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Fuchs, M.1; Goergen, H.1; Kobe, C.2; Eich, H.3; Baues, C.4; Greil, R.5, 6; Sasse, S.1; Zijlstra, J. M.7; Lohri, A.8; Rosenwald, A.9; von Tresckow, B.1; Diehl, V.1; Kuhnert, G.2; Dietlein, M.2; Borchmann, P.1; Engert, A.1

doi: 10.1097/01.HS9.0000561556.28202.f8
Simultaneous Sessions II: Hodgkin lymphoma - Clinical

1German Hodgkin Study Group (GHSG), Department I of Internal Medicine

2Department of Nuclear Medicine, University Hospital of Cologne, Cologne

3Department of Radiotherapy, University Hospital of Muenster, Muenster

4Department of Radiooncology and Cyberknife Center, University Hospital of Cologne, Cologne, Germany

5Salzburg Cancer Research Institute on behalf of the AGMT Study Group

6IIIrd Medical Department, Paracelcus Medical University, Salzburg, Austria

7Department of Hematology, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands

8Onko-Praxis Bethesda, Birsfelden, on behalf of the SAKK Study Group, Berne, Switzerland

9Institute of Pathology, Julius Maximilian University of Würzburg and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany

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In our HD16 study for early-stage favorable Hodgkin lymphoma (HL), we used PET after 2 cycles of ABVD to guide involved-field radiotherapy (IFRT). As in our parallel HD18 trial, we defined a Deauville score (DS) ≥3 as positive. However, HD18 showed that DS3 did not indicate an increased risk of treatment failure in advanced-stage HL, while DS≥4 added prognostic information to baseline risk factors.

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We investigated whether these results also hold true in the context of early-stage favorable HL patients treated with ABVD and IFRT in our international HD16 trial (NCT00736320).

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Between November 2009 and December 2015, we recruited 1150 patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard combined-modality treatment (CMT) with 2xABVD and 20 Gy IFRT or PET-guided treatment, where IFRT was restricted to patients with DS ≥3 after 2xABVD. PET was centrally assessed by an expert panel blinded towards the randomization result. A central objective of the trial was to prospectively test whether a DS ≥3 was associated with impairment in progression-free survival (PFS) among patients treated with CMT (i.e. those randomized to the standard group and those from the PET-guided randomization group with DS ≥3). We also explored the association of DS with baseline characteristics and treatment outcomes considering different cutoffs for positivity. We analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons.

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Among 1007 randomized patients with regular PET, 667 (66%), 218 (22%) and 122 (12%) had DS 1-2, 3 and 4, respectively. Of those, 693 were assigned to treatment with CMT (353, 218 and 122 with DS 1-2, 3 and 4, respectively). Clinical stage II and bulky disease at initial staging were associated with an unfavorable DS after 2xABVD. CT-based complete remission as final treatment outcome after IFRT was observed in 344/348 patients (99%) with interim DS1-2, 209/214 (98%) with DS3, and 108/117 (92%) with DS4 (p = 0.016 for DS1-2 vs. 3-4; p = 0.0012 for DS1-3 vs. 4). Of note, all six progressions in this trial occurred in the DS4 subgroup. With a median follow-up of 46 months, the estimated 5-year PFS was 93.2% (90.2-96.2) among patients with DS1-2, 92.8% (88.8-96.9) for those with DS3 and only 80.9% (72.2-89.7) in the DS4 subgroup. Considering DS ≥3 as cutoff, the PFS difference was just statistically significant (HR 1.71 [1.00-2.93], p = 0.047). An analysis adjusting for baseline stratification factors led to similar, but non-significant results (HR 1.73 [0.99-3.02], p = 0.055). With DS4 as cutoff, the difference became more pronounced, indicating a threefold risk for treatment failure in patients with DS4 after chemotherapy (HR adjusted for baseline factors 2.94 [1.63-5.31], p = 0.0004). Overall survival was on a high level with no differences between any subgroups defined by DS (5-year overall survival 98.2% [96.7-99.8] for DS1-2, 98.6% [96.0-100] for DS3, 96.5% [92.3-100] for DS4).

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In early-stage favorable HL, a positive PET after 2xABVD is associated with a larger tumor volume and represents a risk factor for PFS among patients treated with standard CMT, particularly when DS4 is considered as cutoff for positivity. PET-guided treatment intensification in this high-risk subgroup might help to reduce the frequency of relapses.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.