Frailty-comorbidity discordance and non-relapse mortality after allogeneic hematopoietic cell transplantation.

6552 Background: Non-relapse mortality (NRM) is a barrier to successful allogeneic hematopoietic cell transplantation (HCT). The HCT-Comorbidity Index (HCT-CI) is used for pre-HCT risk assessment but does not capture physiological reserve. Frailty, assessed by the validated Hematopoietic Cell Transplantation-Frailty Scale (HCT-FS), independently predicts post-HCT outcomes; however, the clinical consequences of frailty-comorbidity discordance remain poorly defined. We hypothesized that such discordance identifies patients whose transplant risk may be misclassified by HCT-CI alone. Methods: We retrospectively analyzed 692 patients undergoing first allogeneic HCT at our center. Frailty was assessed using HCT-FS and categorized as fit, pre-frail, frail. For discordance analyses, HCT-FS was dichotomized as fit vs pre-frail/frail. HCT-CI was dichotomized as low (<3) vs high (≥3). Patients were classified into 4 groups: fit+low HCT-CI (group I), fit+high HCT-CI (group II), pre-frail/frail+low HCT-CI (group III), and pre-frail/frail+high HCT-CI (group IV). Fine-Gray competing-risk models and Cox regression was used for NRM and overall survival (OS), respectively. Results: The median age was 61 years (Q1-Q3: 52-67), and 399 (58%) were male. At baseline, 287 (42%) patients had an HCT-CI ≥3. HCT-FS classified 252 (36%) as fit, 373 (54%) as pre-frail, and 67 (10%) as frail. Overall, 355 (51%) patients demonstrated discordant HCT-FS and HCT-CI scores: 78 (11%) as group II, and 277 (40%) classified as group III. At 2 years, NRM and OS were 11.2% (95% CI, 7-16) and 79.3% (95% CI, 73-84) in fit patients, 17.4% (95% CI, 14-22) and 67.0% (95% CI, 62-72) in pre-frail patients, and 33.5% (95% CI, 22-45) and 54.9% (95% CI, 42-66) in frail patients, respectively (p<0.01 for both). In multivariable analyses, HCT-FS, HCT-CI, and age at HCT were independently associated with NRM and OS. Compared with fit patients with low HCT-CI (group I), pre-frail/frail patients with HCT-CI ≥3 (group IV) experienced the highest risk of NRM (sub-distribution hazard ratio (sHR) 2.7, 95% CI 1.5-5, p<0.01). Pre-frail/frail patients with HCT-CI <3 (group III) also had an increased risk of NRM (sHR 1.9, 95% CI 1.1-3.5, p=0.01). Fit patients with HCT-CI ≥3 (group II) did not have a significant increase in NRM risk (sHR 1.7, 95% CI 0.8-3.7, p=0.15). The corresponding HR for OS were 2.1 (95% CI 1-3; p<0.01) for group IV, 1.7 (95% CI 1-3; p<0.01) for group III, and 1.4 (95% CI 0.8-2.5; p=0.18) for group II, compared with group I. Conclusions: Frailty-comorbidity discordance was observed in 51% of patients and has prognostic implications. Pre-frail and frail patients with low HCT-CI experience higher NRM than would be predicted by HCT-CI alone, suggesting underestimation of transplant risk when frailty is not assessed. Integrating HCT-FS with HCT-CI may improve risk stratification and better identify patients at high risk for NRM.