Health-Related Quality of Life Outcomes in Older Hematopoietic Cell Transplant Survivors

Abstract

Background:

Hematopoietic cell transplantation (HCT) use for older patients has been increasing. Distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors is largely unknown.

Methods:

In this secondary analysis using data from two randomized controlled trials, we analyzed baseline cancer and treatment distress (CTXD) and confidence in survivorship information (CSI) surveys of survivors who were ≥60 years at transplant and alive and disease-free ≥1 year post-autologous or allogeneic HCT. We analyzed associations of these parameters with physical and mental component summary (PCS/MCS) scores of SF-12 and healthcare adherence (HCA) scale, after adjusting for transplant and demographic factors.

Results:

A total of 567 patients were included. Median age at HCT was 65 years, 68% received autologous HCT. Median CTXD score was mild at 0.7, and the highest distress was reported in the “Health Burden” subscale. Median CSI score was moderate-high at 1.4, with the lowest confidence reported in the “Late Effects” subscale. We found a negative Spearman correlation between CTXD and PCS (p= −0.59)/MCS (p= −0.54) and positive Spearman correlation between CSI and PCS (p= 0.23)/MCS (p= 0.30). Median HCA was high at 0.8. Male sex, autologous HCT, increased distress level, and worse CSI were associated with lower use of preventive care.

Conclusion:

Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

INTRODUCTION

Advances in HCT practices over the past 2 decades, particularly the introduction of reduced-intensity conditioning regimens and the improvement in palliative/supportive care services, have resulted in HCT becoming better tolerated in older (≥60 years) patients who were previously excluded from transplant consideration. Consequently, the upper age limit for patients undergoing HCT has expanded.¹ In 2016, 30% of allogeneic HCT recipients were older than 60 years with an increasing trend in the number of HCTs done for patients over the age of 70. Moreover, as autologous HCTs tend to require less strict upper age limit than allogeneic HCTs, substantial increase in the number of autologous HCTs over the last decade has contributed to overall increase in the age at HCT. The trend of an increasing number of older HCT recipients is expected to continue, with the projected number of HCT survivors ≥60 years exceeding 100,000 by 2030.² Recently, instead of using a numerical age limit, overall fitness for HCT has become the parameter to determine transplant candidacy.^3–5 Organ-specific late complications of HCT increase over time and active surveillance and engagement in promoting a healthy lifestyle are strongly recommended for all HCT survivors.⁶ As older HCT recipients now constitute a considerable proportion of long-term survivors, they need a unique approach to their long-term care.

Recent studies, mostly from solid tumor oncology, have reported an association between older age and lower distress scores compared to younger counterparts.^7–9 However, older patients have unique vulnerabilities likely predisposing them to different patterns of psychosocial challenges, anxiety, and depression, with up to 40% of older cancer patients reporting significant distress during their treatment course.¹⁰ Proposed explanations for such vulnerabilities include an increased need for assistance in activities of daily living, social isolation, and increased risks for treatment-related short- and long-term toxicities in older patients due to age-related decline in physiologic reserve.^11–14

Despite the marked increase in numbers of older patients undergoing HCT over the past decade, the impact of HCT on distress, psychosocial functioning, and health-related quality of life (HRQOL) in older survivors remains largely unknown. Syrjala et al. recently published the outcomes of an Internet-based Survivorship Program with Information and Resources (INSPIRE) with or without Problem-Solving Treatment (PST) telehealth calls, randomized controlled trial (RCT) that examined the efficacy of an innovative internet/telehealth-based approach to evaluate and follow distress, depression, and fatigue in over 1,300 HCT survivors.¹⁵ Surprisingly, for survivors aged ≥40 compared to <40 years, distress was more likely to be improved with study interventions compared to controls. Furthermore, the researchers reported significant interactions for distress outcomes between age and each intervention arm indicating greater effectiveness in patients ≥40 rather than <40 years ¹⁴. Moreover, in yet another recent multicenter RCT of individualized survivorship care plans (SCP), Majhail et al. reported an independent association between older age and lower Cancer and Treatment Distress (CTXD) scores and higher HRQOL mental component summary (MCS) scores.^15,16 However, data on distress and patient-reported health status in older adult transplant survivors are still limited and require further investigation.^17–21 Furthermore, confidence in survivorship information (CSI) in this unique group has not been clearly investigated in the past. Better understanding of the risk factors for distress and CSI and the types of distress experienced can identify individuals who may benefit from interventions to improve the long-term care for this population. Additionally, routine healthcare adherence (HCA) to recommended preventive care and cancer screening is an important surrogate outcome and the correlation between HRQOL and HCA has not been largely studied in HCT survivors. In this study, we investigated the distress and CSI of HCT survivors who were 60 years or older at time of transplantation and analyzed the correlation with HRQOL and HCA in this population.

