinsp;\u0026gt;\u0026thinsp;500/\u0026micro;L, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (11\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (13\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.611\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to platelet\u0026thinsp;\u0026gt;\u0026thinsp;20K/\u0026micro;L, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (19\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (13\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.129\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to aGvHD, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.5 (9-2577)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (9-3963)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.470\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaGvHD, G3/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.838\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to cGvHD, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.5 (0.6-119.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.4 (1.2-121.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.334\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecGvHD, extensive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.771\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ANC, absolute neutrophil count; aGvHD, acute graft versus host disease; cGvHD, chronic graft versus host disease\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026sect;Cumulative incidence of competing events and Grey\u0026rsquo;s test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGraft versus host disease\u003c/h2\u003e \u003cp\u003eThe median time to aGvHD onset was 41.5 days (range, 9\u0026ndash;2577) in the upfront group and 47 days (range, 9\u0026ndash;3963) in the delayed group (p\u0026thinsp;=\u0026thinsp;0.469). The cumulative incidence of grade 3\u0026ndash;4 aGvHD was comparable (p\u0026thinsp;=\u0026thinsp;0.838). Chronic GvHD developed at a median of 38.5 months (range, 0.6\u0026ndash;119.6) in the upfront group and 4.4 months (range, 1.2\u0026ndash;121.7) in the delayed group (p\u0026thinsp;=\u0026thinsp;0.334). The cumulative incidence of extensive cGvHD was also similar (p\u0026thinsp;=\u0026thinsp;0.771).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eUnivariate and multivariate survival analyses are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The 5-year OS was higher in the upfront group (73.5%) compared to the delayed group (56.4%), with a trend toward significance (p\u0026thinsp;=\u0026thinsp;0.059), though the difference was attenuated when calculated from diagnosis (p\u0026thinsp;=\u0026thinsp;0.155). Patients with ECOG performance status\u0026thinsp;\u0026le;\u0026thinsp;1 had significantly higher 5-year OS compared to those with ECOG\u0026thinsp;\u0026gt;\u0026thinsp;1 (66.9% vs. 30.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-year survival rate (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale vs. male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 vs. 79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.5 vs. 62.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpfront vs. Delayed alloHCT after IST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 vs. 107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73.5 vs. 56.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.337\u0026ndash;4.586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at alloHCT \u0026le;60 years vs. \u0026gt;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e155 vs. 18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.9 vs. 53.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.934\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.883\u0026ndash;4.237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime from Dx to alloHCT\u0026thinsp;\u0026le;\u0026thinsp;6 months vs. \u0026gt;6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 vs. 79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.7 vs. 62.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched related donor vs. Unrelated donor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 vs. 50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.7 vs. 57.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.517\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eABO compatible vs. incompatible\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 vs. 72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.0 vs. 64.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.951\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLA full match vs. mismatch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e134 vs. 39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.4 vs. 60.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers vs. female donor-to-male recipient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139 vs. 34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.8 vs. 63.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status at HCT; \u0026le;1 vs. \u0026gt;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 vs. 17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.9 vs. 30.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.736\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.336\u0026ndash;9.602\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior PRC transfusion\u0026thinsp;\u0026lt;\u0026thinsp;15 U vs. \u0026ge;15 U\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 vs. 92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.4 vs. 60.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.490\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior PC transfusion\u0026thinsp;\u0026lt;\u0026thinsp;100 U vs. \u0026ge;100 U\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 vs. 91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.5 vs. 58.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.639\u0026ndash;1.906\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.724\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConditioning with vs. without fludarabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109 vs. 64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.2 vs. 58.