HCT frailty scale for younger and older adults undergoing allogeneic hematopoietic cell transplantation

The HCT Frailty Scale is an easy prognostic tool composed of (a) Clinical Frailty Scale; (b) Instrumental Activities of Daily Living; (c) Timed-up-and-Go test; (d) Grip Strength; (e) Self-Health Rated Questionnaire; (f) Falls tests; (g) Albumin and C-reactive protein levels. This scale was designed to classify allogeneic hematopoietic cell transplant (alloHCT) candidates into fit, pre-frail and frail groups, irrespective of age. This study evaluates the ability of this frailty classification to predict overall survival (OS) and non-relapse mortality (NRM) in adult patients of all ages, in a prospective sample of 298 patients transplanted between 2018 and 2020. At first consultation, 103 (34.6%) patients were fit, 148 (49.7%) pre-frail, and 47 (15.8%) were frail. The 2-year OS and NRM of the three groups were 82.9%, 67.4%, and 48.3% (P < 0.001), and 5.4%, 19.2%, and 37.7% (P < 0.001). For patients younger than 60 years (n = 174), the 2-year OS and NRM of fit, pre-frail, and frail groups were 88.4%, 69.3% and 53.1% (P = 0.002), and 5.8%, 22.8%, and 34.8% (P = 0.005), respectively; and in patients older than 60 (n = 124), OS and NRM were 75.5%, 63.8% and 41.4% (P = 0.006), and 4.9%, 16.4%, and 42.1% (P = 0.001). In conclusion, frailty predicted worse transplant outcomes in both younger and older adults.


INTRODUCTION
Allogeneic hematopoietic cell transplantation (alloHCT) is a curative strategy for patients with high-risk hematologic disorders [1,2].In recent years, efforts have been made to refine the assessment of patients' fitness before HCT by including frailty evaluations [3][4][5][6].Frailty results from different multisystem deregulations leading to a loss of dynamic homeostasis, decreased physiologic reserve, and to an increased vulnerability when the patient is exposed to a stressor [7,8].This syndrome is prevalent in patients undergoing HCT, and, when present, has been associated with a higher risk for post-transplant morbidity and mortality [9][10][11][12][13][14][15][16][17].
Different methodologies of frailty assessment protocols have been proposed to be implemented in the HCT setting [9][10][11][12][13][14][15][16][17][18].Although these protocols provided relevant information for prognostication and the improvement of transplant outcomes, their application in regular clinical practice has been selective because it required the participation of qualified specialists, and these were time and resources consuming.Moreover, since frailty has been associated more or less explicitly with patients above a certain age, the assessment of this syndrome in patients undergoing HCT has been restricted to older patients, and without a clear and consistent criterion for the cut-off point of patients' age: 50, 60 or 65 years [9][10][11][12][13][14][15][16][17][18].
In this context, a Frailty and Functionality Evaluation for alloHCT candidates was designed and implemented in our program in 2018.The project was designed and executed under the premise that frailty was not a state of fitness relevant only for transplant candidates above a certain age, but a state of fitness relevant for transplant outcomes of patients independent of age.Since the frailty assessment had to be extended to all patients, the evaluation methodology was designed to be implemented in a busy clinic, performed in 5-6 min, and without human and material resources additional to the transplant medical and nursery team [19].Consecutively, the Hematopoietic Cell Transplant (HCT) Frailty Scale was developed to classify alloHCT candidates into one of the three frailty categories: fit, pre-frail, and frail, and to predict transplant outcomes such as overall survival (OS) and non-relapse mortality (NRM) [20].
This study is a step forward in the analysis of the clinical relevance of including an assessment of frailty, using the HCT Frailty Scale, for all candidates for alloHCT.In particular, the research examines the characteristics of fit, pre-frail and frail patients, and the ability of the frailty classification to predict OS and NRM.Moreover, the study investigates if the frailty classification has the same power in predicting transplant outcomes in the subgroups of younger (60 or less) and older adults (older than 60 years).

