Interaction of Age and Comorbidities and Their Impacts on Hematopoietic Cell Transplantation (HCT) Outcomes
Authors: Ostronoff Fabiana , Storer Barry , Storb Rainer , Bhatia Smita , Maziarz Richard T. , Pulsipher Michael A. , Maris Michael T. , Deeg H. Joachim , Martin Paul J. , Appelbaum Frederick R. , Maloney David G. , Sandmaier Brenda M. , Sorror Mohamed L. 
Published: October 2019

Abstract
Abstract 665
Historically, age has been the main patient (pt)-specific decision-making factor for allogeneic HCT. The HCT comorbidity index (CI) was developed to capture pretransplant comorbidities. The index predicts non-relapse mortality (NRM) and has revolutionized outcome analysis for allogeneic HCT. Whether calendar age adds additional level of information to the HCT-CI in outcome prediction is unknown. Here, we investigated 1) how well the HCT-CI predicts outcomes across different age groups and 2) whether age could be incorporated into the HCT-CI. Data from 3033 consecutive pts treated with allogeneic HCT between January 2000 and December 2006 from HLA-matched related or unrelated donors at five collaborating institutions were used for this study. All data were collected by a single investigator, who was blinded from the final outcomes of pts, to ensure consistent comorbidity coding. Median age was 45 (range 0.1–74.5) years.
Overall, there was a weak correlation between increasing age and increasing HCT-CI scores (r=0.26). Pts were randomly divided into training (n=1853) and validation (n=1180) sets. In the training set, the HCT-CI predicted increased cumulative incidence rates of NRM and worsening of overall survival (OS) rates consistently in the 5 separate age groups (Table 1). Pulmonary function tests were not performed in 51% of pts <20 years of age, which might have affected the assignment of HCT-CI scores. Scores of 0, 1–2, and ≥3 were assigned to 28%, 32%, and 40%, respectively, of pts ≥20 years of age compared to 55%, 27%, and 18% of pts <20 years of age. Nevertheless, HCT-CI scores predicted OS of 73%, 61%, and 41% (p<0.0001), respectively, among pts <20 years of age.
Table 1: NRM and OS by HCT-CI scores across different age groups in the training set Age groups, years Cumulative incidences of NRM p Rates of overall survival p HCT-CI scores HCT-CI scores 0 1–2 ≥3 0 1–2 ≥3 0–19 (n=245) 8 26 28 <0.001 73 61 41 <0.001 20–39 (n=475) 11 20 39 <0.001 80 62 33 <0.001 40–49 (n=429) 12 26 43 <0.001 75 56 39 <0.001 50–59 (n=457) 21 31 39 <0.001 60 48 33 <0.001 ≥60 (n=247) 7 27 38 <0.001 63 47 27 <0.001
A proportional hazards model was used to estimate the hazard ratios (HRs) for NRM and OS associated with different age intervals and other covariates, including the HCT-CI scores (Table 2). In this model, tests of homogeneity of HRs associated with HCT-CI scores of 1–2 and ≥3 across age groups were not rejected for either NRM (p=0.66 and p=0.86, respectively) or OS (p=0.76 and p=0.24, respectively). Increasing HCT-CI scores were associated with the highest HRs for NRM compared to other covariates. Pts in age groups 40–50, 50–60, and >60 years had HRs for NRM ranging between 1.48–1.84 compared to pts <20 years of age. Accordingly, age >40 years was assigned a score of 1 to be added to the HCT-CI scores. In the validation set, although we continued to observe increases in HRs for NRM with increasing age, only minor improvement in c-statistics for NRM (0.66 versus 0.68) was detected when age was added to the HCT-CI.
Table 2: Multivariate risk factors in the training set (n=1853) Non-relapse mortality HR* P Age     0–19 (13%) 1.0     20–39 (26%) 1.21 0.29     40–49 (23%) 1.48 0.04     50–59 (25%) 1.75 0.004     60+ (13%) 1.84 0.005 HCT-CI     0 (31%) 1.0     1–2 (33%) 2.13 <0.0001     3+ (37%) 3.63 <0.0001 Donor     Related (55%) 1.0     Unrelated (45%) 1.42 0.0001 Regimen intensity     Myeloablative (62%) 1.0     Reduced-intensity (15%) 0.71 0.01     Nonmyeloablative (23%) 0.61 0.0001 Use of ATG     No (92%) 1.0     Yes (18%) 0.90 0.61 Diagnoses     Myeloid (59%) 1.0     Lymphoid (35%) 1.25 0.03     Other cancers (2%) 0.73 0.44     Aplastic Anemia (2%) 1.40 0.49     Non-malignant diseases (2%) 4.69 <0.0001 Disease Risk     Low (38%) 1.0     High (62%) 1.65 <0.0001 Stem cell source     BM (20%) 1.0     PBSC (80%) 1.38 0.02 Pt CMV sero-status     Negative (36%) 1.0     Positive (64%) 1.52 <0.0001 Prior regimens     0–3 (76%) 1.0     4+ (34%) 1.13 0.25 Karnofsky performance status percentages     >80 (75%) 1.0     ≤80 (25%) 1.41 0.0004 * also adjusted for institution type
These results indicate that the HCT-CI is valid for outcome prediction across all age groups and that age per se has a relatively minor impact on HCT outcome prediction in models that account for comorbidities. Age >40 years had an impact equivalent to a single comorbidity with a weight of 1, and therefore should be assigned a score of 1 when using the HCT-CI/Age composite index.

Disclosures:
No relevant conflicts of interest to declare.