Return to Work After Hematopoietic Stem Cell Transplantation: A Longitudinal Analysis of Fatigue and Organ-Specific Chronic Graft-versus-Host Disease.

Introduction

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with hematological malignancies, and advances in transplantation techniques have markedly increased the number of long-term survivors 1 . As survival rates continue to improve, attention in nursing and survivorship care has shifted toward long-term functional outcomes and quality of life among HSCT survivors 2 . Return to work (RTW) is widely recognized as a key indicator of comprehensive rehabilitation, reflecting not only physical recovery but also psychosocial well-being, financial independence, and societal reintegration 3 . Beyond its economic benefits, RTW represents a critical step in “ returning to normalcy", strengthening survivors' self-identity, and serving as concrete evidence of recovery 3 .

Despite these benefits, employment remains a substantial challenge across the post-transplant trajectory. Previous studies have demonstrated that only 62.4% of survivors were employed one year post-transplant 4 , and up to 23% remained unemployed even after five years 5 . Importantly, these employment challenges are not confined to adult HSCT recipients; individuals who undergo transplantation during childhood or adolescence continue to experience vocational disadvantages well into adult life 6 , 7 . These findings highlight that the gap between clinical cure and functional recovery persists long after hospital discharge, driven by multifaceted barriers including treatment-related sequelae and persistent symptom burdens.

Among late effects after HSCT, fatigue is one of the most prevalent and persistent symptoms and is consistently identified as highly burdensome 8 . Fatigue compromises both cognitive and physical functioning essential for sustained employment 9 , and has been consistently associated with delayed or unsuccessful RTW during the first post-transplant year 4 , 5 . Chronic graft-versus-host disease (cGvHD) represents another complex barrier to vocational reintegration 10 - 13 . However, most prior studies have treated cGvHD simply as a binary variable (present vs. absent) 11 , 12 , overlooking the heterogeneity of its organ-specific manifestations. Crucially, binary classifications fail to capture the distinct functional impairments imposed by different organs. This limitation underscores the need for research that evaluates individual organ involvement to guide more precise, symptom-tailored survivorship interventions.

Existing evidence on treatment-related predictors of RTW remains inconsistent, making it difficult to accurately stratify risk of RTW outcomes and guide follow-up care. With respect to transplant modality, Morrison et al. (2016) did not identify HSCT type as a significant determinant of employment outcomes 4 , whereas Kurosawa et al. (2023) reported that transplant type significantly predicted RTW 12 . Similarly, Winterling et al. (2018) observed no significant association between total body irradiation (TBI) exposure and RTW 7 , while Bhatt et al. (2021) observed poorer employment outcomes among recipients of myeloablative conditioning that included TBI 14 . Such inconsistencies likely reflect heterogeneity in study populations and methodologies. This emphasizes the critical need for longitudinal approaches that do not view treatment factors in isolation but integrate them with dynamic, symptom-level predictors to better understand the complex survivorship trajectory.

Most existing research is constrained by cross-sectional designs that provide only a static snapshot of employment status. Such designs fail to capture the dynamic trajectory of RTW, overlooking critical patterns such as delayed workforce entry, recurrent sick leave, or later involuntary withdrawal from employment 5 , 7 , 12 . Moreover, few studies have evaluated the effects of organ-specific cGvHD 10 , leaving gaps in understanding how distinct symptom presentation differentially impede vocational functioning. To address these gaps, this study employed a retrospective longitudinal design to quantify the probability and timing of RTW, thereby accounting for variations in follow-up time and reflecting the dynamic nature of work resumption. We further evaluated the impact of symptom burden—specifically fatigue and organ-specific cGvHD—alongside treatment factors, to identify modifiable predictors of vocational recovery.

Materials and Methods

Study design and setting

This retrospective longitudinal cohort study investigated factors associated with RTW among adult HSCT recipients. The study was conducted at a tertiary comprehensive cancer center in Taiwan, which performs an average of 2–3 HSCT procedures per month. Data were collected from patients treated between January 1, 2016, and December 31, 2021. To allow for an adequate evaluation of long-term vocational outcomes and survivorship trajectories, patients were followed for a minimum of 12 months post-transplant. The study design and reporting adhered to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

Participants

Eligible criteria included: (1) age ≥ 18 years; (2) receipt of HSCT during the study period; (3) history of paid employment prior to cancer diagnosis; and (4) survival with ≥ 12 months of follow-up after hospital discharge. Patients with incomplete demographic or clinical data were excluded. All consecutive eligible HSCT recipients were included to minimize selection bias and enhance representativeness. The final analytical cohort consisted of 2,334 longitudinal nursing assessment records derived from 80 HSCT recipients. During the follow-up period, 8 patients (10.0%) experienced disease relapse, and 6 patients (7.5%) died from treatment-related or disease-related complications; however, all longitudinal assessments prior to these events were included in the time-dependent analysis to maximize data utility. This extensive dataset allowed for a granular, time-dependent analysis of symptom trajectories and vocational outcomes.