Patient selection
The present study includes the 298 consecutive adults who underwent alloHCT at our Institution between July 2018 and December 2021.All patients were evaluated for frailty after providing informed consent.The study cohort selected for the conduction of this study integrates into a single sample the totality of patients designated to calibrate and validate the HCT Frailty Scale in a previous investigation conducted by the authors [20].
Eligibility Criteria and HCT information are detailed in Supplementary Material.This study was prospective and observational.The results from the frailty assessment were not used to determine the patient´s eligibility or to design the transplant platform.No patient underwent pre-transplant interventions based on the results provided by the evaluation.Data were updated in March 2022.This study was approved by the Ethics Committee at the Princess Margaret Cancer Centre, Toronto, and conducted following the Declaration of Helsinki.Data deposition will be considered after specific request.

Frailty and functionality evaluation and HCT frailty scale
A Frailty and Functionality Evaluation comprising the following eight variables: Clinical Frailty Score (CFS) [21]; the Instrumental Activities of Daily Living (IADL) test [22]; a Self-Rated Health question (SRH-Q); a question on falls (Falls-test); a grip strength score (GS) [23]; the Timed Up and Go Test (TUGT) [24]; and the measurement of serum albumin and C-reactive protein (CRP) [25,26], was designed in 2018.This new evaluation was designed to be completed in 5-6 min, performed by hematologists, clinical fellows, and non-physician specialists such as nurse transplant coordinators, and implemented in a busy clinic using human resources [19].
After evaluating 298 candidates for alloHCT, the HCT Frailty Scale was designed to classify alloHCT candidates in three levels of frailty (fit, pre-frail, and frail), and to evaluate whether these levels of frailty impact OS [20].As detailed in a previous publication (Fig. 1), respective weights were assigned to each variable based on its statistically estimated contribution to the probability of a worse OS.This contribution was measured by calculating the hazard ratios (HR) using a multivariable Cox regression model, with OS as a dependent variable and the eight frailty-related variables (with values of 0 or 1) as explanatory variables.To facilitate the applicability of the scale, the estimated value of each coefficient provided by the HR was rounded to the closest value of 1 (for variables IADL, GS, SRH-Q, and Falls-Test), 1.5 (for variables CFS, TUGT, and Alb), and 2 (CRP).
Consecutively, the HCT Frailty Scale was designed to classify alloHCT candidates in one of three levels of frailty (fit, pre-frail, frail) depending on the total score resulting from the weighted sum of the scores for each of the eight frailty covariates measured in the Frailty and Functionality Evaluation.The continuous value (ranging from 0 to 10.5) obtained by application of the scale was transformed to a classification scheme using cut-off values calculated using the binary partitioning method and defined as follows: fit ≤1; pre-frail 1-5.5; frail ≥5.5) [20].

Statistical analysis
Predictors for frailty were explored using logistic regression analyses, considering frailty status (vs.fit/pre-frail) as the primary variable of interest.The main outcome variables in the analysis were OS and NRM.Moreover, supplementary information was provided about the explanatory power of the HCT Frailty Scale on the duration of transplant hospitalization, and about the cumulative incidences of relapse (CIR), Intensive Care Unit (ICU) admission, and GVHD.Lastly, the impact of frailty in post-transplant results was explored using Cox and Fine-Grey regression analyses.P-values were 2-sided, and P < 0.05 indicated a statistically significant result.Statistical analysis was performed using version 9.4 of the SAS system for Windows, Copyright © 2002-2012 SAS Institute, Inc., Cary, NC.
Predictors for frailty at first consultation As reported in Table 2, frailty, at the first consultation, was more likely to be diagnosed in patients with acute leukemia (OR 2.55, P = 0.021) than in patients with other hematological disorders; in patients with an HCT-CI > 3 (OR 2.44, P = 0.029); and with a KPS < 90% (OR 6.69, P < 0.001).Furthermore, the probability of being frail was not affected by the patient´s age (P = 0.183).
Post-transplant information among fit, pre-frail and frail patients The median of time from the first consultation to the HCT admission was 6 weeks (range: 3-21).The main post-transplant  information according to the frailty status is reported in Table 3.All HCTs were performed on an inpatient basis.A total of 296 (99.3%) adults engrafted, and the median of days to neutrophil and platelet engraftment were not significantly different between the three frailty groups (P = 0.384, 0.360, respectively).Compared with patients classified as fit or pre-frail, the duration of transplant hospitalization was longer in frail patients (median of 34 vs. 29 vs. 30 days, P < 0.001).As shown in Fig. 2 and Table 3, in reference to fit patients, frail (HR = 3.32 (95% CI 1.82-6.06),P < 0.001) and pre-fail (HR = 1.68 (95% CI 0.98-2.87),P = 0.059) patients had an increased risk for ICU admission secondary to any cause.The day +180 cumulative incidence of ICU admission of fit, pre-frail and frail was 8.0%, 10.5%, and 30.4% (P = 0.004), respectively.
Disease relapse was documented in 53 (17.8%) patients.As shown in Table 3 and Fig. 2, the degree of frailty did not have a significant impact in relapse risks; the fit, pre-frail and frail adults had comparable relapse rates with an estimated 2-year CIR of, respectively, 21.1%, 26.2% and 22.4% (P = 0.894).

Impact of frailty on overall survival and non-relapse mortality
With a median follow-up among survivors of 17 months (IQR: 8-22 months), 77 (25.8%) patients died.The leading causes of death were infection and relapse.As shown in Fig. 3 and Table 3, the 2-year OS and NRM of fit, pre-frail, and frail patient, classified according to the HCT Frailty Scale, were 82.9%, 67.4% and 48.3% (P < 0.001), and 5.4%, 19.5% and 37.7%, (P < 0.001), respectively.Moreover, the differences in post-transplant outcomes among the three frailty groups were statistically significant.
The impact of frailty in OS and NRM was explored using regression analyses.As reported in Table 4, the multivariable analysis controlling for HCT-CI and KPS, confirmed that pre-frail and frail patients had lower OS (Pre-frail: HR = 2.10, P = 0.021/Frail: HR = 4.51, P < 0.001) and higher NRM (Pre-frail: HR = 4.22, P = 0.006/Frail: HR = 9.40, P < 0.001) than fit patients.On the other hand, being more aged was neither a risk factor for OS nor for NRM; and finally, those patients with grade 3-4 aGVHD had lower OS (HR = 5.94 P < 0.001).
Lastly, the impact of frail and pre-frail status in post-transplant outcomes in younger and older adults was compared using regression analysis.As reported in Table 6, the HRs of OS and NRM of frail patients relative to the fit ones, were statistically different in the younger (HR for OS 5.08, P = 0.001/HR for NRM 2.86, P = 0.010) and the older (HR for OS 3.86, P = 0.004/HR for NRM 2.97, P = 0.008) groups.Moreover, multivariable analysis confirmed the absence of a significant difference between the power of the HCT Frailty scale to predict OS and NRM in the two groups of older and younger adults (Table 6).
Frailty and comorbidities: Results from the HCT Frailty Scale and HCT-CI Last, the interaction between frailty, measured using the HCT Frailty Scale, and comorbidities, calculated using the HCT-CI, was investigated.As shown in Table 2, frailty was more likely to be diagnosed in patients with an HCT-CI > 3 (OR 2.44, P = 0.029).However, while the incidence of frailty was not correlated with chronological age (OR 0.60, P = 0.183), adults older than 60 tend to have a higher number of comorbidities than the younger ones (HR 1.67, P = 0.092).
When frailty and comorbidities were evaluated in younger and older adults, no differences in the proportion of patients with an HCT-CI > 3 were documented in younger and older adults classified as fit (15.8% vs. 15.8%,P = 0.872), but the proportion of frail patients with an HCT-CI > 3 was higher in patients older than 60 years (15.8% vs. 52.6%,P = 0.034) (Table 5).Last, the predictive ability of the HCT Frailty Scale and HCT-CI was calculated for using Harrell´s Concordance Index (C-Index).To conduct the comparison and based, patients were categorized into the following two risk groups: frail vs. pre-frail and fit patients and HCT-CI score >3 vs. 0-3.According to the C-Index, the predictive accuracy of the HCT Frailty Scale and HCT-CI for OS and NRM prediction were, respectively, 65.4% and 79%, and 54.6% and 69%.

