Introduction: Classic Hodgkin lymphoma (HL) is one of the most common cancers in adolescents and young adults (AYA; 15-39 years [y]). Nationally representative studies demonstrate inferior outcomes among AYA patients versus children with conventional HL therapy. Drivers of inferior outcomes in AYA patients are likely multifactorial with much of the published data being focused on differences in care delivery across the age spectrum. Few studies have evaluated how clinical and disease-related factors may vary by age or across the two most common HL histology subgroups, mixed cellularity (MC) and nodular sclerosing (NS) disease, and therefore contribute to these inferior outcomes. This is an important gap for two reasons: 1) the incidence of HL differs by age, and 2) the magnitude of the association between age and outcome in HL differs by histologic subgroup – a likely proxy for yet-undescribed biologic variations. For example, among patients with MC disease enrolled on Children's Oncology Group (COG) clinical trials for newly diagnosed HL, we identified a 17% decrease in event free survival among older (≥15y) patients compared to younger patients (<15y) for reasons that remain unknown. To fill this gap, the present analysis leverages a novel cohort of children, adolescents, and young adults (CAYA) from clinical trials and the COG registry to evaluate patient, disease, and presenting characteristics by histology (MC vs. NS) and by age within the MC subgroup.

Methods: Pooled analyses were performed using individual-level data from 4,673 patients with either MC (ICD-O 9652) or NS (ICD-O Morphology codes 9663, 9664, 9665, 9667) histology enrolled on COG registry APEC14B1 (N = 2310, 2015-2025) and four phase III COG clinical trials for HL (N = 2363, 2002-2019). Descriptive analyses of sociodemographic variables (age, sex, race, ethnicity) and clinical characteristics including Ann Arbor stage (I-IV), B-symptoms, bulky disease (nodal aggregate >6cm or mediastinal mass greater than 1/3 thoracic diameter), and bone marrow involvement within stage IV were performed. Sociodemographic and clinical characteristics were compared by histology and age (<15y vs. ≥15y) within those with MC disease using test for categorical variables and analysis of variance for continuous variables.

Results: The analytic cohort included N=493 patients with MC histology and N=4,180 with NS histology. Mean age of the cohort was 15.2y (+/- 3.5) with 1,850 (40%) patients <15y and 50% being female. At presentation, patients with MC (vs. NS) histology were younger (13.4y vs. 15.5y, p<0.001) and were more likely to be Hispanic (29% vs. 17%, p<0.001), male (68% vs. 48%, p<0.001), and publicly insured (39% vs. 30%, p<0.001). Patients with MC (vs. NS) histology were also more likely to present with stage I disease (15% vs. 3.2%, p<0.001), and were less likely to have B-symptoms (33% vs. 37%, p=0.040) or bulky disease (55% vs. 65%, p<0.001). Among those with stage IV disease, 33% (31/95) of those with MC had bone marrow involvement compared to only 15% (156/1050) among Stage IV NS patients (p<0.001).

Within the MC histology cohort of patients, 56% were <15 years. Younger (vs. older) patients with MC histology were more likely to be male (75% vs. 58%, p<0.001), be publicly insured (44% vs. 34%, p=0.024), and were less likely to have B-symptoms (26% vs. 40%, p =0.001). Within the MC cohort, there was no difference by age in race/ethnicity, presenting stage, presence of bulky disease, or bone marrow involvement among those with stage IV disease.Conclusion: In the largest cohort of CAYA patients with MC histology in North America, we identify a distinct clinical phenotype compared to NS. The phenotype associated with MC histology is notable for more favorable prognostic features, including earlier stage at diagnosis and fewer patients with B symptoms or bulky disease at presentation. The observation that a significantly higher proportion of those with MC (vs. NS) histology with stage IV disease had bone marrow involvement is novel and warrants further study. Although some clinical differences were noted between younger and older patients with MC histology, these do not appear to fully account for the previously reported age-related disparities in survival outcomes. Future work will investigate whether treatment-related factors (e.g. chemo sensitivity, interim disease response, efficacy of radiotherapy) account for inferior survival among older MC patients.

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2025
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