Data source and variables

Data were extracted from institutional medical records and transplant follow-up databases, including routinely documented clinical assessments performed as part of survivorship care. Baseline variables were collected at the time of transplantation and included sociodemographic characteristics (age, sex, and educational attainment) and clinical variables, specifically primary diagnosis, conditioning regimen (stratified by anti-thymocyte globulin [ATG] or TBI), and HSCT type (autologous vs. allogeneic).

Time-varying variables were assessed at each follow-up visit to capture changes in clinical status over time. These included: (1) time since HSCT, measured in days post-transplant; (2) fatigue, which was assessed as part of routine clinical follow-up and reflects patients' functional status in survivorship care. Fatigue intensity was evaluated using a standard 0–10 Numeric Rating Scale; (3) organ-specific cGvHD manifestations, which were analyzed to capture the functional heterogeneity of cGvHD and its potential impact on vocational outcomes. Organ involvement was assessed for the skin, oral cavity, eyes, gastrointestinal tract, lungs, and joints/fascia; and (4) hepatic cGvHD, which was evaluated based on established clinical thresholds of serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels; (5) disease relapse status, which was monitored as a time-dependent covariate to adjust for its impact on vocational reintegration; and (6) a history of acute graft-versus-host disease (aGvHD), identified through longitudinal nursing records as documented episodes of aGvHD involving the skin, gastrointestinal tract, or liver.

RTW status was determined through routine nursing inquiries regarding employment status and was documented during follow-up visits as part of survivorship care.

Outcome measures

The primary outcome was time to RTW, defined as the interval from the date of HSCT to the first resumption of any form of paid employment. The probability and timing of RTW were estimated at key milestones (6, 12, and 24 months) using the Kaplan-Meier method. To account for varying follow-up durations, the incidence rate was calculated and expressed as the number of RTW events per 100 person-years of observation.

Statistical analyses

Descriptive statistics were used to summarize sociodemographic and clinical characteristics. As the Shapiro-Wilk test confirmed the non-normal distribution of the data, continuous variables were reported as medians with interquartile ranges (IQR), while categorical variables were presented as frequencies and percentages.

The probability of RTW over time was estimated using the Kaplan–Meier method, and the log-rank test was used to compare RTW probabilities between groups. To provide a clearer understanding of the data density, risk tables showing the number of patients at risk were included with the Kaplan–Meier curves.

Multivariable time-dependent Cox proportional hazards regression models were constructed to identify predictors of RTW. To minimize bias and adjust for potential confounders, variables such as age, sex, conditioning regimen, and disease relapse status were included in the models. To leverage the longitudinal nature of the dataset (2,334 assessments), time-varying variables—including fatigue and cGvHD status—were incorporated to capture their dynamic impact on vocational outcomes. For analysis, fatigue level was dichotomized according to the NCCN guideline definition, with scores of 4 or higher (≥ 4) considered high fatigue 15 .

Two separate models were developed: Model 1 (Entire Cohort) included all HSCT recipients to assess the impact of sociodemographic factors, clinical characteristics, and fatigue levels. Model 2 (Allogeneic Subgroup) was restricted to allogeneic HSCT recipients to evaluate the impact of organ-specific cGvHD involvement, while adjusting for other sociodemographic and clinical variables, including disease relapse status and history of aGvHD. For both models, the proportional hazards assumption was verified using Schoenfeld residuals to ensure the validity of the Cox regression.

Results were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) derived from the multivariable models. A two-tailed p < 0.05 was considered statistically significant. All analyses were conducted using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY, USA).

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Koo Foundation Sun Yat-Sen Cancer Center (Approval No. 20230518A). The requirement for informed consent was waived because of the retrospective nature of the study and the use of de-identified data.

Results

Participant characteristics and data structure

The analytic cohort comprised 80 HSCT recipients. After excluding ineligible patients ( Figure 1 ), the final dataset comprised 2,334 longitudinal nursing assessment records. The median follow-up duration was 507 days (IQR 224–797), ranging from 8 to 1,505 days. During the study period, 8 patients (10.0%) experienced disease relapse, and 6 patients (7.5%) died.

