Risk Stratification of Non-Relapse Mortality After Allogeneic Hematopoietic Stem Cell Transplantation Based on Pre-Transplant Sarcopenia and HCT-CI.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established curative therapy for hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS). Despite advances in conditioning regimens, donor selection, and supportive care, transplant outcomes remain strongly influenced by transplant-related complications and patient-specific factors 1 - 3 . In particular, as the allo-HSCT population continues to age, the risk of non-relapse mortality (NRM) is high, emphasizing the need for more accurate prognostic tools and refined risk stratification strategies 4 - 6 .

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is widely used for pre-transplant risk assessment 7 . However, recent reports have indicated that its predictive performance is lower than originally described, potentially reflecting advances in transplantation techniques and supportive care 8 .

Sarcopenia has emerged as an independent adverse prognostic factor across a range of malignancies and has been associated with increased susceptibility to infection, greater treatment-related toxicity, and shorter overall survival (OS) 9 . In allo-HSCT, pre-transplant sarcopenia is associated with poor OS 10 - 12 ; however, its relationship with non-relapse mortality remains inconsistent, with mixed findings reported across studies 10 - 13 . One explanation for these discrepancies is the complex, multifactorial nature of NRM, which is influenced by diverse mechanisms, including graft-versus-host disease (GVHD), infection, and organ toxicities, rather than a single biological domain 14 - 16 . These observations highlight the need for risk stratification approaches that incorporate physical function and physiological reserve alongside conventional comorbidity-based indices.

Supporting this concept, Armenian et al. demonstrated an association between computed tomography (CT)-defined sarcopenia and NRM, as well as markedly elevated 2-year NRM in patients with both sarcopenia and high HCT-CI (≥ 3), suggesting the additive prognostic value of integrating physical reserve with comorbidity burden 10 . In their multicenter prospective study conducted by the Spanish Group for Hematopoietic Transplantation and Cell Therapy (Grupo Español de Trasplante Hematopoyético y Terapia Celular [GETH-TC]), Salas et al. further showed that frailty assessed by the HCT Frailty Scale―integrating handgrip strength, Timed Up and Go, instrumental activities of daily living, Clinical Frailty Scale, serum albumin, and C-reactive protein―was strongly associated with transplant outcomes 17 . However, these prior studies relied on CT-based measurements or institution-specific frailty scoring systems, and validation using standardized, widely applicable diagnostic criteria remains limited.

The diagnostic framework proposed by the Asian Working Group for Sarcopenia (AWGS) incorporates muscle mass, handgrip strength, and gait speed, reflecting ethnic-specific body composition and physical performance characteristics 18 . These measures are reproducible, clinically feasible, and require minimal resources. We previously demonstrated that pre-transplant sarcopenia defined according to the AWGS 2019 criteria independently predicted OS but was not significantly associated with NRM 13 . To date, however, no study has examined whether combining pre-transplant sarcopenia, assessed using standardized diagnostic criteria, with the HCT-CI improves NRM risk stratification in allo-HSCT recipients. Therefore, the present study investigated the utility of an integrated approach combining sarcopenia and HCT-CI for stratifying NRM risk after allo-HSCT.

Materials and Methods

Patient selection

This single-center retrospective cohort study consecutively enrolled adult patients (≥ 18 years) who underwent their first allo-HSCT at our institution between May 2017 and December 2024.

Clinical data were retrospectively extracted from the patients' medical records. All patients underwent assessment of skeletal muscle mass, handgrip strength, and gait speed prior to transplantation, and no missing data were present for these variables. Administrative censoring was applied on October 31, 2025, and follow-up information was obtained from the medical records at that time.

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the institutional ethics committee (Approval No. 251018). The study also complied with the Act on the Protection of Personal Information and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. Informed consent was obtained using an opt-out procedure.

Sarcopenia assessment

Sarcopenia was diagnosed according to the AWGS 2019 criteria 18 . Skeletal muscle mass was measured using bioelectrical impedance analysis (BIA) (InBody 770; InBody Japan, Tokyo), and the skeletal muscle mass index (SMI) was calculated. BIA measurements were performed within one week before conditioning regimen initiation, at least one hour after completing intravenous fluid administration, and under resting conditions without clinically evident edema. Handgrip strength and gait speed were assessed during the same period.

