Background: There are a lack of clinical prediction tools in early-stage Hodgkin lymphoma (E-HL). We developed and validated a modern-day model, known as E-HIPI, to predict progression-free survival (PFS) within the first 5 years (y) incorporating detailed individual patient (pt) data from international clinical trials and prospective registry data that were standardized, normalized & harmonized as part of the HoLISTIC Consortium (www.hodgkinconsortium.org).
Methods: Model development utilized Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines (Moons, Ann Intern Med 2015) on a cohort of 3,080 newly-diagnosed E-HL pts treated on 4 seminal phase 3 clinical trials (NCIC: Meyer, NEJM 2012; RAPID: Radford, NEJM 2015; EORTC-GELA H9U: Ferme, E ur J Cancer 2017; EORTC/LYSA/FIL H10: Andre, JCO 2017). External validation was done in an independent cohort of 462 E-HL pts from a large registry (Princess Margaret, Toronto). Pts with classic HL, stage I or II disease, and ages 18-65 y were included. The primary outcome was PFS. Cox models were utilized with follow-up truncated at 5 years. Baseline predictors were: sex, stage, B symptoms, histology, number & location of nodal sites, and continuous data values of age, maximum tumor diameter (MTD), white blood cell count (WBC), lymphocyte count, hemoglobin, albumin & erythrocyte sedimentation rate (ESR). Multiple imputation was used for missing data. To consider possible non-linear relationships for continuous variables we examined plots & cubic splines. We used backward elimination ( P<0.1) to develop the models & internal validation with 200 bootstrap samples was conducted to estimate optimism & correct for overfitting. The final prediction equations applied optimism corrections to beta coefficients & hazard ratios (HR). Sensitivity analyses included model results stratified by PET staging (vs CT) and each HL trial. The models were evaluated in the external validation cohort & compared using c-statistics. Model scores were also grouped by tertiles for visualization in Kaplan-Meier (KM) curves.
Results: Median age in the development cohort was 35y; 51% were female; 81% had nodular sclerosis & 77% stage II disease; 26% had B symptoms; 32% had mediastinal bulk (≥10cm or >1/3 diameter) and the mean MTD was 6.4 cm (interquartile range (IQR), 3.9-8.2). Median follow-up was 60 months (IQR 45-75). KM estimates at 5y was 90.7% (264 events) for PFS, and 97.1% (78 events) for overall survival (OS). After backward elimination, significant variables retained were age, sex, nodal location (cervical region), MTD & albumin. Stage, ESR, or the number of nodal sites were not significant. Age was modeled with piecewise linear splines due to its non-linear relationship. See the Table for the final prediction model and optimism-corrected HRs. Optimism-corrected c-statistics in the development model was 0.63. Sensitivity analyses of stratification by type of imaging at staging or by each clinical trial demonstrated no change in model parameters or c-statistics. Most baseline characteristics and outcomes of the external validation cohort were similar besides median follow-up time (74 months, IQR 37-129). C-statistics for the E-HIPI model in external validation was 0.63. In addition, observed 5y outcomes stratified by tertile of predicted risk in the external cohort separated pts into a low & higher-risk group, which comprised 1/3 & 2/3 of pts, respectively ( Figure). Finally, model diagnostics revealed the potential for time dependency in the retained covariates. Further assessment of differential prediction between early (<2y) vs. later (2-5y) PFS events is ongoing.
Conclusion: Following TRIPOD methodology, we rigorously developed and externally validated the E-HIPI among >3,500 E-HL pts.Discrete risk groups were delineated, and we identified several novel factors, including nodal location, sex & key continuous variables that predict 5y PFS. Additional model refinement is underway, including formal calibration & external validation via other HL registries (Stanford, Mayo/Iowa SPORE). A web-based calculator to simplify application of the E-HIPI will also be presented at ASH. Future planned modeling includes integration of differing treatments & response-adapted imaging via multistate modeling to enrich individualized survival estimates and simulation modeling to predict late consequences.
Disclosures
Evens:Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Maurer:BMS: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Research Funding; Roche/Genentech: Research Funding. Advani:Genentech: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Cyteir: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Merck: Research Funding; Gilead: Research Funding; Seagen: Research Funding. Hay:Seattle Genetics: Research Funding; Incyte: Research Funding; Merck: Research Funding; Roche: Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding. Hutchings:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Parsons:Seagen: Consultancy. Radford:GlaxoSmithKline: Current equity holder in publicly-traded company; AstraZeneca: Divested equity in a private or publicly-traded company in the past 24 months; Takeda: Research Funding; ADC Therapeutics, Takeda, Sobi: Honoraria; ADC Therapeutics, Takeda: Speakers Bureau; ADC Therapeutics, Takeda, Sobi: Consultancy.
