IMPORTANCE: The current standard-of-care salvage therapy in relapsed/refractory classic Hodgkin lymphoma (cHL) includes consolidation high-dose chemotherapy (HDCT)/autologous stem cell transplant (aSCT). OBJECTIVE: To investigate whether presalvage risk factors and fludeoxyglucose-18 (FDG) positron emission tomography (PET) response to reinduction chemotherapy can guide escalation or de-escalation between HDCT/aSCT or transplant-free consolidation with radiotherapy to minimize toxic effects while maintaining high cure rates. DESIGN, SETTING, AND PARTICIPANTS: EuroNet-PHL-R1 was a nonrandomized clinical trial that enrolled patients younger than 18 years with first relapsed/refractory cHL across 68 sites in 13 countries in Europe between January 2007 and January 2013. Data were analyzed between September 2022 and July 2024. INTERVENTION: Reinduction chemotherapy consisted of alternating IEP (ifosfamide, etoposide, prednisolone) and ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients with low-risk disease (late relapse after 2 cycles of first-line chemotherapy and any relapse with an adequate response after 1 IEP/ABVD defined as complete metabolic response on FDG-PET and at least 50% volume reduction) received a second IEP/ABVD cycle and radiotherapy (RT) to all sites involved at relapse. Patients with high-risk disease (all primary progressions and relapses with inadequate response after 1 IEP/ABVD cycle) received a second IEP/ABVD cycle plus HDCT/aSCT with or without RT. MAIN OUTCOMES AND MEASURES: The primary end point was 5-year event-free survival. Secondary end points were overall survival (OS) and progression-free survival (PFS). PFS was identical to event-free survival because no secondary cancers were observed. PFS data alone are presented for simplicity. RESULTS: Of 118 patients analyzed, 58 (49.2%) were female, and the median (IQR) age was 16.3 (14.5-17.6) years. The median (IQR) follow-up was 67.5 (58.5-77.0) months. The overall 5-year PFS was 71.3% (95% CI, 63.5%-80.1%), and OS was 82.7% (95% CI, 75.8%-90.1%). For patients in the low-risk group (n = 59), 41 received nontransplant salvage with a 5-year PFS of 89.7% (95% CI, 80.7%-99.8%) and OS of 97.4% (95% CI, 92.6%-100%). In contrast, 18 received HDCT/aSCT off protocol, with a 5-year PFS of 88.9% (95% CI, 75.5%-100%) and OS of 100%. All 59 patients with high-risk disease received HDCT/aSCT (and 23 received post-HDCT/aSCT RT) with a 5-year PFS of 53.3% (95% CI, 41.8%-67.9%) and OS of 66.5% (95% CI, 54.9%-80.5%). CONCLUSION AND RELEVANCE: In this nonrandomized clinical trial, FDG-PET response-guided salvage in relapsed cHL may identify patients in whom transplant-free salvage achieves excellent outcomes. HDCT/aSCT may be reserved for primary progression and relapsed cHL with inadequate response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00433459.

Children's Health Ireland Crumlin Dublin Ireland

Department of Cellular Pathology University College Hospital London London United Kingdom

Department of Nuclear Medicine University Hospital Leipzig Leipzig Germany

Department of Paediatric Haematology and Oncology St Anna Children's Hospital Medical University of Vienna St Anna Children's Cancer Research Institute Vienna Austria

Department of Paediatric Haematology and Oncology University Hospital Motol and 2nd Medical Faculty of Charles University Prague Czech Republic

Department of Paediatric Haematology Oncology and Immunodeficiency University Hospital Justus Liebig University Giessen Giessen Germany

Department of Paediatric Oncology and Haematology Hôpital Armand Trousseau Sorbonne Université Paris France

Department of Paediatrics and Adolescents Medicine Rigshospitalet Copenhagen The Juliane Marie Centre Copenhagen Denmark

Department of Pathology Hematopathology Section University Hospital Schleswig Holstein Christian Albrechts Universität Kiel Germany

Department of Pediatric Hematology and Oncology University Children's Hospital University Medical Centre Ljubljana Ljubljana Slovenia

Department of Pediatrics University Hospital Magdeburg Magdeburg Germany

Department of Radiation Oncology AYA Oncology and Pediatric Radiotherapy Unit CRO Centro di Riferimento Oncologico IRCCS Aviano Italy

Department of Radiology University Hospital Halle Germany

Department of Radiooncology Allgemeines Krankenhaus Wien Medical University Vienna Vienna Austria

Department of Radiooncology University Hospital Halle Germany

Disease and Comenius University Bratislava Bratislava Slovakia

Division of Pediatrics Department of Woman Mother Child Pediatric Hematology Oncology Unit University Hospital of Lausanne and University of Lausanne Lausanne Switzerland

Hôpital Robert Debré Service d'Hématologie Pédiatrique and Université Paris Cité Paris Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Jagiellonian University Medical College Institute of Pediatrics Krakow Poland

Medical Faculty of the Martin Luther University Halle Wittenberg Halle Germany

Oslo University Hospital Department of Oncology and KG Jebsen Centre for B cell malignancies University of Oslo Oslo Norway

Pediatric Division Children and Young People's Cancer Services University College London Hospital London United Kingdom

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Universidad de Sevilla Hospital Universitario Virgen Macarena Sevilla Spain

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ClinicalTrials.gov
NCT00433459