STUDY METHODS

Study Design/Methods

This cross-sectional retrospective secondary analysis used baseline data from two randomized controlled trials of survivorship interventions in HCT recipients that enrolled patients in survivorship care plan [SCP] trial [NCT00799461] and INSPIRE [NCT01602211] trials in the United States.^15,16,22 Briefly, the SCP trial assessed the impact of individualized SCPs in terms of changes in patient-reported outcomes of HCT adult survivors who were 1–5 years post-transplant. And the INSPIRE trial tested an internet- and social media-based trial to address the medical and psychosocial needs of transplant survivors who were 2–10 years post-transplant. The protocols were approved at the Institutional Review Boards for all enrolling transplant centers. The study was reviewed and approved by the Institutional Review Board of the University of Florida where the statistical analyses were conducted as well as the sites where the studies were conducted for the parent randomized controlled trials.

Patients/Inclusion Criteria

From a combined dataset of the two clinical trials, we selected patients who were ≥60 years at the time of HCT performed in 2003–2014, who survived ≥1-year post-transplant with no evidence of disease relapse/progression or secondary cancers. An age cutoff of 60 was chosen for inclusion criteria for these analyses in accordance with several studies on older adults using that age cutoff to denote “older” HCT recipients.^17–19 All transplant types, diagnoses, donor sources, graft types, and conditioning regimens were included

Study Measures

Baseline distress level, as measured by CTXD overall mean score (higher score reflects worse distress),²³ HRQOL (measured by SF-12 Mental and Physical Component Summaries [PCS/MCS]),²⁴ and CSI (measured by a 15-item CSI questionnaire)^16,25 were collected for the subgroup of patients included in this analysis. CTXD scale included 22 questions in which responses were none (0) to severe (3) distress and the mean score >1.1 was confirmed as significant distress.²⁶ Of note, these tools used in the parent trials (INSPIRE and SCP) are validated and often used to evaluate outcomes in HCT recipients.^16,25

The HCA is a widely pretested measure of recommended screening and preventive evaluations.^15,16,27 The HCA summary score ranges from 0 to 1, indicating the proportion of tests or exams completed in the timeframe recommended for 17 preventive services and cancer screenings. A higher HCA score indicates more up-to-date HCA.

Sociodemographic variables were collected as a part of baseline surveys. Disease and transplant factors were extracted from clinical trial datasets.

Statistical Analyses

Clinical and sociodemographic variables were summarized in descriptive statistics. Anderson-Darling test was used to check the normality assumption of continuous variables. Non-parametric tests (i.e., Wilcoxon rank-sum test and Kruskal-Wallis test) were used for comparing continuous variables across groups. Fisher exact test was used for comparing categorical variables across groups. The relationship between chronic graft-versus-host disease (cGVHD) and CTXD and CSI was assessed in allogeneic HCTs only.

Spearman correlation was used to evaluate the relationship between CTXD scores, CSI summary scores, PCS and MCS scores. Multivariable linear regression was built for outcome HCA. Clinical covariates considered were sex, age at transplant by groups (<65, 65 - <70, vs. ≥70 years), transplant types (autologous vs. allogeneic), time from transplant to baseline survey (1 - ≤2 vs. >2 years), PCS, MCS, CTXD summary score and CSI summary score. Multivariable linear regressions were built for CTXD and CSI summary scores, respectively. Clinical covariates considered were sex, age at transplant, transplant types, time from transplant to baseline survey, PCS, and MCS. Similarly, multivariable linear regressions were built for all CTXD and CSI subscales. Clinical covariates considered were sex, age at transplant, transplant types, and time from transplant to the baseline survey. Final multivariable models were selected by Akaike information criterion (AIC) through a stepwise selection procedure. Given differences in autologous and allogeneic HCTs and their survivorship, we performed a subgroup analysis for allogeneic HCT survivors in CTXD and CSI analyses. P<0.05 was considered statistically significant, and all analyses were two-sided. Analyses were performed using R (version 3.6.0).

RESULTS

Patient Characteristics

A total of 567 patients satisfied the eligibility criteria and were included in this analysis. Baseline CTXD, CSI, SF-12, and HCA results were available on >95% of cases. The median age at the time of survey was 65 years with slight male predominance (57%; Table 1). Almost two-thirds of the HCT survivors in this analysis were autologous HCT recipients. This was the first HCT for 96% of survivors. Median age at survey was slightly higher in autologous HCT (69.7, range 67.1–73.0) than in allogeneic HCT (68.3, range 66.0–71.4, p< 0.001), and more Non-White participants had undergone autologous HCT (8%) than allogeneic HCT (2.8%, p= 0.016).