The median age of participants was 53.5 years (IQR 46.8–58.2). The majority were male (62.5%) and had a college or higher level of education (50.0%). Clinically, half of the cohort was diagnosed with lymphoma (50.0%), followed by leukemia (26.3%). Slightly more than half (52.5%) underwent autologous HSCT, while 48.5% received allogeneic HSCT. Conditioning regimens containing ATG and TBI were used in 7.5% and 8.8% of patients, respectively ( Table 1 ).

Incidence and incidence rate of return to work

During the follow-up period, 44 survivors (55.0%) successfully returned to work. The overall RTW incidence rate was 37.8 events per 100 person-years. The median time to first RTW was 312.5 days (IQR 144.0–567.2, range: 8–1,224 days). Based on Kaplan-Meier estimates, the probability of RTW for the entire cohort was 17.8% at 6 months, 34.1% at 12 months, and 53.3% at 24 months post-transplant, reaching an estimated 74.3% by the end of the follow-up period ( Table 2 and Figure 2 ).

Stratified by transplant type, autologous HSCT recipients had a relatively higher probability at 24 months (54.2% vs. 52.8%) and a faster rate of return (41.73 vs. 34.05 per 100 person-years) than allogeneic recipients ( Table 2 ), although the difference in the overall trajectory did not reach statistical significance (log-rank p =0.49). The Kaplan-Meier curves with the associated risk table illustrate the RTW trajectories between the two groups ( Figure 3 ), where autologous recipients appeared to achieve earlier vocational reintegration during the first year, though this trend was not sustained over the longer follow-up period.

Predictors of RTW in the entire cohort (Model 1)

After adjusting for sociodemographic and clinical characteristics, allogeneic HSCT was associated with a significantly lower likelihood of RTW (HR=0.17, 95% CI: 0.10–0.28, p < 0.001). Higher fatigue intensity (score ≥ 4) was also significantly associated with a lower likelihood of RTW (HR=0.67, 95% CI: 0.47–0.96, p =0.029).

Among the control variables, male sex (HR=3.87, p < 0.001), younger age (HR=0.95, p < 0.001), and a diagnosis of leukemia (HR=1.48, p =0.046) were significantly associated with a higher likelihood of RTW. Conversely, lymphoma (HR=0.49, p =0.010) and lower educational attainment (HR=0.57, p =0.022) were associated with delayed vocational recovery ( Table 3 ).

Impact of cGvHD and fatigue in allogeneic recipients (Model 2)

Among allogeneic HSCT recipients, organ-specific manifestations of cGvHD demonstrated differential associations with RTW. Involvement of joints/fascia (HR=0.39, 95% CI: 0.21–0.73, p =0.003) was significantly associated with delayed RTW. Although lung involvement showed a similar trend toward delayed RTW, it did not reach statistical significance after multivariable adjustment in this model (HR=0.44, 95% CI: 0.17–1.12, p =0.084). In contrast, oral (HR=1.67, 95% CI: 1.13–2.45, p =0.010) involvement was associated with a higher likelihood of RTW. After inclusion of organ-specific cGvHD variables, fatigue was no longer significantly associated with RTW ( p =0.287). Male sex (HR=3.40, p < 0.001) and younger age (HR=0.95, p < 0.001) remained significant predictors, while disease relapse (HR=0.34, p =0.100) and history of aGVHD (HR=0.74, p =0.460) did not show significant associations in this specific subgroup ( Table 4 ).

Discussion

This study provides longitudinal evidence that return to work after HSCT is not solely determined by treatment intensity or transplant type, but is largely influenced by functional symptom burden, particularly joint/fascia manifestations of cGvHD. While pulmonary involvement also showed a clinical trend toward delayed RTW, its statistical impact was less pronounced in our cohort after multivariable adjustment. By examining organ-specific cGvHD involvement over time, our findings extend prior work that treated cGvHD as a binary exposure and highlight the importance of organ-specific assessment in survivorship care.

In our cohort, 55% of HSCT survivors returned to work, with a median time to first RTW of 312.5 days (IQR 144.0–567.2) and an incidence rate of 37.8 events per 100 person-years. These findings reflect the gradual and heterogeneous recovery trajectory. Kaplan–Meier estimates indicated that the probability of RTW reached 74.3% by the end of follow-up, indicating that while initial reintegration is slow, a substantial proportion of survivors eventually resume employment over an extended period. This recovery timeline appears slower compared to U.S. cohorts, where 60–70% of survivors typically resume employment within one to two years 4 , 14 . Taken together, recovery in our cohort appears to proceed more slowly, potentially reflecting differences in transplant composition, symptom burden, and work-related cultural contexts.

