Transplant and Nontransplant Salvage Therapy in Pediatric Relapsed or Refractory Hodgkin Lymphoma: The EuroNet-PHL-R1 Phase 3 Nonrandomized Clinical Trial

Abstract

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.

Figure 1.. Study Flowchart and Patient Disposition of the EuroNet-R1 Trial

Of 118 patients analyzed, all were stratified into 3 groups: relapse group 1 (RG-1), patients with late relapse after 2 cycles of first-line treatment; relapse group 2 (RG-2), any other relapse; relapse group 3 (RG-3), patients with primary progressive disease. Patients in RG-1 (n = 12) were considered low risk, and those allocated to RG-3 (n = 24) were considered high-risk. Patients in RG-2 (n = 82) were stratified to low risk (n = 29) or high risk (n = 35), according to their positron emission tomography (PET) response after the first IEP-ABVD (ifosfamide, etoposide, prednisone-adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) cycle. Eighteen patients in RG-2 with an adequate response (AR) were treated with BEAM (carmustine, etoposide, cytarabine, melphalan) and autologous stem cell transplant off protocol. IR indicates inadequate response; nLPHL, nodular lymphocyte-predominant Hodgkin lymphoma; RT, radiotherapy.

Figure 2.. Kaplan-Meier Plot for Progression-Free Survival (PFS) and Overall Survival (OS) of the EuroNet-PHL-R1 Cohort

Kaplan-Meier estimates of 118 patients analyzed in the EuroNet-PHL-R1 trial for OS and PFS are illustrated in this figure. Because no secondary cancers were documented, the event rates consist of only death and/or disease progression. Thus, PFS depiction was chosen.

Figure 3.. Progression-Free Survival (PFS) of Distinct Subgroups in a Forest Plot

Of 118 patients analyzed, all were stratified into 3 groups: relapse group 1 (RG-1), patients with late relapse after 2 cycles of first-line treatment; relapse group 2 (RG-2), any other relapse; relapse group 3 (RG-3), patients with primary progressive disease. PFS rates at 5 years with 95% CIs are illustrated in the forest plot. All patients with an inadequate response (IR) in RG-3 and RG-2 were considered high risk and received BEAM, (carmustine, etoposide, cytarabine, melphalan). All patients in RG-1 and any patients in RG-2 with AR were considered low risk and treated with radiotherapy (RT) per protocol. Eighteen patients in RG-2 with an adequate response (AR) were treated with BEAM (carmustine, etoposide, cytarabine, melphalan) and autologous stem cell transplant off protocol. LRA indicates late response assessment.

Figure 4.. Kaplan-Meier Plot for Progression-Free Survival (PFS) and Overall Survival (OS) of Different Risk Groups

Of 118 patients analyzed, all were stratified into 3 groups: relapse group 1, patients with late relapse after 2 cycles of first-line treatment; relapse group 2, any other relapse; relapse group 3, patients with primary progressive disease. All patients with an inadequate response in risk groups 2 and 3 were considered high risk and received BEAM, (carmustine, etoposide, cytarabine, melphalan). All patients in risk group 1 and any patients in risk group 2 with adequate response were considered low risk and treated with radiotherapy (RT) per protocol. Eighteen patients in RG-2 with an adequate response (AR) were treated with BEAM (carmustine, etoposide, cytarabine, melphalan) and autologous stem cell transplant off protocol.