Stage IIb High Risk Hodgkin Lymphoma Treated in the H10 and AHL2011 Trials: Similar Efficacy of Both Strategies and Prognostic Impact of Baseline Tmtv and PET2 Response
Authors: Rossi Cédric , André Marc , Joubert Clémentine , Fortpied Catherine , Brice Pauline , Deau-Fisher Bénédicte , Ghesquieres Herve , Fornecker Luc Mathieu , Gac Anne-Claire , Lazarovici Julien , Stamatoullas Aspasia , Raemakers John , Federico Massimo , Maerevoet Marie , Bailly Sarah , Kanoun Salim , Meignan Michel , Cottereau Anne Ségolène , Casasnovas Rene-Olivier 
Published: February 2020

Introduction
High risk stage IIB Hodgkin lymphoma (HL) with mediastinum-to-thorax ratio of ≥0.33 or extranodal localization are defined as a poor prognosis subset according to German Hodgkin study group (Sieber et al., Ann. of Oncol. 2000). These patients were treated consecutively in our group as limited stage in the EORTC/LYSA/FIL H10 study (André et al, JCO 2017) or advanced stage in the AHL2011 LYSA trial (Casasnovas et al., Lancet Oncol 2019). However, the relative efficacy of each of these strategies to control disease is unknown in this uncommon subset of patients. In the present retrospective study, we compared the outcome of patients with high risk stage IIB included in the H10 and AHL2011 studies, and analyzed prognostic factors.
Methods
We included patients with Ann-Arbor disease stage IIB with mediastinum-to-thorax (M/T) ratio of ≥0.33 or extranodal localization enrolled in the H10 or AHL2011 trials, aged between 16 and 60 years for AHL2011 and 18-60 years for H10 with newly diagnosed Hodgkin lymphoma excluding nodular lymphocyte predominant subtype, who had baseline PET and PET2 images available in the LYSA database. In H10 trial, after 2 cycles of ABVD patients received in the standard arm 2 additional cycles of ABVD plus INRT 30 Gy, in the experimental arm 2 to 4 additional cycles of ABVD;- in PET2 negative patients 4 additional cycles of ABVD (or after the trial amendment 2 additional cycles of ABVD plus INRT 30 Gy); - in PET2 positive patients 2 cycles of escalated BEACOPP plus INRT 30Gy. PET2 were reported according to IHP criteria. In AHL2011 study, after 2 upfront escalated BEACOPP patients received either 4 additional escalated BEACOPP in the standard arm and PET2 positive patients of the PET-driven arm, or 4 cycles of ABVD in PET2 negative patients of the PET-driven arm. PET2 were reported using Deauville score (DS 1-2-3 vs 4-5), DS4 being defined positive if SUVmax of the residual lesion &gt;140% of SUVmax of the liver background.
Baseline clinical and biological characteristics of patients enrolled in both studies were compared. Total metabolic tumor volume (TMTV) at baseline was calculated with the Beth Israel Fiji software based on a 41% SUVmax cutoff of each lesion. In this study, all PET2 response was reanalysed using Deauville score And PET positivity was defined according to the criteria used in the AHL2011 trial.
Results
148 patients were eligible for the study, including 83 and 65 patients enrolled in the AHL2011 and H10 trials respectively. The median age was 27 years (16; 59), 51.4% of patients were treated according to the experimental arm of each trial, the median size of the bulky mass was 84 mm (20-197), the index prognostic score (IPS) was 3 or higher in 29.1% of cases (38.6% in AHL2011 and 16.9% in H10 patients), the median TMTV value was 155.5 ml (8.3-782.9). Most patients had M/T ratio of ≥0.33 (98.6%) and 10.9% had an extra-nodal involvement. 62.2 % of patients had a treatment strategy including escalated BEACOPP and 31.8% received radiotherapy. PET2 was positive in 16.9% (n=14) of AHL2011 cohort and 9.2% (n=6) in H10 cohort patients. With a median follow-up of 4.2 and 4.4 years in AHL2011 and H10 trials respectively, 16 patients (10.8%) relapsed including 7 (10.7%) patients in H10 and 9 (10.8%) in AHL2011, and five deaths occurred with three due to lymphoma progression . Eleven relapses (68.8% for all, 8 for AHL2011 and 3 for H10) were localized in mediastinum.
In univariate analysis, PET2 response, baseline TMTV (155 ml cut off) and IPS (0-2 vs 3-7) significantly influenced PFS with hazard ratios of 6.26 (2.29-17.07), 3.37 (1.093-10.371), 2.89 (0.94-8.86) respectively. The strategy of treatment, either H10 or AHL2011, did not influence PFS. In multivariate analysis stratified on the study (figure 1), only the TMTV as continuous variable (HR: 1.003; 1.000-1.005) and PET2 response (HR: 5.38; 1.99-14.56) were prognostic factors. Among the thirteen patients with high TMTV and PET2 positivity, 7 relapsed (4 for AHL2011 and 3 for H10).
Conclusions
This is the first study comparing two strategies of treatment in high risk stage IIB lymphoma patients included in two large randomized clinical trials. PFS of these patients was 88.0% (95%CI = [81.2%; 92.4%]) at 4 years and similar regardless the study treatment. Baseline TMTV and PET2 response were the main factors influencing the outcome of high risk stage IIB lymphoma patients.
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Disclosures
André: Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. Stamatoullas:Takeda: Consultancy; Celgene: Honoraria. Federico:Seattle Genetics: Research Funding; Allos: Research Funding; Spectrum: Consultancy, Honoraria; Medimmune: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Casasnovas:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees.