HCT Frailty Scale Application and Baseline Information of Fit, Pre-Frail and Frail Patients
Figure 1 shows the implementation of the application of the Frailty and Functionality evaluation and the HCT Frailty Scale to each candidate for alloHCT included in the study. According to the HCT Frailty Scale, 103 (34.6%) adults were classified as fit, 148 (49.7%) as pre-frail, and 47 (15.8%) as frail.
The median age of the 298 patients included was 58 (range: 19-76), 153 (51.3%) patients were males, and myeloid malignancies were the most prevalent indications for alloHCT. As reported in Table 1, there were significantly more frail patients than pre-frail and fit patients with an HCT-CI score > 3 (34.0% vs. 18.7% vs. 12.6%, P=0.009) and with a KPS<90% (48.9% vs. 16.1% vs. 9.6%, P<0.001). Nevertheless, age, sex, or alloHCT characteristics (including the proportion of MAC alloHCTs) did not significantly differ between fit, pre-frail, and frail patients.
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 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 Figure 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. In terms of GVHD, frail (HR=2.18 (95% CI 1.36-3.49), P=0.001) and pre-frail (HR=1.67 (95% CI 1.15-2.44), P=0.008) patients had a higher risk for grade II-IV aGVHD than fit patients. The day +100 cumulative incidences of grade II-IV aGVHD of fit, pre-frail and frail patients was 11.9%, 29.7%, and 26.3% (P=0.005). Furthermore, compared with fit patients, frail (HR=2.17 (95% CI 1.27-3.70), P=0.005) and pre-frail (HR=1.43 (95% CI 0.92-2.24, P=0.114) adults tend to have higher risk for grade III-IV aGVHD, and the day +100 cumulative incidences of grade III-IV aGVHD were 4.9%, 11.7%, 11.1% (P=0.242), respectively. Lastly, similar rates of cGVHD were documented between the three study groups, with cumulative incidences of moderate/severe cGVHD at 1-year of 18.4%, 20.5%, and 18.6% (P=0.505).
Disease relapse was documented in 53 (17.8%) patients during the follow-up. As shown in Table 3 and Figure 2, the degree of frailty did not have a significant impact in relapse risks; the fit, pre-fral 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 Figure 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).
Applicability of the HCT Frailty Scale in Younger and Older Adults
The predictive capacity of the HCT Frailty Scale was additionally explored after stratifying the study cohort into two groups according to the following age ranges: 18-60 years (n=174) vs. >60 years-76 years (n=124). As reported in Table 5, the HCT Frailty Scale classified patients into the three groups in comparable proportions in the two age groups (P=0.984). Among the 174 (58.4%) adults aged 60 or younger, the proportions of fit, pre-frail and frail patients were 34.5% (n=60), 49.4% (n=86), and 16.1% (n=28), respectively; and among adults older than 60 (n=124), these proportions were respectively 34.7% (n=43), 50.0% (n=62), and 15.3% (n=19).
As shown in Figure 4 the estimated 2-years likelihoods of OS and NRM of fit, pre-frail and frail adults aged 60 or younger 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 adults aged 61 or older the likelihoods of 2-years OS and NRM were, respectively, 75.5%, 63.8%, 41.4% (P=0.006), and 4.9%, 16.4%, and 42.1% (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).