DISCUSSION
The HCT Frailty Scale is a time-efficient and easily applicable tool that combines items from validated geriatric scales together with laboratory biomarkers for the classification of adult candidates for alloHCT into fit, pre-frail, and frail categories.This study shows that the frailty status of alloHCT candidates evaluated at first consultation is predictive of NRM and OS irrespective of the patient´s age.Furthermore, comparable levels of frailty can be found in younger and in older adults.
The HCT Frailty Scale was designed based on the Frailty and Functionality Evaluation results with purpose of classifying patients into fit, frail, and pre-frail categories [19,20].Different models of assessment have been proposed to evaluate frailty before HCT [13][14][15][16][17][18].However, this is the first time that a particular scale has been proposed to classify alloHCT patients into three levels of frailty.The intermediate status of pre-frail includes a group of vulnerable patients intermediate between fit and frail.This state is based on a similar sub-group classified as "pre-frail" in geriatric patients who have a higher propensity of progressing to the frail state [27].Furthermore, the fact that pre-frail patients had a higher mortality risk than fit patients supports the design of frailty scales capable to distribute candidates for alloHCT into the defined groups.
Of the patients included in the sample, the HCT Frailty scale classified 15.7% of them as frail and 49.7% as pre-frail.The incidence of frailty was similar to the incidence reported by prospective studies, in the range from 15% to 25% of frail patients [13-18, 28, 29].The relatively high incidence of frail patients documented in these studies is remarkable, as all the patients classified as frail were previously considered fit to be referred for alloHCT by the Medical Team who treated the underlying disease.This fact emphasizes the usefulness of incorporating objective and validated frailty scales in the evaluation of candidates to alloHCT for better decision making.
Chronological age was not associated with an increased likelihood of frailty at the first consultation.In fact, the observed prevalence of this syndrome was similar in patients younger and older than 60.Frailty is generally considered a geriatric syndrome that can result from an age-associated decline in physiologic reserve and function across multiple organ systems, with an estimated incidence of 10% in adults older than 65 years, and of 30% in adults older than 80 years [8,21,27].However, frailty and aging are not synonymous.Underlying diseases play an important etiologic role in driving or accelerating the development of frailty [21].Notably, patients with acute leukemia, with a higher number of comorbidities, and with a KPS < 90% had a higher likelihood of    being frail than patients otherwise.Therefore, the development of frailty in candidates for alloHCT can be triggered or accelerated secondary to the underlying hematological diseases, recent intensive treatments, and additional comorbidities present in the non-geriatric patients included in the study [3,5].In this study, frail and pre-frail patients had a higher NRM and a lower OS, irrespective of their chronological age and/or additional risk factors, such as the number of comorbidities or the KPS.The association between frailty and increased mortality after HCT in cohorts of patients above a certain age has been reported [13-18, 28, 30, 31].Our study has pioneered the assessment of frailty in patients across all ages, demonstrating that the negative impact of frailty in transplant outcomes is comparable in patients younger and in patients older than 60 years.This finding is relevant because, in geriatric patients, frailty is dynamic and potentially reversible with specific interventions [32,33], and there is evolving evidence to recommend the assessment of frailty in the alloHCT setting to diagnose and treat this syndrome with multidimensional interventions [14,[34][35][36].
As reported, frail and pre-frail patients had a lower OS, secondary to an increased NRM and without affecting relapse risk.Moreover, frailty correlated with a more prolonged transplant hospitalization and a higher risk for ICU admission.Recent studies have reported that frail elderly adults admitted to the ICU had worse outcomes [37][38][39].Furthermore, frailty before alloHCT had predictive power for ICU admission in a sample of older patients, with an incidence of admission of 35% [40].In our study, frail adults had a 3-fold higher risk of being admitted to the ICU than fit patients, with an overall day +180 incidence ICU admission of 30.4%.This result aligns with others found in previous research, but with the important difference that is has been obtained in a cohort of both young and old patients.
