Should Adolescents and Young Adults with Hodgkin Lymphoma be Treated As Children or Adults?

Background Hodgkin lymphoma (HL) is one of the most common cancers in adolescents and young adults (AYA). While no specific recommendations exist for this age group, AYA with HL can be treated according to pediatric or adult therapeutic strategy, with the same major challenge: maintaining optimal efficacy with less long-term toxicity and promoting treatment adherence. Adult strategies are mainly based on ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) with/without radiotherapy, whereas pediatric protocols include OEPA (vincristine, etoposide, prednisolone, doxorubicin) and COPDAC (cyclophosphamide, vincristine, prednisolone, dacarbazine) with radiotherapy for inadequate early responses. Despite different treatment regimens, both approaches have shown excellent efficacy with 5-year overall survival (OS) rates above 95% in patients under 25 years old. However, very few studies have compared the outcome of AYA with HL treated with a pediatric protocol to that of AYA treated with an adult protocol.

Methods From 2012 to 2018, 148 patients aged from 15 to 25 were treated at Saint-Louis Hospital for newly diagnosed HL. Among them, 71 were treated using an adult strategy and 77 according to the pediatric EuroNet protocol. The primary objective of this study was to compare the 5-year progression-free survival (PFS) by treatment group. Secondary objectives were to compare the 5-year OS, the interim PET response, the cumulative doses of chemotherapy received, the short-term toxicity profile, and the number of hospitalization days.

Results Patients in both treatment groups were comparable in terms of baseline characteristics. In the adult group patients were older than in the pediatric group (median age 21.8 vs 18.6, p<0.0001) and more often overweight (BMI>25kg/m², 27% vs 9%, p=0.005). EORTC risk stratification was comparable between the 2 groups (14% localized, 41% unfavorable localized and 45% advanced stage).

The median follow-up was 4.3 years (3.6 years in pediatric vs 5 years in adult group). The 5-year OS and PFS was respectively 100% and 85% for the whole cohort, with no significant difference between treatment groups (85% in pediatric vs 86% in adult group, HR=0.84, 95%CI [0.35-2.04], p=0.7) (Figure 1). In both strategies, the 5-year PFS was 100% for localized stage and 78% for advanced stage. Early response assessed by interim PET was associated with a shorter PFS in both groups. We observed a partial response at interim PET in 21% of pediatric and 10% of adult patients, associated with a 5-year PFS of respectively 68% and 44%, with no significant difference. In patients with negative interim PET, the 5-year PFS was 90% in both groups.

Regarding early toxicities, cytopenias and infectious complications were comparable between the 2 types of regimens. However, pediatric treatments induced more steroid-related (weight gain, psychiatric disorders or osteo-necrosis) or vincristine-related adverse events (peripheral neuropathies). Due to the short follow-up, the late effects in both groups could not be evaluated. However, patients treated with adult regimens were exposed to higher cumulative doses of bleomycin (86mg/m² vs 1 mg/m², p<0.001), anthracycline (240mg/m² vs 167 mg/m², p<0.001), dacarbazine (3.0g/m² vs 2.1g/m², p<0.001), procarbazine (802mg/m² vs 0mg/m², p<0.001) and radiotherapy (30% vs 5% in pediatric group, p<0.001), whereas pediatric protocols included higher doses of corticosteroids (3.5g/m² vs. 0.4g/m², p<0.001), cyclophosphamide (2.7g/m² vs 1.5g/m², p<0.001) and etoposide (1.3g/m² vs 0.7g/m², p<0.001). (Figure 2)

Pediatric protocols required more hospitalization days than adult protocols (26 vs 12 days) for the whole treatment, which may have an impact on quality of life.

Conclusion Both adult and pediatric therapeutic strategies yield excellent and comparable OS and PFS in AYA with HL. The toxicity profile was different, with a higher risk of short-term steroid-related toxicities and more hospitalizations in pediatric regimens, and a higher expected risk of late toxicities in adult regimen. These results justify a tailor-made therapeutic decision, adapted to each patient, and highlights the importance of managing these AYA patients in dedicated units with professionals trained in the specificities of this particular age group.

Landman-Parker:GSK: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Research Funding; Janssen: Research Funding. Boissel:GILEAD: Honoraria; AMGEN: Honoraria; ARIAD/INCYTE: Honoraria; ASTELLAS: Honoraria; NOVARTIS: Honoraria; SERVIER: Honoraria.