PET-Guided Treatment in Patients with Early-Stage Favorable Hodgkin Lymphoma: Follow-up Analysis of the HD16 Trial By the German Hodgkin Study Group (2021)

Abstract Background The primary analysis of the HD16 trial initiated in 2018 found that, in the treatment of early-stage favorable Hodgkin lymphoma (HL), involved-field radiotherapy (IF-RT) cannot be omitted from standard combined-modality treatment (CMT) without a clinically significant loss of tumor control. We thus complement the published analysis with prolonged follow-up and data on long-term toxicity. Methods Between 11/2009 and 12/2015, we enrolled 1150 patients aged 18-75 years with newly diagnosed HL in stages I or II without risk factors. Patients were randomized between standard CMT, with 2 cycles of ABVD followed by a centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy IF-RT regardless of PET-2 result, and PET-2-guided treatment, with 2 cycles ABVD followed by 20 Gy IF-RT only in case of a positive PET-2 in terms of a Deauville score (DS) ≥3. Primary endpoint was PFS, analyzed according to Kaplan-Meier using Cox regression and log-rank test as applicable. We aimed at excluding inferiority of the PET-2-guided regimen in terms of a Hazard ratio (HR) of 3.01 or above in the PET-2-negative per-protocol cohort. Another aim was to assess the prognostic impact of PET-2 among those patients assigned to receive CMT. This follow-up analysis aims at repeating the main analyses with prolonged follow-up and complement efficacy results with long-term safety data. Findings With a median follow-up of 64 months, PET-2-negative patients had five-year PFS of 94.2% (95% CI 91.6-96.9) after CMT (n=328) and 86.7% (82.5-90.9) after ABVD alone in the PET-2-guided treatment group (n=300; HR 2.05 [1.20-3.51] including the non-inferiority margin; log-rank p=0.0072). The difference primarily resulted from recurrences that were at least in part located within the potential radiation field, with 5-year cumulative incidences of 2.0% (0.4-3.7) after CMT vs. 10.4% (6.7-14.1) after ABVD alone (p=0.0002). There was no difference regarding second primary malignancies, with 5-year cumulative incidences of 4.6% (2.1-7.1) after CMT vs. 4.2% (1.6-6.8) after ABVD (p=0.57). Five-year overall survival was 98.3% (96.9-99.8) and 98.8% (97.4-100), respectively (p=0.14), with 4 of the 12 documented deaths caused by second primary malignancies and only 1 by HL. Among patients assigned to receive CMT, PFS was superior in the PET-2-negative subgroup (DS 1-2) (n=353; 5-year PFS 94.0% [91.4-96.6]) compared with those having DS ≥3 (n=340; 90.3% [86.9-93.6]; p=0.012). The difference was more pronounced when the more commonly used cutoff of DS 4 was used for positivity (DS 1-3: n=571; 94.0% [91.9-96.0] vs. DS ≥4: n=122; 83.6% [76.6-90.6]; p&amp;lt;0.0001). OS was not impaired in PET-2-positive patients (DS 1-3: 98.8% [97.9-99.8] vs. DS ≥4: 97.2% [94.1-100]; p=0.98). After 5 years of follow-up, cardiac parameters showed normal outcomes in both randomized treatment groups and no relevant decrease compared with baseline values. Among 293 female patients aged 18-40 years at enrollment, the 5-year incidence of childbirth after therapy was 24.0% (15.9-32.2) after standard CMT vs. 17.9% (10.4-25.5) after PET-guided treatment. Conclusion We conclude that radiotherapy cannot be omitted from the treatment of early-stage favorable HL after a negative PET-2 without a clinically relevant and statistically significant loss of efficacy. We could not observe any disadvantage of standard CMT over PET-guided therapy in terms of acute or late toxicities. Overall survival is on a high level and not impaired by the omission of radiotherapy due to effective second-line therapies. Noteworthy the results of the HD16 trial became more pronounced with longer follow-up. This holds true for the per-protocol as well as for the intention-to-treat group. A positive PET after 2 cycles of ABVD in terms of DS ≥4 is associated with significantly inferior efficacy compared with a negative PET, indicating the need for further improvement in this group of patients. Taken together, we recommend that CMT is to be regarded as standard treatment for early-stage favorable HL. Disclosures Fuchs: BMS: Honoraria; Takeda: Consultancy, Honoraria; MSD: Honoraria; Celgene: Honoraria; Lukon: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Topp: Amgen: Consultancy, Research Funding; Macrogeniecs: Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Universitatklinikum Wurzburg: Current Employment; Janssen: Consultancy; Celgene: Consultancy, Research Funding. Hertenstein: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Sanofi: Honoraria. Zijlstra: Takeda: Research Funding. Engert: Astra Zeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Tessa Therapeutics: Consultancy; Hexal: Honoraria; MSD: Honoraria; Amgen: Honoraria; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.