Handgrip strength was measured twice on each hand using a digital dynamometer, and the highest recorded value was used for analysis. Gait speed was assessed using the 10-meter walk test at a comfortable pace and calculated as distance (m) divided by time (seconds).

According to the AWGS 2019 criteria, low muscle mass was defined as an SMI < 7.0 kg/m 2 for males and < 5.7 kg/m 2 for females, low muscle strength as handgrip strength < 28 kg for males and < 18 kg for females; and slow gait speed as < 1.0 m/s. Sarcopenia was diagnosed as the presence of low muscle mass with either low muscle strength or slow gait speed.

Clinical data

The following variables were collected from medical records: age, sex, body mass index (BMI), underlying disease, conditioning intensity (myeloablative conditioning [MAC] or reduced-intensity conditioning [RIC]) 19 , stem cell source (bone marrow, peripheral blood, or cord blood), donor type (related or unrelated), disease status at transplantation, GVHD prophylaxis, HCT-CI score, performance status (PS) 20 , SMI, handgrip strength, and usual gait speed. Underlying diseases were classified as AML, ALL, MDS, non-Hodgkin lymphoma (NHL), or others.

Outcomes and definitions

The primary outcome was NRM at 2 years after transplantation. NRM was defined as death without prior relapse or disease progression, with relapse treated as a competing event. The secondary outcomes included OS, progression-free survival (PFS), and the cumulative incidence of relapse (CIR). OS was defined as the time from transplantation to death from any cause, and PFS as the time from transplantation to relapse/disease progression or death, whichever occurred first. CIR was calculated by treating relapse or disease progression as the event of interest and NRM as the competing event.

Statistical analysis

The normality of continuous variables was assessed using the Shapiro-Wilk test. As all variables demonstrated non-normal distributions, data are presented as medians with interquartile ranges (IQR). Comparisons between groups were performed using the Mann-Whitney U test for continuous variables and χ 2 or Fisher's exact tests, as appropriate, for categorical variables. OS and PFS were estimated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test.

Cumulative incidence functions for NRM were calculated by treating relapse as a competing event, and group comparisons were performed using Gray's test. Based on previous reports, HCT-CI scores were categorized into low-risk (≤ 2) and high-risk (≥ 3) groups. In addition, a predefined composite risk classification was constructed, in which patients with both sarcopenia and an HCT-CI ≥ 3 were classified as high risk, and all others as low risk. NRM and CIR were compared using Gray's test, whereas OS and PFS were compared using log-rank test.

Multivariable analysis for NRM was performed using the Fine-Gray subdistribution hazard model, with relapse treated as a competing event. Age and BMI were analyzed as continuous variables, whereas PS was dichotomized using a clinically meaningful cutoff (≥ 1) due to its ordinal nature. To minimize overfitting relative to the number of events, variables were selected based on clinical relevance and univariable results, with the composite risk classification retained as the primary variable of interest in the multivariable model to estimate subdistribution hazard ratios (sHR) with 95% confidence intervals (CI).

All statistical analyses were conducted using EZR version 4.5.1 (Jichi Medical University Saitama Medical Center, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) 21 . Two-sided p < 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 95 adult patients underwent allo-HSCT at our institution during the study period. All patients were successfully followed, and no missing data were observed. Baseline patient characteristics are summarized in Table 1 . The median age was 59.0 years (IQR, 45.0-66.0 years), and 54 patients (56.8%) were male. The median follow-up duration was 1.7 years (IQR, 0.7-4.1 years).

Underlying diseases included AML (n=40), ALL (n=19), MDS (n=18), NHL (n=12), and others (n=6). The stem cell sources were bone marrow (n=38, 40.0%), peripheral blood (n=40, 42.1%), and cord blood (n=17, 17.9%). The conditioning regimens consisted of MAC (43 patients, 45.3%) and RIC (52 patients, 54.7%). The median HCT-CI score was 1.5 (IQR, 0-3), and 35 patients (36.8%) had an HCT-CI ≥ 3. Sarcopenia was identified in 22 patients (23.2%) and was more prevalent in patients with PS ≥ 1 than in those with PS 0 (46.9% [15/32] vs. 11.1% [7/63], p < 0.001; data not shown). Based on the composite risk classification, 12 (12.6%) and 83 (87.4%) patients were categorized into the high- and low-risk groups, respectively. Compared with the low-risk group, the high-risk group had significantly lower BMI, handgrip strength, usual gait speed, and SMI, as well as significantly poorer PS. Age, sex, underlying disease, disease status at transplantation, donor type, conditioning intensity, and GVHD prophylaxis did not differ significantly between the groups.