An increased risk for grade 2-4 aGVHD was observed in frail and pre-frail adults.The presence of systemic low-grade chronic inflammation has been detected as an essential mediating factor in frailty [41,42].The cytokine storm provoked by the interaction between donor's and the recipient's immune cells would have been higher in pre-frail and frail adults, as they may have higher baseline levels of circulating pro-inflammatory cytokines.
Our study supports the hypothesis described by Fried et al., that frailty and comorbidity are distinct clinical entities [27].Although these conditions exacerbate each other and can occur    As reported in the above table, the HR for OS for frail younger adults was 5.08 (95% CI 1.91-13.55),and for frail older adults was 3.86 (95% CI 1.55-9.60).The intersection observed between these two confidence intervals supports that the differences in HR are not statistically significant.The same conclusions were obtained in the rest of the estimations reported in the table.A multivariable analysis was calculated to test whether any HRs were significantly different in predicting OS and NRM between Younger and Older patients, and the p-values (P = 0.794 and P = 0.8411) showed no evidence of a significant difference in the HCT Frailty scale in predicting NRM between older and younger adults.
simultaneously, each condition can occur independently and has high clinical significance [43].Since these two conditions are distinct clinical entities, and both have been demonstrated to impact transplant results negatively, implementing frailty scales in alloHCT can strongly complement the standard assessment of comorbidities.Future studies, including a larger sample size of patients, will investigate the benefits of designing compositepredictive scales that include the assessment of frailty, comorbidities, and additional variables relevant to the transplant's success.
One of the study's main limitations is the need for external validation before findings can be considered definitive.In particular, more extensive use of frailty and functionality assessments, together with additional evaluations of the predictive power of the HCT Frailty Scale, are needed to consolidate our findings and recommendations for clinical practice.
The knowledge gained in Geriatric Oncology has been pivotal in eliminating the use of age alone as a key indicator of patient fitness, health, and, ultimately, as an eligibility criterion for intensive treatments such as HCT [3,7,44].Our study documents that in the HCT setting, frail patients can be found in adults of all ages.Since it has been shown that frailty has a negative impact on transplant outcomes, it is recommended to extend the frailty evaluation to all transplant candidates.This will increase the demand and use of resources for this evaluation.It is therefore important to use reliable, easy to apply and low-cost frailty evaluation protocols to regularly use in clinical practice.
The HCT Frailty Scale satisfies all the pre-defined conditions of reliability and low cost since it has been demonstrated that it can be applied at first consultation by the existing transplant teams, and completed in a median of 5-6 min [19,20].The limited number of variables included in the scale can underestimate the burthen of frailty in adult candidates for alloHCT.Furthermore, this scale did not include the measurement of dynamic variables such as cardiopulmonary exercise stress test [45].However, this scale was elaborated under the criterion of simplicity and convenience for the patients, encouraging its regular use.Additional variables such as cognition, comorbidities, social status, anxiety, and nutrition, are being evaluated at the first consultation, and an ongoing study is evaluating how this information can be integrated with the results provided by the HCT Frailty Scale and used to design multidimensional pre-transplant interventions to prevent or minimize the negative impact of frailty in transplant outcomes.

xFig. 1
Fig.1Frailty and Functionality Program and HCT Frailty Scale.

Fig. 2
Fig. 2 Impact of frailty on GVHD and Incidence of ICU Admission.

FitFig. 3
Fig. 3 Correlation Between Fit, Pre-Frail and Frail Status and OS, NRM and CIR.

Fig. 4
Fig. 4 Correlation Between Frailty and Post-Transplant Outcomes in Younger and Older Adults.

Table 1 .
Baseline Characteristics, AlloHCT Information in the 298 Patients Included and After Classifying the Study Cohort in Fit, Pre-Frail and Frail.

Table 2 .
Predictors for Frailty at First Consultation.

Table 3 .
Main Post-Transplant Information and Outcomes According to Frailty Status.
ICU insensitive care admission, GVHD graft-versus-host disease.a ANOVA F-test p-value.

Table 4 .
Impact of Frailty Syndrome in Overall Survival and Non-Relapse Mortality.

Table 5 .
HCT Frailty Scale for Younger and Older Adults.

Table 6 .
HCT Frailty Scale for Outcome Prediction in Younger and Older Adults.