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.830\u0026ndash;5.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConditioning with vs. without ATG/ALG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e144 vs. 29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.8 vs. 67.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCy-ATG conditioning vs. other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 vs. 118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.9 vs. 64.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.402\u0026ndash;2.697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.933\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBM as a stem cell source vs. Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 vs. 100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.1 vs. 64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.334\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfused CD34\u0026thinsp;+\u0026thinsp;cells\u0026thinsp;\u0026gt;\u0026thinsp;4 vs. \u0026le;4 (\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120 vs. 53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.2 vs. 63.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.933\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: HCT, allogeneic hematopoietic cell transplantation; IST, immune suppression therapy; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate; Cy-ATG, cyclophosphamide-antithymocyte globulin; BM, bone marrow\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCauses of death\u003c/h2\u003e \u003cp\u003eOverall mortality was significantly lower in the upfront group (25.8%) than in the delayed group (42.1%, p\u0026thinsp;=\u0026thinsp;0.030). Infection was the leading cause of death in both groups, accounting for 56.3% and 51.1% of deaths, respectively. GvHD was the second most common cause (18.8% vs. 11.1%). Other causes (e.g., engraftment failure, hemorrhage, secondary malignancy, pulmonary complications, thrombotic microangiopathy, post-transplant lymphoproliferative disease, cardiac events, and hepatic SOS were rare and did not differ significantly between groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic factors on survival\u003c/h2\u003e \u003cp\u003eIn multivariate analysis, upfront alloHCT was independently associated with improved 5-year survival (HR, 2.476; 95% CI, 1.337\u0026ndash;4.586; p\u0026thinsp;=\u0026thinsp;0.004). ECOG\u0026thinsp;\u0026gt;\u0026thinsp;1 was strongly associated with increased mortality (HR, 4.736; 95% CI, 2.336\u0026ndash;9.602; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Other factors\u0026mdash;including age at transplant, time from diagnosis to HCT, donor type, ABO compatibility, HLA matching, and conditioning regimen\u0026mdash;were not statistically significant.\u003c/p\u003e \u003cp\u003eFludarabine use in conditioning showed a non-significant trend toward improved survival in univariate analysis (65.2% vs. 58.3%, p\u0026thinsp;=\u0026thinsp;0.170), which was not confirmed in multivariate analysis (HR, 2.090; 95% CI, 0.830\u0026ndash;5.264; p\u0026thinsp;=\u0026thinsp;0.118). The use of bone marrow as a stem cell source was also not predictive of survival.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe crude incidence of acquired AA in Korea is approximately 71.8 cases per million, significantly higher than reported in Western countries. The number of alloHCT for AA has steadily increased, with more than 60 procedures performed annually.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Despite this upward trend, published Korean data remain limited, emphasizing the need for national-level analyses. Ethnic differences may influence disease characteristics, treatment responses, and transplant outcomes, highlighting the importance of region-specific evidence.\u003c/p\u003e \u003cp\u003eAlloHCT from a MRD is the standard and potentially curative treatment for severe AA, taking precedence over IST when a MRD is available.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Large-scale studies have reported 5-year overall survival (OS) rates exceeding 80% with MRD alloHCT.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Outcomes are particularly favorable in younger patients and those with limited transfusion histories. In the absence of an MRD, IST remains the first-line alternative, with initial response rates ranging from 61\u0026ndash;77%. However, relapse remains a challenge, with rates between 12% and 37%.\u003csup\u003e25\u0026ndash;28\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCy-ATG is widely used as the standard conditioning regimen for MRD alloHCT, although the role of ATG in this setting remains debated.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e TBI is generally avoided in MRD alloHCT due to concerns over long-term toxicity. In contrast, TBI has traditionally been considered essential in conditioning regimens for alloHCT using AD, particularly MUD.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e However, data from the Japan Marrow Donor Program and other recent studies suggest that regimens with minimal irradiation can yield survival outcomes comparable to MRD alloHCT.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Moreover, several investigators have explored non-irradiation-based conditioning regimens for AD alloHCT and reported promising results.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Korean studies have also demonstrated excellent outcomes with non-TBI regimens in unrelated donor transplantation.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e These findings collectively suggest that non-TBI conditioning may be a viable and effective option for unrelated donor alloHCT.\u003c/p\u003e \u003cp\u003eIn our recent study comparing Cy-ATG with a fludarabine-based regimen (Cy-Flu-ATG), the latter was associated with reduced toxicity, indicating it may be a more favorable conditioning strategy.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Based on these data, conditioning regimen was included as a key variable in our analysis.