Table 1.

Survivor Characteristics (N=567)

Age at HCT, years; median (range)	65.0 (60.0–81.1)
60 to <65	281 (50%)
65 to <70	195 (34%)
≥70	91 (16%)
Age at survey, years; median (range)	69.1 (61.0 – 84.5)
60 to <65	50 (9%)
65 to <70	256 (45%)
≥70	261 (46%)
Gender; N (%)
Male	323 (57%)
Female	244 (43%)
Race; N (%)
White	531 (94%)
Non-White	36 (6%)
Ethnicity, Hispanic or Latino; N (%)	12 (2%)
Diagnosis; N (%)
Multiple myeloma	202 (36%)
NHL	191 (34%)
AML	92 (16%)
MDS/MPN	46 (8%)
ALL	14 (2%)
Other	22 (4%)
Years post HCT; Median (range)	4 (1 – 11)
Transplant Type; N (%)
Allogeneic	181 (32%)
Autologous	386 (68%)
Donor Source; N (%)
Autologous	386 (68%)
Unrelated donor	118 (21%)
HLA identical sibling	55 (10%)
HLA mismatched/ other relative	5 (1%)
Missing	3 (<1%)
Graft Type; N (%)
Peripheral blood	545 (96%)
Bone marrow	14 (3%)
Umbilical cord blood	8 (1%)
Conditioning Regimen Intensity; N (%)
Myeloablative	341 (60%)
Non-myeloablative/RIC	85 (15%)
Missing	141 (25%)
TBI as part of conditioning regimen; N (%)	70 (12%)
Hx of cGVHD; N (%)	147 (81% of 181)

ALL = acute lymphoid leukemia; AML= acute myeloid leukemia; cGVHD = chronic graft-versus-host disease; HCT = hematopoietic cell transplantation; HLA = human leukocyte antigen; MDS = myelodysplastic syndrome; MPN = myeloproliferative neoplasm; NHL = non-Hodgkin lymphoma; RIC = reduced intensity conditioning; TBI = total body irradiation

Cancer and Treatment Distress

The median CTXD score for older HCT survivors was 0.7 (range 0–2.7, IQR 0.4–1.2) indicating a low and clinically insignificant level of distress post-HCT. Transplant type (p= 0.297) and age at HCT (<65 vs. 65-<70 vs. ≥70) was not associated with the mean CTXD score from univariable models and years from HCT (>2 vs. ≤2) was not associated with mean CTXD score (p= 0.127) from a multivariable analysis.

When CTXD subscales were analyzed in this cohort, the mean distress level in the “Health Burden” subscale was high (>1.1), compared to low (≤1.1) in all other subscales (Figure 1). Advanced age at HCT was associated with lower distress level in “Finances” (overall p= 0.016; ≥70 vs. <65 Coefficient [C]= −0.19, p= 0.030; 65 - <70 vs. <65 C= −0.17, p= 0.014) and “Identity” (overall p= 0.043; ≥70 vs. <65 C= −0.18, p= 0.018) subscales. The multivariable model showed that female sex was associated with higher distress in the “Uncertainty” subscale compared to male sex (p= 0.014), whereas there was no significant association between increasing age at HCT and worse distress in any other subscale. None of the subscales were different based on transplant type (autologous vs. allogeneic). Analyses of responses to individual CTXD questions showed that 20–30% of older HCT survivors reported moderate distress when asked about concerns regarding relapse risk, loss of energy, and functional decline.

Figure 1.

Cancer and Treatment Distress of Older Transplant Survivors

Error bars indicate SD.

A separate subgroup analysis of allogeneic HCT survivors only revealed mean CTXD overall score (0.85, SD 0.44) and subscale score similar to the overall analysis, with their highest distress reported in “low energy” (mean 1.42, SD 0,87) followed by “feeling tired and worn out” (mean 1.32, SD 0.93).

Confidence in Survivorship Information

The median summary CSI score was 1.4 (range 0–2, IQR 1.1–1.7) which reflects a moderate/high level of confidence. The summary score was consistent with the median score across all age groups reported by the original trial,¹⁶ indicating that older adult HCT survivors expressed similar levels of CSI as their younger counterparts. No significant association was identified between CSI in older survivors and transplant type (p= 0.104) or age at HCT (age <65, 65-<70, vs. ≥70; p= 0.066). Moreover, the presence or history of cGVHD was not associated with reported confidence levels among allogeneic HCT survivors. Reviewing the CSI subscales, we observed that items relating to details on disease and treatment (“Past details”) scored the highest in confidence level (Figure 2). On the other hand, reviewing the individual questions, close to 20% of the HCT survivors reported low CSI when asked about strategies for prevention and treatment of long-term effects of HCT and when asked about their confidence in the availability of community resources to deal with long-term HCT complications.

