Age-Based Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI) in a Real-World Danish Study: Suboptimal Performance in Older Patients
Authors: Rask Kragh Jørgensen Rasmus , Eloranta Sandra , Christensen Jacob Haaber , Hutchings Martin , Dahl-Soerensen Rasmus Bo , Kamper Peter , Evens Andrew M , Maurer Matthew J. , Parsons Susan K , Rodday Angie Mae , Upshaw Jenica , El-Galaly Tarec Christoffer Christoffer , Jakobsen Lasse Hjort 
Published: December 2023

Purpose: Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI (development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL.
Methods: This study utilized data from the population-based, nationwide Danish National Lymphoma registry. Pts with advanced-stage cHL (Ann Arbor stage III-IV or IIB with extra nodal disease) were included and categorized by age in two groups: ages ≤65 years vs. &gt;65 years. In the primary analysis, all pts regardless of therapy were included. A sensitivity analysis restricting to pts starting on BEACOPP or ABVD was performed (Only ABVD in the &gt;65 cohort). Concordance index (C-index) and calibration were used to assess model performance and generalizability. Calibration was visualized using calibration plots and quantified by calibration in the large (CITL) and calibration slope (CS) at 5-years post diagnosis.
Results: A total of 893 advanced-stage HL pts fulfilled the inclusion criteria (634 in the ≤65 cohort and 259 in the &gt;65 cohort). The 5-year OS and PFS in the &gt;65-year cohort were 44% (Confidence intervals (CI); 37-51%) and 35% (CI; 30-42%), respectively. Fifty-six pts in the &gt;65 cohort were classified as low-intermediate-risk (IPS; 1-2), 128 intermediate-risk (IPS; 3-4), and 75 high-risk (IPS; 5-7). For the ≤65 cohort, the 5-year OS and PFS was 88% (CI; 85-90%) and 76% (CI; 73-80%), respectively. Twenty-three pts were classified as low-risk (IPS; 0), 244 low-intermediate-risk, 286 intermediate-risk, and 81 high-risk.
The A-HIPI had a C-index of 0.74 and 0.63 for OS and PFS, respectively in the ≤65 years cohort vs. 0.65 and 0.64 for OS and PFS, respectively, in the &gt;65 cohort. The IPS had a C-index in the ≤65 cohort of 0.66 and 0.60 for OS and PFS, respectively, vs. 0.58 and 0.59 for OS and PFS, respectively, in the &gt;65 cohort (i.e., the IPS performed better in the ≤65 cohort in terms of OS and PFS but was inferior to the A-HIPI). When restricting to pts treated with ABVD or BEACOPP, the A-HIPI C-index in the &gt;65 cohort (116 pts) were reduced to 0.55 for OS and 0.54 for PFS. For the ≤65 cohort (595 pts), the A-HIPI C-index was stable at 0.75 and 0.62 for OS and PFS, respectively.
In terms of A-HIPI calibration in the &gt;65 cohort, CITL and CS were -0.78 and 0.39 for OS vs. -0.98 and 0.80 for PFS. In the ≤65 cohort, CITL and CS were -0.06 and 0.99 for OS vs. 0.21 and 1.18 for PFS. Visual inspection of the calibration plot (Figure 1) for the &gt;65 cohort showed that the A-HIPI underestimated the observed proportion for both OS and PFS (i.e., the observed events were higher than the predicted). Calibration plot for the ≤65 cohort (Figure 2) indicated that the A-HIPI accurately modelled the observed proportion for both OS and PFS (i.e., the predicted probability was consistent with the observed proportion).
Conclusion: The newly developed A-HIPI was validated in a large population-based cohort of Danish pts with advanced-stage cHL. Performance of the A-HIPI was high in the ≤65 cohort and superior to the IPS for OS prediction. Calibration of A-HIPI was excellent in pts ages ≤65 years. However, A-HIPI performed significantly worse among pts &gt;65 years and attained poor performance in pts receiving ABVD or BEACOPP, which is not surprising since patients older than 65 were not included in the development. This study emphasizes the importance of further efforts to develop or update models that apply specifically in older individuals. The inclusion of additional variables reflecting comorbidities and pts fitness into a prognostic model may be necessary to effectively deliver accurate prognoses and risk assessments for the older pt.