\u003c/p\u003e \u003cp\u003eComparison of upfront versus delayed alloHCT revealed similar outcomes in terms of engraftment failure, neutrophil and platelet recovery, SOS, and both acute and chronic GvHD. The comparable time to neutrophil and platelet engraftment suggests that delaying transplantation does not compromise hematopoietic recovery, which is a critical determinant of post-transplant success. These findings support the flexibility of transplant timing and allow clinicians to tailor alloHCT based on individual patient characteristics without adversely impacting engraftment.\u003c/p\u003e \u003cp\u003eAdditionally, the incidence and severity of grade 3/4 acute GvHD and chronic extensive GvHD were not significantly different between groups, indicating that delayed alloHCT does not increase the risk of GvHD. This reinforces the safety of deferring alloHCT when clinically appropriate and supports a more individualized, patient-centered approach to transplantation planning.\u003c/p\u003e \u003cp\u003eImportantly, upfront alloHCT was associated with significantly improved 5-year overall survival compared to delayed alloHCT, suggesting that early transplantation may offer a survival advantage. Furthermore, performance status, particularly ECOG scores, was a strong predictor of survival, highlighting the importance of functional assessment and patient selection in optimizing transplant outcomes.\u003c/p\u003e \u003cp\u003eAn analysis of causes of death revealed that infection and GvHD were the most frequent causes of mortality in both groups. However, the delayed alloHCT group experienced higher overall mortality, largely due to transplant-related complications. These findings underscore the importance of timely transplantation and effective prophylactic strategies to mitigate post-transplant complications. Notably, other causes of death were infrequent and did not differ significantly between groups, suggesting that upfront alloHCT does not increase non-transplant-related mortality risks.\u003c/p\u003e \u003cp\u003eThrombopoietin receptor agonists (TPO-RAs) have emerged as effective agents in both first- and second-line settings.\u003csup\u003e\u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e TPO-RAs have been shown to enhance the efficacy of IST, both in initial treatment and in refractory cases, which may shift treatment strategies toward delaying alloHCT until after IST and TPO-RA failure.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e However, our results indicate that alloHCT from AD does not lead to significantly inferior outcomes compared to MRD, supporting consideration of upfront transplantation even in the absence of a matched sibling donor. As such, treatment decisions must now account for donor availability, TPO-RA response, and individual patient risk profiles.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings suggest that upfront alloHCT offers superior survival compared to delayed transplantation in elderly AA patients. With the increasing availability of TPO-RAs and evolving donor options, continued investigation is needed to optimize treatment sequencing and transplant timing. These data provide important insights for guiding individualized, evidence-based care for patients with severe AA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflicts of interest related to this study. No financial or non-financial interests influenced the design, execution, interpretation, or reporting of this research.\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKillick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A \u003cem\u003eet al.\u003c/em\u003e Guidelines for the diagnosis and management of adult aplastic anaemia. \u003cem\u003eBr J Haematol\u003c/em\u003e 2016; 172(2): 187\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScheinberg P, Young NS. 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Aplastic Anemia. \u003cem\u003eN Engl J Med\u003c/em\u003e 2018; 379(17): 1643\u0026ndash;1656.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6873313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6873313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe role of allogeneic hematopoietic cell transplantation (alloHCT) as first-line therapy in elderly patients with acquired aplastic anemia (AA) remains uncertain. While immunosuppressive therapy (IST) is the standard initial treatment for patients aged ≥40 years, recent evidence suggests that upfront alloHCT may offer improved outcomes. We conducted a retrospective multicenter study of 173 Korean patients aged ≥40 years who underwent alloHCT between 1999 and 2017. Patients received either upfront alloHCT without prior IST (n=66) or delayed alloHCT following IST failure or relapse (n=107). The upfront group had a higher rate of matched sibling donors (78.8% vs. 50.5%, p\u0026lt;0.001) and shorter time to transplant (median, 3.4 vs. 8.3 months; p=0.046). Rates of engraftment, hematopoietic recovery, and acute and chronic graft-versus-host disease were comparable. Five-year overall survival was higher in the upfront group (73.5% vs. 56.4%, p=0.059). In multivariate analysis, upfront alloHCT (hazard ratio [HR], 2.476; p=0.004) and ECOG performance status ≤1 (HR, 4.736; p\u0026lt;0.001) were independently associated with improved survival. These findings suggest that upfront alloHCT may be a viable first-line option for selected elderly AA patients and support re-evaluation of treatment algorithms that currently prioritize IST.\u003c/p\u003e","manuscriptTitle":"Upfront versus Delayed Allogeneic Hematopoietic Cell Transplantation in Elderly Patients with Acquired Aplastic Anemia: A Multicenter Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-25 10:22:55","doi":"10.21203/rs.3.rs-6873313/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"46df7f14-94e2-40c2-b52b-da27b1da464e","owner":[],"postedDate":"June 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50263135,"name":"Health sciences/Medical research/Stem-cell research"},{"id":50263136,"name":"Biological sciences/Stem cells/Haematopoietic stem cells"}],"tags":[],"updatedAt":"2025-07-21T14:10:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-25 10:22:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6873313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6873313","identity":"rs-6873313","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}