Figure 2.

Confidence in Survivorship Information of Older Transplant Survivors

Error bars indicate SD.

In a subgroup analysis including allogeneic HCT survivors, overall mean score was also 1.4 (SD 0.44) with the subscale “Past details” scoring the highest in the confidence level as well.

Health-related Quality of Life

The median PCS of this cohort was 48.2 (range 21.1– 62.9, IQR 39.0 –55.5) and a median MCS of 54.7 (range 14.9 – 67.2, IQR 47.1–59.2), similar to disability reported in the general U.S. population. Figure 3 illustrates a negative Spearman correlation between CTXD and PCS (ρ= −0.59)/ MCS (ρ= −0.54) and positive Spearman correlation between CSI and PCS (ρ= 0.23)/ MCS (ρ= 0.30).

Figure 3.

Correlation Plot of Distress and Confidence with Health-related Quality-of-Life

CSI = confidence in survivorship information; CTXD = cancer and treatment distress; MCS = mental component summary score of SF-12; PCS = physical component summary score of SF-12.

Healthcare Adherence

The mean HCA summary score was high at 0.8 (SD 0.1) for this cohort indicative of adequate up-to-date utilization of preventative and cancer screening healthcare services. The multivariable regression model (Table 2) showed that HCA was significantly lower in males compared to females (p= 0.002), and autologous HCT was associated with significantly lower HCA compared to allogeneic HCT (p= 0.034). Moreover, an increasing mean CTXD score (reflecting an increasing distress level) is associated with significantly lower HCA (p= 0.013), whereas an increasing mean CSI score (reflecting higher confidence) was associated with a statistically significant increase in HCA (p= 0.032). Age at HCT, years from HCT, and HRQOL measures had no significant association with HCA.

Table 2.

Multivariable Analysis of Factors associated with Healthcare Adherence by Older Adult HCT Survivors

	Coefficient	95% CI	p-value
Intercept	0.85	0.80 to 0.90
Sex (male vs. female)	−0.04	−0.06 to −0.01	0.002
Autologous vs. allogeneic HCTs	−0.03	−0.05 to 0.00	0.034
Mean CTXD summary score	−0.03	−0.05 to −0.01	0.013
Mean CSI summary score	0.03	0.00 to 0.06	0.032

CI = confidence interval; CSI = confidence in survivorship information; CTXD = cancer and treatment distress; HCT= hematopoietic cell transplantation.

DISCUSSION

To our knowledge, this analysis is the largest to date to investigate patient-reported distress, HRQOL, and CSI in older HCT survivors. Our data indicate that over half of older HCT survivors have low (<1.1) levels of distress after HCT and exhibited high levels of confidence in their knowledge in most aspects of their survivorship care.¹⁶ These findings are similar to those of a previous analysis that found that overall and financial distress of adult transplant survivors 65 years or older were less than younger counterparts, partially due to decreased financial distress with older age at transplant.²⁸ This has been attributed to access to Medicare for all older survivors, whereas younger survivors depend largely on private healthcare insurance in the U.S. While our analysis was limited by lack of information regarding insurance status of survivors, which may have contributed to patients’ financial distress before, during, and after HCT, our study did not demonstrate significant differences in CTXD scores among older adults based on age, while previous studies indicated that better HRQOL was reported with increased age at HCT among older survivors.^19,20 Given the findings of prior studies,^19,29,30 distress of older adults likely stays lower than that of younger adults throughout the post-HCT course possibly due to different social situations and perspectives that survivors experience.

Our analysis of the CTXD subscales indicated that “Health Burden” (i.e., low energy level and late effects) was the most significant area of distress in older HCT survivors while “Uncertainty” (i.e., the possibility of relapse, complications, or death) had a more pronounced effect on females. Stresses in “Finances” (i.e., insurance and cost of treatment) and “Identity” (i.e., changes in appearance, feeling masculine or feminine, sex life) decreased as age at HCT increased and this finding was congruent with that of a previous study.²⁸

Of note, as in Figure 1, low-energy and fatigue stood out as one of the most prevalent symptoms from the CTXD scale raising concern in older HCT survivors as these are more tangible symptoms that can significantly influence survivors’ mood and limit survivors’ functional independence. In previous studies, fatigue was also shown as one of the prevalent persistent symptom for older HCT recipients.¹⁸ Persistent fatigue was associated with decreased exercise capacity and increased risk of depression in HCT survivors.^31,32 Gut microbiota dysbiosis is a common consequence of HCT and was recently found to be associated with fatigue.³³ Studies on the duration and trajectory of fatigue long-term after HCT are lacking and may enhance our understanding of how survivors recover from HCT. It will be important to characterize patient or transplant related factors that are associated with low-energy and fatigue of older transplant survivors in future studies so that specific intervention strategies can be developed.

