Infradiaphragmatic Hodgkin Lymphoma In Patients Treated With State-Of-The-Art Therapies: A Risk Factor Analysis From The German Hodgkin Study Group (GHSG) HD13 and HD14 Trials
Authors: Tresckow Bastian von , Görgen Helen , Plütschow Annette , Böll Boris , Eichenauer Dennis A. , Sasse Stephanie , Rothe Achim , Fuchs Michael , Behringer Karolin , Engert Andreas , Borchmann Peter 
Published: October 2019

Abstract

Introduction
The prognostic impact of isolated infradiaphragmatic Hodgkin Lymphoma (HL) is controversial and no large risk factor analysis in patients treated with state-of-the-art therapies exists. Therefore, we performed a risk factor analysis focusing on isolated infradiaphragmatic nodal disease in patients treated within the German Hodgkin Study Group (GHSG) HD13 (2xABVD vs 2xABV, 2xAVD and 2xAV; followed by 30Gy IFRT each) and HD14 (4xABVD vs 2xBEACOPPescalated plus 2xABVD; followed by 30 Gy IFRT each) trials.

Methods
The characteristics and outcomes of patients with isolated infradiaphragmatic nodal disease qualified for and treated within the HD13 and HD14 trials were compared to patients with supradiaphragmatic nodal disease. Patients with extranodal disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared between groups using the log-rank test. The Cox proportional hazards regression model was applied for multivariate analyses. To assess whether the prognostic impact of infradiaphragmatic disease depends on treatment intensity, patients were divided into groups of less intensive (HD13 arms 2xABV/2xAVD/2xAV and HD14 arm 4xABVD) and more intensive (HD13 arm 2xABVD and HD14 arm 2xBEACOPPescalated plus 2xABVD) chemotherapy, and groups were analyzed separately. All Hazard Ratios (HR) reported for these subgroup analyses were obtained from Cox proportional hazards regression models adjusted for age (HRa).

Results
1500 and 1403 patients with nodal disease from the HD13 and HD14 trials, respectively, qualified for the analysis. Of those, 139 patients from HD13 (9.3%) and 84 patients from HD14 (6.0%) had isolated infradiaphragmatic disease. Compared to patients with supradiaphragmatic disease, these patients were older (median age 47 vs 35 years, p<0.001), had a WHO index >0 more frequently (22.4 vs 15.2%, p<0.01), and had the subtype of nodular sclerosis less frequently (29.7 vs 55.3%, p<0.001). More patients with infradiaphragmatic disease were male (69.5 vs 52.1%, p<0.001). After a median follow-up of 51 months, PFS was significantly worse in patients with infradiaphragmatic disease (5-year PFS 80.1% vs 91.2%, p<0.001). In a multivariate model adjusted for age and sex, infradiaphragmatic HL remained a significant risk factor in terms of PFS (HR 1.6, 95%-CI [1.2-2.3], p<0.01). However, the inferior PFS could only be observed in the group receiving less intensive chemotherapy (HRa 2.1 [1.4-3.0], p<0.001, figure 1A) whereas there was no difference in patients treated within the more intensive arms (HRa 1.1 [0.5-2.3], p=0.8, figure 1B). Similarly, infradiaphragmatic disease was a significant risk factor for OS when analyzed univariately (5-year OS 91.5 vs 97.6%, p<0.001) and in a multivariate model adjusted for age, trial and WHO index (HR 2.2 [1.3-3.7], p=0.002), but this difference was also restricted to the arms with less intensive chemotherapy (HRa 3.0 [1.7-5.5], p<0.001; more intensive chemotherapy: HRa 1.3 [0.5-3.5], p=0.6). To assess if the current GHSG standard for early favorable HL is sufficient to treat patients with infradiaphragmatic disease, 299 patients who received 2xABVD and 20Gy IFRT within the GHSG HD10 trial were additionally analyzed. The rate of infradiaphragmatic disease was 8.4% (25 patients). In this limited number of patients, there was no PFS or OS difference (HRa 1.0 [0.3-3.2], p=0.95 for PFS; HRa 0.8 [0.1-6.0], p=0.8 for OS).

Conclusion
Isolated infradiaphragmatic disease is a risk factor for PFS and OS in HL patients that can be overcome with the current GHSG standard therapies for early favorable (2xABVD followed by 20Gy IFRT) and early unfavorable (2xBEACOPPescalated plus 2xABVD followed by 30Gy IFRT) disease.

Disclosures:
von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Böll:Celgene: Travel Grant Other. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other.