Primary outcome

The 2-year NRM for the entire cohort was 19.3% (95% CI, 11.8-28.2%) ( Figure 1A ). The 2-year NRM did not differ significantly between the non-sarcopenia and sarcopenia groups (16.9% [95% CI, 8.9-27.0%] vs. 28.1% [95% CI, 10.9-48.3%], p =0.230; Figure 1B ). Similarly, stratification by HCT-CI alone (≤ 2 vs. ≥ 3) did not yield a significant difference in 2-year NRM (14.8% [95% CI, 6.8-25.7%] vs. 26.9% [95% CI, 13.0-42.9%], p =0.126; Figure 1C ). When patients were stratified according to the composite risk classification, the high-risk group showed a significantly higher 2-year NRM compared with the low-risk group (41.7% [95% CI, 13.7-68.0%] vs. 16.1% [95% CI, 8.8-25.5%], p =0.026; Figure 1D ). In univariable analyses, age, PS, and the composite risk classification showed a trend or significant association with NRM ( Table 2 ). In the multivariable Fine-Gray model including these variables, the composite high-risk group remained independently associated with increased NRM (sHR=3.48, 95% CI, 1.26-9.64, p =0.018; Table 2 ).

Secondary outcomes

The 2-year OS for the entire cohort was 66.0% (95% CI, 55.0-74.9%) ( Figure 2A ). Based on the composite risk classification, the 2-year OS was significantly lower in the high-risk group than in the low-risk group (33.3% [95% CI, 10.3-58.8%] vs. 71.0% [95% CI, 59.2-79.9%], p =0.002; Figure 2B ). The 2-year PFS for the entire cohort was 56.4% (95% CI, 45.4-66.0%) ( Figure 2C ), and the high-risk group had a significantly lower 2-year PFS compared with the low-risk group (25.0% [95% CI, 6.0-50.5%] vs. 61.0% [95% CI, 49.0-71.0%], p < 0.001; Figure 2D ). The 2-year CIR for the entire cohort was 24.3% (95% CI, 16.0-33.6%) ( Figure 2E ) and did not differ significantly between the high- and low-risk groups (33.3% [95% CI, 8.7-61.0%] vs. 22.9% [95% CI, 14.3-32.8%], p =0.304; Figure 2F ).

Discussion

The present study suggests that a composite index combining pre-transplant sarcopenia and the HCT-CI may help improve risk stratification for NRM after allo-HSCT. In this cohort, neither sarcopenia nor the HCT-CI alone was significantly associated with NRM, whereas patients with both sarcopenia and a high HCT-CI (≥ 3) exhibited a higher cumulative incidence of NRM and poorer OS. These findings are consistent with the concept that integrating objective assessment of physical reserve with organ-related comorbidity burden may offer a more comprehensive characterization of peri-transplant vulnerability. However, given the limited number of NRM events and the small size of the high-risk group, the results should be interpreted as exploratory and hypothesis-generating rather than definitive evidence for clinical implementation.

Previous studies have linked reduced muscle mass and impaired physical function to adverse transplant outcomes; however, results have been inconsistent, partly because of heterogeneity in sarcopenia definitions and assessment methods 10 - 12 . A major strength of the present study is the use of the AWGS 2019 criteria, a standardized and clinically feasible diagnostic framework incorporating handgrip strength, gait speed, and muscle mass 18 . Using this standardized assessment, we observed that the composite index integrating pre-transplant sarcopenia and the HCT-CI was associated with a higher risk of NRM and poorer OS after allo-HSCT. In our previous single-center retrospective cohort study of 86 adult first allo-HSCT recipients 13 , AWGS 2019-defined sarcopenia was present in 24.4% of patients. Sarcopenia independently predicted OS (2-year OS: 42.9% vs. 75.7%; adjusted HR=2.28, 95% [CI], 1.07-4.84; p =0.033) but was not significantly associated with NRM (2-year NRM: 28.6% vs. 15.9%; p =0.225). This discrepancy suggests that physical reserve alone may be insufficient to capture the multifactorial mechanisms underlying NRM after allo-HSCT. The present study extends this observation by indicating that combining sarcopenia with comorbidity burden, as assessed by the HCT-CI, may help identify patients at higher risk of NRM. Taken together, these findings support a complementary framework in which objective assessment of physical reserve augments conventional comorbidity-based risk stratification rather than replacing existing clinical indices.

