Current Clinico-Epidemiological Characteristics of Adult T-Cell Leukemia-Lymphoma (ATL) Based on the 11th Nationwide Survey in Japan
Authors: Nosaka Kisato , Iwanaga Masako , Ishizawa Kenichi , Ishida Yoji , Uchimaru Kaoru , Ishitsuka Kenji , Amano Masahiro , Ishida Takashi , Imaizumi Yoshitaka , Uike Naokuni , Utsunomiya Atae , Ohshima Koichi , Kawai Kazuhiro , Tanaka Junji , Tokura Yoshiki , Tobinai Kensei , Watanabe Toshiki , Tsukasaki Kunihiro 
Published: November 2019

Abstract
Introduction: Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-cell lymphomacaused by human T-lymphotropic virus type I (HTLV-1), which is endemic in Japan. Only a small percentage of HTLV-1 carriers infected through breast-feeding develop the disease. Previous nationwide surveys during 1980s-2000s in Japan provided a comprehensive view on the clinio-epidemiological profiles of ATL, including the establishment of the subtype-classification (i.e., the Shimoyama criteria: acute, lymphoma, chronic, and smoldering type) based on the diversity of the clinical features and prognosis. Treatment strategies have been developed by the subtype-classification; watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive ATL. The aim of this 11th survey is to characterize the current clinio-epidemiological features of ATL in Japan in the light of previous surveys.
Methods: In 2013-14, we conducted an anonymous, cross-sectional, hospital-based survey of patients with ATL who were newly diagnosed during 2010-2011 across Japan. First, we asked 2500 hospitals with departments of hematology and dermatology to participate in this survey, and then we sent questionnaires to 128 participating hospitals to accumulate data of ATL. Skilled five hematologists reviewed the data of each questionnaire sheet, and the agreements of ATL diagnosis including the subtypes between the central review and participating hospitals were evaluated using Kappa statistics. Most of the collected data were analyzed by descriptive statistics.
Results: A total of 996 ATL patients were registered; of these, 41 were eliminated because of the insufficient information for the diagnosis of ATL. Overall diagnostic agreement on subtype of ATL was substantial, with a kappa value 0.71 (standard error, 0.021); most of the disagreement was within aggressive/indolent category, acute vs. lymphoma types or acute vs. unfavorable chronic types. Among the 955 evaluable patients (M/F ratio, 1.12), 70% were diagnosed in the southwest region of Japan (Kyusyu/Okinawa) where HTLV-1 is endemic, which was consistent with the past surveys. The mean age at diagnosis was 68.3 years (median 68.8, range 24.7-100.3), which was significantly higher than 60.3 years in 1994-1995 and 57.7 years in 1986-1987. The proportion of ATL patients aged over 65 years was 79 % in this survey (whereas, 48% in the 1990-1991 survey), which indicates that the allo-HSCT is not applicable to the majority of current ATL patients in Japan. The proportion of acute, lymphoma, chronic, and smoldering types was 48, 28, 10 and 13%, respectively. The proportion of smoldering and chronic types tended to be greater than previous surveys (7% and 10% in the 1988-1997 surveys combined). The proportion of subtype by age group in this survey showed that the older in age at diagnosis are, the higher proportion of lymphoma subtype (10% in those aged younger than 40 years, 20% in those 50-59, and 31% in those 70 years or older.
Discussion: This 11th survey revealed several clinio-epidemiological features of current ATL in Japan different from those in past two decades. First, a considerably increasing proportion of elderly ATL patients were diagnosed, which may be expected from a recent distribution of nationwide HTLV-1 carriers in Japan (Satake, et al, 2011). Second, there is an increasing tendency in the proportion of indolent types of ATL. This may be partly influenced by participation of the dermatology departments for the first time, because early phase of ATL localized in skin were frequently diagnosed in the dermatology department. Third, the proportion of lymphoma subtype was increased with age, which suggests that aging-related unknown mechanisms may affect the subtype distribution. More detailed analysis and subsequent surveys are planned to further evaluate clinical features and the efficacy of modern therapies on prognosis of ATL.

Disclosures
Ishizawa: Kyowa Kirin: Speakers Bureau; GSK: Research Funding; Takeda: Research Funding; Celgin: Speakers Bureau; Kyowa Kirin: Research Funding; Celgin: Research Funding; Janssen: Research Funding; Takeda: Speakers Bureau; Pfizer: Speakers Bureau. Ishida:Bristol-Myers Squibb: Honoraria. Ishida:Kyowa Hakko Kirin Co., LTD: Honoraria, Other: Research Funding to my institution; Bayer Pharma AG: Other: Research Funding to my institution; Celgene K.K.: Other: Research Funding to my institution. Tobinai:Gilead Sciences: Research Funding. Watanabe:Daiichi Sankyo Co., Ltd.: Research Funding.