Clinical Outcomes of Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received an ABVD Regimen: A Multi-Center Retrospective Study in Japan (HORIZON study)
Authors: Makita Shinichi , Kusumoto Shigeru , Maeshima Akiko Miyagi , Hashimoto Hiroya , Tsujimura Hideki , Uchida Toshiki , Inoue Hiroaki , Ohtsuka Eiichi , Kurosawa Mitsutoshi , Takayama Nobuyuki , Negoro Eiju , Suzuki Yasuhiro , Kuroda Junya , Murayama Kayoko , Takahashi Naoki , Shimada Kazuyuki , Okamoto Masataka , Makita Masanori , Iwasaki Hiromi , Yoshida Masahiro , Asano Naoko , Tamaru Jun-ichi , Maruyama Dai , Yamaguchi Motoko , Nagai Hirokazu 
Published: November 2021

Abstract
Introduction
The prognosis of classic Hodgkin lymphoma (cHL) in young adults has improved following advances in current therapeutics. However, evidence of elderly patients with cHL has limited due to its rarer. To analyze clinical outcomes and risk factors in elderly patients with advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, we conducted a nationwide multi-center retrospective study in Japan (UMIN000033264).
Methods
The key eligibility criteria of the current study were as follows: 1) patients with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis &gt; 60 years; and 4) had received at least one cycle of an ABVD regimen as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m 2 at first cycle). Patients with human immunodeficiency virus infection or methotrexate-associated cHL were excluded. The primary endpoint was 5-year overall survival (OS). Secondary endpoints included progression-free survival (PFS) and event-free survival (EFS), the latter defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause in this study. The average relative dose intensity (ARDI) of ABVD was calculated as the sum of the relative dose intensity of each drug divided by four.
Results
A total of 171 patients from 45 institutions were included in this study. The central pathological review could be performed in 140 cases (82%), in which histological subtypes of cHL were determined as follows: mixed cellularity, 89 (64%); nodular sclerosis, 33 (24%); lymphocyte-deleted, 4 (3%); lymphocyte-rich, 2 (1%); not otherwise specified, 12 (9%). The median age was 71 years (interquartile range [IQR] 65-76). The number of patients in each 10-year age group was 79 (46%) for 61-70 years, 78 (46%) for 71-80 years, and 14 (8%) for &gt; 81 years. The numbers of patients with ECOG performance status (PS) ≥2 and B symptoms were 33 (19%) and 85 (50%), respectively. Bulky mediastinal diseases were found in four patients (2%). The risk factors used for the International Prognostic Score (IPS), including male sex, stage IV, hypoalbuminemia, anemia, leukocytosis, and lymphopenia, were not significantly different among these age groups. The median number of cycles of ABVD was 6 (IQR:5-7), and 66% of patients completed at least 6 cycles. The median ARDI was 77%. The median ARDI in each 10-year age group was 88% for 61-70 years, 71% for 71-80 years, and 54% for &gt; 81 years. With a median follow-up time of 52 months (IQR:31-76), the estimated OS, PFS, and EFS at 5 years were 72%, 59%, and 54%, respectively. Among 131 patients whose Epstein-Barr virus (EBV) status was analyzed using EBV-encoded small RNA1 (EBER1) in situ hybridization, 61 (46%) were positive for EBER1. The OS was not significantly different between EBV-positive and EBV-negative patients (75% and 76% at 5 years, respectively). Univariate analysis for OS revealed that age, PS ≥ 2, hypoalbuminemia, anemia, lymphopenia, and the presence of B symptoms were significantly associated with short OS. In multivariate analysis, age (hazard ratio [HR] 1.568 per 10-year increase, 95% confidence interval [CI] 1.020-2.411) was only an independent risk factor for OS, whereas lymphopenia (HR 1.967, 95% CI 1.196-3.235) was an independent risk factor for EFS. Higher ARDI was significantly associated with improved OS and EFS. Bleomycin-induced lung toxicity (BLT), observed in 41 (24%) patients, was not associated with OS. In this study, we found that 55 patients died: 23 within two years after diagnosis mainly due to cHL progression (n = 10, 43%) and treatment-related toxicity (infection [n = 4, 17%] and BLT [n = 4, 17%]). The remaining 32 patients died more than two years after diagnosis mainly due to second primary malignancies (n = 14, 44%), including solid tumors (n = 6), other types of lymphoma (n = 4), and myelodysplastic syndrome/acute myeloid leukemias (n = 4).
Conclusions
The HORIZON study showed relatively good prognosis for elderly patients with advanced-stage cHL who received an ABVD regimen (estimated five-year OS rates was 72%). Age and lymphopenia were an independent risk factors for OS and EFS, respectively. The development of novel therapies is warranted to improve the outcomes of such patients.

Disclosures
Makita: SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kusumoto: Kyowa Kirin: Honoraria; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Research Funding. Tsujimura: Takeda: Honoraria; Chugai: Honoraria; Kyowa Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria. Takayama: Chugai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding. Kuroda: Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Shimada: BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Otsuka: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; SymBio: Honoraria. Okamoto: Chugai: Research Funding; Kyowa Kirin: Research Funding; Ono: Research Funding; Taiho: Research Funding; Takeda: Research Funding. Asano: Takeda: Honoraria. Maruyama: Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Research Funding; MSD: Honoraria, Research Funding; Otsuka: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yamaguchi: Chugai: Honoraria, Research Funding; Genmab: Research Funding; MSD: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Takeda: Honoraria; Ono: Honoraria; Celgene: Honoraria; Otsuka: Honoraria; Sumitomo Dainippon: Honoraria; Eisai: Honoraria; AstraZeneca: Consultancy. Nagai: AbbVie: Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chordia Therapeutics: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; Novartis: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Research Funding.