PS is a widely used and clinically meaningful indicator of overall functional capacity in patients undergoing allo-HSCT 20 . In the present cohort, sarcopenia and PS partially overlapped, and patients classified as high risk by the composite index tended to have poorer PS. Sarcopenia was more prevalent in patients with PS ≥ 1 than in those with PS 0, although it was also observed in a subset of patients with PS 0. These findings indicate that, while related, PS and sarcopenia capture different aspects of patient vulnerability. PS represents a global, observer-dependent assessment of functional status, whereas sarcopenia provides an objective evaluation of physical reserve based on standardized measures of muscle mass, strength, and gait speed.

From a pathophysiological standpoint, the HCT-CI primarily reflects intrinsic risks related to organ impairment and pre-existing comorbidities, whereas sarcopenia captures broader systemic vulnerability characterized by reduced muscle strength, impaired exercise capacity, chronic inflammation, and undernutrition. These factors may compromise physiological resilience to infection, GVHD, and treatment-related toxicities, thereby contributing to NRM 14 - 16 . Accordingly, a combined assessment of sarcopenia and the HCT-CI represents a rational strategy to identify high-risk patients more accurately in the peri-transplant setting.

Physical frailty and sarcopenia are potentially modifiable through nutritional and exercise-based prehabilitation 22 . Therefore, the composite index may have clinical relevance beyond prognostication, such as identifying candidates for prehabilitation, informing decisions regarding conditioning intensity, and reinforcing post-transplant supportive care strategies. Handgrip strength and gait speed are simple, reproducible, and easily incorporated into routine pre-transplant assessments, further supporting the feasibility of this approach in clinical practice.

This study has several limitations. First, the limited number of NRM events and the small size of the high-risk group may have affected the stability of the Fine-Gray model; thus, the estimated effect sizes should be interpreted cautiously. Second, this was a single-center retrospective study with a relatively small sample size, which may limit statistical power and generalizability. Third, follow-up duration was insufficient to fully evaluate long-term NRM, survival, and recovery of physical function. Fourth, external validation was not performed. Finally, all assessments were conducted before publication of the AWGS 2025 criteria, which introduced revised cutoffs and diagnostic algorithms 23 . Future multicenter prospective studies are warranted to validate the reproducibility and clinical applicability of this composite index.

In conclusion, integrating pre-transplant sarcopenia with the HCT-CI may serve as a practical framework for NRM risk stratification after allo-HSCT by jointly assessing physical reserve and organ-related comorbidity burden. This composite approach may capture vulnerabilities not adequately identified by conventional single-dimension assessments and underscores the importance of incorporating physical reserve into pre-transplant evaluation. Future studies should focus on external validation and prospective evaluation to determine whether integrating objective measures of physical reserve can meaningfully refine clinical decision-making in allo-HSCT.

Author contributions

KK performed conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, and writing of the original draft. AK and WK performed formal analysis, supervision, review and editing. TU performed data curation and formal analysis. HA and KH measured skeletal muscle mass. KM, HI, SO, TM, and TI performed review and editing. All authors approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website.

Data availability

The clinical data collected for this study are maintained by authors and may be shared upon reasonable request.

Acknowledgments

We thank all the patients who participated in this study. We are also grateful to the medical staff of the Department of Medical Technology, the Department of Nursing, the Department of Pharmacy, and LSI Medience Corporation for their invaluable support during allo-HSCT. The manuscript was edited and proofread by Editage ( https://www.editage.jp/ ).

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Associated Data

Data Availability Statement

The clinical data collected for this study are maintained by authors and may be shared upon reasonable request.