When discussing distress post HCT, we must pay considerable attention to the long-term physical effects that result from or contribute to it. Our analysis reveals that the baseline CSI level in older HCT survivors was the lowest regarding prevention and treatment of physical long-term effects and community resources for the long-term effects of HCT. This may echo with our finding that “Health Burden” subscale of CTXD scored the highest in the mean distress level. Preussler et al. showed that survivorship guides can be a helpful tool to understand the commended check-up appointments.³⁴ Overall, studies on patient education on long-term effects or survivorship are limited partially because the specific chronic health concerns for older HCT survivors are not well known and it may be difficult to distinguish symptoms due to transplant from those from aging.^35,36 This uncertainty can contribute to a decrease in confidence level in late effects. Moreover, community resources to mitigate long-term effects can differ significantly depending on the patient’s residence. It is speculated that access to the internet and social media to find local information may have an impact on patients’ and caregivers’ ability to obtain online resources and social media recently have become venues for rapid and efficient conversation among patients, providers, and researchers.³⁷ In short, targeted interventions should focus on improving strategies for prevention, treatment, and availability of community resources to deal with long-term effects of HCT, aspects that were reported as points of poor CSI by older HCT survivors in this study. Also, knowledge of these factors and measures in older HCT patients may help guide targeted interventions and/or modification of treatment regimen, timeline, or follow-up to increase healthcare adherence and improve overall outcomes of HCT in older patients.

This study provides evidence that better physical functioning is associated with lower distress and increased CSI in older HCT survivors. Overall, more studies on HRQOL and other patient-reported outcomes in older survivors are needed; however, our study confirmed that findings of CTXD and CSI in older HCT survivors are meaningful and informative in guiding other aspects of care as well.

As seen in the early post-HCT period,¹⁷ transplant and demographic factors were not associated with long-term distress in older survivors. Interestingly, contrary to previous studies showing an association between cGVHD and worse HRQOL as well as distress in older adults,^38,39 our study did not reveal an association between the cGVHD status (resolved vs active) and post HCT distress and CSI older allogeneic HCT survivors. While >80% patients reported a history of cGVHD, it was unclear how many had cGVHD at the time of survey, and this is a limitation of this study.

HCA has been employed in financial analyses of disease processes or procedures but has not been studied well in the post-HCT setting.⁴⁰ In our cohort, older HCT survivors had a high rate (summary score of 0.8) of preventive healthcare service use, indicative of appropriate adherence to HCT-specific guidelines. This summary score was similar to preventive service use by all age groups combined in the original PCORI-SCP trial.¹⁶ Nonetheless, in this study, we uncovered important factors contributing to poorer HCA for preventive care among older HCT long term survivors. Male sex, autologous HCT, increased distress levels, and lower CSI all associated significantly with worse preventive HCA. This finding may be explained by the fact that 2/3 of the patients in our analysis had undergone an autologous HCT, and also partly by the higher rate of reported history of cGVHD (around 80%) in the alloHCT subgroup.⁴⁰ These findings serve as a platform for focused and goal-directed interventions for these groups to improve overall HCT outcomes in older patients.

There are some limitations to this study including the cross-sectional design rather than the longitudinal cohort study which precludes our ability to make causal attributions. Also, our analysis did not include race/ethnicity or diagnosis as co-variables. Further large-scale interrogations comparing different age groups can incorporate insights from the findings from this study and can lay a foundation to developing evidence-based guidelines for survivorship care of older adults.

Overall, this study which is the largest so far demonstrates low/clinically-insignificant level of distress and moderate-high level of CSI in older HCT survivors. Our study provided evidence that better physical and mental functioning are associated with lower distress levels and increased CSI in older HCT survivors. Interrogation about fatigue post-HCT, education on long-term effects, and community resources to mitigate long-term effects may enhance the quality of life of older HCT recipients’ survivorship by improving physical and mental QOL and increasing preventive healthcare adherence. Focused interventions should target these groups to optimize utilization of preventive care which may improve overall HCT outcomes in this unique group of patients.