Comparative Analysis of Japanese and European Typical CLL Patients
Authors: Takizawa Jun , Gruber Michaela , Suzuki Ritsuro , Nakamura Naoya , Hoermann Gregor , Muellauer Leonhard , Aoki Sadao , Suzumiya Junji , Jaeger Ulrich 
Published: October 2019

Abstract
Background: Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the Western countries but very rare in the East Asia including Japan. The previous reports from Japan showed that CLL patients in Japan have different characteristics including atypical morphology and immunophenotypes compared to those of Western countries. We started the cooperative study of CLL between Japan and Austria from 2012.
Aim: The aim of this retrospective study is to compare the characteristics of typical CLL patients in Japan and Austria.
Material and Methods: Diagnostic procedures were first harmonized between sites and laboratories. Samples were exchanged between Japan and Austria, and morphology, flow cytometry (FCM), FISH and IGVH gene sequence were independently assessed. After technical agreement, we selected 86 Austrian CLL patients from the database of the Medical University of Vienna, and 80 Japanese patients from the CLLRSG-01 prospective observational study. All CLL cases had typical immunophenotypes (Matutes score 4 or 5). The analyses of morphology, FCM and FISH including the deletion in 11q22, 13q14, and 17p13, and trisomy 12 were performed. Immunoglobulin heavy chain variable region (IGHV) gene mutation was also analysed.
Results: Median age of CLL patients was 62.5 years old (range: 35-93) in Austria and 66.4 years (range: 34-93) in Japan. Japanese patients were significantly older at diagnosis than Austrian patients (P = 0.027). No differences were found for sex and the Binet stage. Also, there were no differences in laboratory findings (lymphocyte and platelet counts and serum LDH and beta-2-microglobulin levels) except for hemoglobin (Hb) level (median: 13.8g/dL in Austria vs. 13.1g/dL in Japan, P = 0.005) between two countries. Immunophenotypic study by FCM showed higher proportion of CD38 expression in Austrian CLL patients (34% in Austria vs. 10% in Japan, P < 0.001). No differences were found for chromosomal aberrations by FISH analyses between Austria and Japan. del(13q14) was found in 62% and 56% (P = 0.456), trisomy 12 in 7% and 13% (P = 0.315), del(11q22) in 13% and 10% (P = 0.513) and del(17p13) in 7% and 3% (P = 0.179), in Austria and Japan, respectively. The IGHV mutation rate was higher in Japan (P = 0.002). Mutated IGHV was found in 61% of Austrian and 84% of Japanese patients. IGHV family usage profile was significantly different. In Austrian patients, VH1, 2, 3, 4, 5, 6, and 7 were 24%, 1%, 54%, 19%, 1%, 1% and 0%, respectively. However, in Japanese patients, they were 2%, 0%, 75%, 20%, 2%, 0% and 2%, respectively. The proportion of VH1 was surprisingly lower in Japan (P = 0.006). Notably, none of the Japanese patients used VH1-69, in contrast to the use of 10% in Austrian patients.
Conclusion : Our analysis indicates that there are clear differences between Japanese and European CLL patients, in age, Hb level, CD38 expression and IGHV usage and mutations. The reason for particular IGHV usage should further be investigated.

Disclosures
Takizawa: Teijin: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Janssen: Honoraria; Sumitomo Dainippon: Honoraria, Research Funding; MSD: Honoraria, Research Funding. Suzuki:Bristol-Myers Squibb: Honoraria; Kyowa Hakko kirin: Honoraria; Chugai: Honoraria. Hoermann:Gilead: Research Funding; Novartis: Honoraria; Amgen: Honoraria; Ariad: Honoraria. Aoki:SymBio Pharmaceuticals: Consultancy. Suzumiya:Kyowa Hakko kirin: Research Funding; Eisai: Honoraria, Research Funding; Astellas: Research Funding; Takeda: Honoraria; Toyama Chemical: Research Funding; Chugai: Honoraria, Research Funding. Jaeger:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses.