The Advanced-Stage Hodgkin Lymphoma International Prognostic Index: Development and Validation of a Clinical Prediction Model From the HoLISTIC Consortium

Abstract

PURPOSE The International Prognostic Score (IPS) has been used in classic Hodgkin lymphoma (cHL) for 25 years. However, analyses have documented suboptimal performance of the IPS among contemporarily treated patients. Harnessing multisource individual patient data from the Hodgkin Lymphoma International Study for Individual Care consortium, we developed and validated a modern clinical prediction model. METHODS Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines was performed on 4,022 patients with newly diagnosed advanced-stage adult cHL from eight international phase III clinical trials, conducted from 1996 to 2014. External validation was performed on 1,431 contemporaneously treated patients from four real-world cHL registries. To consider association over a full range of continuous variables, we evaluated piecewise linear splines for potential nonlinear relationships. Five-year progression-free survival (PFS) and overall survival (OS) were estimated using Cox proportional hazard models. RESULTS The median age in the development cohort was 33 (18-65) years; nodular sclerosis was the most common histology. Kaplan-Meier estimators were 0.77 for 5-year PFS and 0.92 for 5-year OS. Significant predictor variables included age, sex, stage, bulk, absolute lymphocyte count, hemoglobin, and albumin, with slight variation for PFS versus OS. Moreover, age and absolute lymphocyte count yielded nonlinear relationships with outcomes. Optimism-corrected c-statistics in the development model for 5-year PFS and OS were 0.590 and 0.720, respectively. There was good discrimination and calibration in external validation and consistent performance in internal-external validation. Compared with the IPS, there was superior discrimination for OS and enhanced calibration for PFS and OS. CONCLUSION We rigorously developed and externally validated a clinical prediction model in > 5,000 patients with advanced-stage cHL. Furthermore, we identified several novel nonlinear relationships and improved the prediction of patient outcomes. An online calculator was created for individualized point-of-care use.

Classic Hodgkin Lymphoma in Adolescents and Young Adults

“…16 However, recently published data from the Hodgkin Lymphoma International Study for Individual Care Consortium demonstrate that the association of age with outcome is nonlinear, with inferior outcomes in younger AYA patients treated on adult regimens compared with older patients (Fig 2). 17 Although the chemotherapeutic agents used for the initial treatment in pediatric regimens are comparable to those used in adults, different strategies have evolved around cumulative doses of alkylators, doxorubicin, and bleomycin as well as use of radiation, as a recognition of the elevated risk for long-term effects in younger patients. 17,18 PEDIATRIC TREATMENT APPROACH Pediatric treatment regimens typically classify patients to low-, intermediate-, and high-risk groups on the basis of stage and B symptoms, with some approaches considering other factors such as disease bulk, extranodal extension, and erythrocyte sedimentation rate (ESR; Table 1).…”

“…17 Although the chemotherapeutic agents used for the initial treatment in pediatric regimens are comparable to those used in adults, different strategies have evolved around cumulative doses of alkylators, doxorubicin, and bleomycin as well as use of radiation, as a recognition of the elevated risk for long-term effects in younger patients. 17,18 PEDIATRIC TREATMENT APPROACH Pediatric treatment regimens typically classify patients to low-, intermediate-, and high-risk groups on the basis of stage and B symptoms, with some approaches considering other factors such as disease bulk, extranodal extension, and erythrocyte sedimentation rate (ESR; Table 1). Specific definitions have varied over time, complicating comparisons across clinical studies (Table 2).…”

“…16 However, recently published data from the Hodgkin Lymphoma International Study for Individual Care Consortium demonstrate that the association of age with outcome is nonlinear, with inferior outcomes in younger AYA patients treated on adult regimens compared with older patients (Fig 2). 17 Although the chemotherapeutic agents used for the initial treatment in pediatric regimens are comparable to those used in adults, different strategies have evolved around cumulative doses of alkylators, doxorubicin, and bleomycin as well as use of radiation, as a recognition of the elevated risk for long-term effects in younger patients. 17,18…”

“…17 Although the chemotherapeutic agents used for the initial treatment in pediatric regimens are comparable to those used in adults, different strategies have evolved around cumulative doses of alkylators, doxorubicin, and bleomycin as well as use of radiation, as a recognition of the elevated risk for long-term effects in younger patients. 17,18…”

“…AYA, adolescent and young adult; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. Printed with permission from Rodday et al 17…”