Furthermore, when compared with other cancer populations in Taiwan, RTW among HSCT survivors appears to be delayed. Our findings show that only 34.1% of HSCT survivors returned to work within one year post-transplant, although the cumulative probability of RTW increased to 74.3% during extended follow-up. Previous studies have reported that approximately 70% of general cancer survivors returned to work within one year after diagnosis or treatment 16 , whereas 82.3% of cervical cancer survivors resumed employment within five years after diagnosis 17 . Collectively, these findings suggest that vocational recovery after HSCT is often prolonged and may require a longer recovery period than that observed in other cancer populations. The persistent symptom burden following transplantation may contribute to delayed work reintegration among HSCT survivors.

Regarding clinical factors, allogeneic transplantation emerged as a strong negative predictor of RTW. While Morrison et al. (2016) did not identify HSCT type as a significant determinant in a cross-sectional analysis 4 , our longitudinal findings highlight the time-dependent nature of this vocational gap. Clinically, work recovery is notably slower among allogeneic survivors—showing a slower rate of reintegration compared with autologous recipients, particularly during the first two years post-transplant. Notably, while disease relapse did not significantly impact the entire cohort, its influence appeared more pronounced among allogeneic recipients (HR=0.34, p =0.100), suggesting that the threat of relapse may represent a more direct barrier to work resumption in this subgroup, even if statistical significance was not reached due to the limited sample size. This prolonged trajectory is attributed to sustained immunosuppression, psychosocial distress, and, most critically, the burden of cGvHD 18 , necessitating a deeper examination of how specific symptoms impede recovery.

High levels of fatigue (score ≥ 4) were identified as a significant negative predictor of RTW in our entire cohort (Model 1), consistent with previous findings that fatigue is a significant barrier to RTW following HSCT 4 . However, a key finding of this study is that when organ-specific cGvHD symptoms were included in the allogeneic subgroup model, the independent effect of fatigue was no longer significant ( p =0.287). This likely reflects overlapping pathophysiology, as cGvHD often manifests with musculoskeletal pain, fascial stiffness, or pulmonary involvement—symptoms that exacerbate fatigue and functional limitation 19 , 20 . Our results suggest that specific physical impairments, particularly joints and fascia, may be the primary driver of physical impairment, thereby “ masking" the effect of general fatigue. While fatigue is a pervasive subjective experience, the structural and mechanical limitations imposed by fascial and joint cGvHD represent more direct barriers to the physical demands of employment. This emphasizes that managing the underlying cGvHD is essential to alleviating the symptom burden that hinders work reintegration.

We found that cGvHD symptoms involving the joints and fascia were significantly associated with lower RTW rates, while lung involvement showed a similar clinical trend. This aligns with Kurosawa et al. (2023), who identified respiratory and musculoskeletal issues as key determinants of sick leave and prolonged unemployment 12 . Possible explanations include that these objective functional limitations may be underreported or misinterpreted by patients as general fatigue. This further explains why organ-specific symptoms “ masked" the effect of fatigue in our multivariable model.

In contrast, oral manifestations of cGvHD in our cohort were associated with a higher likelihood of RTW. This finding differs from prior research, such as Eriksson et al. (2023), which linked overall symptom burden—particularly eating difficulties and appetite loss—to full-time sick leave. One plausible explanation is that oral symptoms, being among the earliest and most visible manifestations of cGvHD, are more likely to be promptly detected and proactively managed. Furthermore, oral involvements, unless severe, may pose fewer direct mechanical barriers to physical labor compared to musculoskeletal constraints. As a result, timely recognition and intervention, coupled with a lower impact on physical mobility, may help preserve the capacity necessary for sustained employment.

Strengths and limitations

One major strength of this study is the availability of extensive longitudinal follow-up data, which enabled a comprehensive analysis of RTW trajectories among HSCT survivors. The longitudinal design allowed for detailed evaluation of both the timing and dynamics of RTW, providing a more thorough understanding than what cross-sectional studies can offer. Another key strength is the use of standardized nurse-assessed symptom records. Unlike studies relying solely on patient self-reports, our approach minimizes recall bias and provides a rigorous clinical basis for evaluating functional barriers. Importantly, this study is among the first to specifically examine the impact of organ-specific cGvHD symptoms on RTW, thereby laying the groundwork for more targeted survivorship interventions. Additionally, the use of incidence rates and Kaplan-Meier estimates provided a standardized approach to capture RTW events across variable follow-up durations, offering a dynamic perspective that enhances comparability across clinical settings.

However, several limitations should be acknowledged. First, the relatively small sample size of the allogeneic subgroup (n=38) may have limited the statistical power to detect significant associations for certain variables, such as pulmonary involvement ( p =0.084), which showed a clinical trend toward delayed RTW but did not reach statistical significance. Second, the absence of National Institutes of Health (NIH)–defined cGvHD severity grading precluded the evaluation of global severity scores combining organ involvement numbers. Third, the lack of multidimensional fatigue assessment tools and psychological measures—such as depression, anxiety, or coping capacity—may have limited our ability to fully characterize their influence on work outcomes. Furthermore, the absence of detailed information on pre-HSCT employment characteristics, such as job intensity (full-time vs. part-time) and physical demands (manual labor vs. desk jobs), restricted our ability to analyze how different occupational requirements moderate the impact of cGvHD symptoms. In addition, although educational attainment was included, other socioeconomic factors, such as employer support, income, and family support, were not available for analysis. Collectively, these limitations suggest that RTW is influenced by complex, multidimensional factors—including disease severity, symptom burden, psychological status, and occupational context—that were not fully captured in this study.

Future research should adopt prospective, multicenter designs to incorporate more comprehensive assessments of cGvHD severity, psychological status, and workplace environmental factors, thereby enabling a more precise evaluation of their influence on employment outcomes. Such efforts will be critical to enhancing the generalizability of these findings and informing the development of tailored survivorship interventions to promote vocational recovery after HSCT.

Implications for practice

Based on these findings, a proactive and targeted clinical approach may support vocational recovery after HSCT. Given the substantial functional impact of musculoskeletal involvement, survivorship care may benefit from rigorous surveillance informed by established clinical frameworks. Specifically, early physical therapy referrals and regular joint range-of-motion assessments, alongside pulmonary function testing 21 , can facilitate early detection and timely management, thereby helping to preserve work-related physical capacity.

Furthermore, systematic organ-specific functional assessment is crucial, as recommended by the NIH Consensus Development Project on cGvHD 22 . Since nurse-led clinical assessments can identify subtle fascial or joint restrictions before they result in profound disability, integrating these evaluations into routine nursing workflows is essential. Emerging digital health tools, such as app-based monitoring systems, can enhance real-time observation of graft-versus-host manifestations and facilitate earlier intervention 23 .

Finally, integrated, multidisciplinary symptom management programs—including intensive physical and occupational therapy, pulmonary rehabilitation, oral care, and fatigue management—may play an important role in promoting functional recovery and facilitating vocational reintegration within survivorship care pathways 18 .

Conclusion

In conclusion, this longitudinal study demonstrated that more than half of HSCT survivors returned to work, with a median time to RTW of 312.5 days and Kaplan–Meier–estimated probability of 74.3% at extended follow-up. These reflect a gradual and heterogeneous recovery trajectory after transplantation, providing a clinically relevant benchmark for evaluating interventions. Allogeneic transplantation emerged as a strong negative predictor of RTW, highlighting the importance of early vocational counseling and individualized survivorship planning.

Moreover, organ-specific manifestations of cGvHD exerted distinct effects on employment outcomes: involvement of the joints and fascia significantly hindered recovery, whereas pulmonary involvement showed a similar restrictive trend. These results underscore the need for systematic, nurse-led clinical assessments to identify specific functional barriers and implement targeted rehabilitation strategies to facilitate successful work reintegration.

Conflicts of Interest

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

Author Contributions

MKC designed the study, analyzed and interpreted the data, conducted the statistical analyses, and drafted the manuscript. YMH contributed to data collection, result interpretation, and manuscript revision. AMA contributed to data management, statistical analysis, methodology refinement, and interpretation of results. TDT and LWC contributed to data collection and manuscript revision. All authors reviewed and approved the final manuscript.

Disclosure of AI Use

Artificial intelligence tools were used exclusively for language polishing and sentence-level editing. The study design, data analysis, interpretation, and conclusions were developed entirely by the authors.

The authors thank the HSCT Functional Group at Koo Foundation Sun Yat-Sen Cancer Center for their support. Special appreciation is extended to Professor Shang-Liang Wu for data management and to Dr. Deborah Ng, Patrick Ng, and Professor Lih-Mih Chen for their critical reviews of the manuscript.

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