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2798 CD56 Is an Unfavorable Prognostic Factor for Acute Promyelocytic Leukemia: Results By Multivariate Analyses in the JALSG-APL204 Study

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Diseases, AML, Myeloid Malignancies
Sunday, December 2, 2018, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Akihiro Takeshita, MD, PhD1, Norio Asou, MD, Ph.D2, Yoshiko Atsuta, MD, PhD3*, Hiroaki Furumaki, MD1*, Toru Sakura, PhD, MD4*, Yasunori Ueda, MD, PhD5, Masashi Sawa, MD, PhD6*, Nobuaki Dobashi, MD7, Rikio Suzuki, MD, PhD8, Yasuhiro Taniguchi, MD9*, Masaru Nakagawa, MD, PhD10*, Shigehisa Tamaki, MD11*, Maki Hagihara, MD, PhD12*, Katsumichi Fujimaki, MD13*, Yasuhisa Yokoyama, MD, PhD14*, Hiroyuki Fujita, MD15, Masamitsu Yanada, MD, PhD16*, Yoshinobu Maeda, MD, PhD17, Noriko Usui, MD, PhD18, Yukio Kobayashi, MD, DSc19, Hitoshi Kiyoi, MD, PhD20, Shigeki Ohtake, MD, PhD21, Itaru Matsumura, MD9, Tomoki Naoe, MD, PhD22 and Yasushi Miyazaki, MD, PhD23

1Hamamatsu University School of Medicine, Hamamatsu, Japan
2Saitama Medical University, International Medical Center, Hidaka, Saitama, Japan
3The Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
4Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan
5Department of Haematology/Oncology, Kurashiki Central Hospital, Kurashiki, Japan
6Anjo Kosei Hospital, Anjo, Japan
7Department of Clinical Oncology and Hematology, The Jikei University Daisan Hospital, Tokyo, Japan
8Tokai University School of Medicine, Isahara, Japan
9Kindai University Faculty of Medicine, Osaka-Sayama, Japan
10Nihon University School of Medicine, Tokyo, Japan
11Ise Red Cross Hospital, Ise, Japan
12Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan
13Fujisawa City Hospital, Fujisawa, Japan
14Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
15Saiseikai Yokohama Nanbu Hospital, Yokohama, Japan
16Fujita Health University School of Medicine, Toyoake, Japan
17Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
18Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
19Hematology Division, IUHW Mita Hospital, Tokyo, Japan
20Nagoya University Graduate School of Medicine, Nagoya, Japan
21Kanazawa University, Kanazawa, Japan
22National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
23Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

Background: CD56 expression is reported to be associated with adverse prognosis in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy (Murray et al, 1999, Ferrara et al, 2000, Montesinos et al, 2011, Ono T et al, 2014). However, the prognostic significance of CD56 has not been elucidated, particularly when more potent agents are used. We recently reported long term analysis of the Japan Adult Leukemia Study Group (JALSG) APL204 study and concluded that maintenance therapy with tamibarotene was more effective than ATRA by reducing relapse in APL patients (Takeshita et al, 2018). In this study, the clinical significance of CD56 was evaluated with other surface markers on APL cells.
Patients and Methods: Newly diagnosed APL patients with documented cytogenetic and/or molecular evidence of t(15;17)/PML-RARA were registered to the APL204 study from April 2004 to December 2010. The eligibility criteria included age between 15 and 70 years, ECOG performance status between 0 and 3, and sufficient function of organs. Induction therapy was composed of ATRA and chemotherapy whose dose and duration were based on initial white blood cell (WBC) count. Patients who achieved molecular remission after three courses of consolidation therapy were randomly assigned to maintenance therapy with tamibarotene 6 mg/day for 14 days or ATRA 45 mg/day for 14 days, which was repeated every 3 months for 2 years. The primary endpoint was hematological or molecular relapse-free survival (RFS). Surface markers, including CD56, were defined as positive if more than 10% of the CD45-gated cells expressed a specific antigen. Clinical characteristics were compared by the chi-square test or the Fisher’s exact test for categorical data and the Wilcoxon rank-sum test for continuous data. RFS, overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier method, and compared using the log-rank test. Cumulative incidence of relapse (CIR) was compared by Gray’s test. Multivariate analyses were also performed by the Cox-proportional-hazards-model. Clinical outcomes were renewed between January 2016 and June 2017 and the median follow-up period was 7.3 years. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as C000000154.
Results: Of the 344 eligible patients, 319 (93%) achieved CR. After completing consolidation chemotherapy, 269 patients underwent maintenance random assignment; 135 to ATRA, and 134 to tamibarotene. Among 344 eligible patients, 325 were assessable for CD-phenotypes, and 45 (14%) were CD56-positive (CD56+). Among 269 patients who underwent the maintenance assignment, 34 (13%) were CD56+. CD56 expression was significantly associated with obvious bleeding (p<0.001). The CR rate and mortality during induction therapy were not significantly different compared with CD56- APL. RFS and CIR was significantly inferior in CD56+ APL (77% vs. 91%, HR 3.04, 95% CI 1.34-6.90, p=0.005 and 24% vs. 8%, p=0.004, respectively), whereas OS was not significantly different between the two groups 80% vs. 89%, p=0.069). In patients whose initial WBC counts were more than 3.0 x 109/L, RFS for the CD56+ group (n=14) was significantly inferior (64% vs. 87%, p=0.028), while in patients whose initial WBC count was under 3.0 x 109/L (n=20), RFS was not different (85% vs. 93%, p=0.164). Other surface markers such as CD13 and CD33 did not show any prognostic significance except for CD34 (p=0.040). By multivariate analysis, CD56 expression was an independent unfavourable prognostic factor for RFS (HR=3.19, 95% CI 1.40-7.25, p=0.006) together with more than 3.0 x 109/L WBC counts (p=0.001) and the ATRA arm in maintenance therapy (p=0.028).
Conclusions: CD56 expression is an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy, especially in patients whose initial WBC count was more than 3.0 x 109/L. The present study supports the prognostic significance of CD56 in the treatment of APL using more potent agents.

Disclosures: Takeshita: Chugai Pharmaceutical Co. Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Takeda Pharmaceutical Co. Ltd.: Research Funding; Bristol-Myers Squibb Co.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding. Asou: Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Sawa: Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Dobashi: Celgene Co.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Sysmex Co.: Research Funding. Kobayashi: Pfizer: Research Funding; Ohtuka: Research Funding; Astellas: Research Funding. Kiyoi: Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria; FUJIFILM Corporation: Research Funding; Celgene Corporation: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Astellas Pharma Inc.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Miyazaki: Chigai: Research Funding; Dainippon-Sumitomo: Honoraria; Pfiser: Research Funding; Kyowa-Kirin: Honoraria; Takeda: Research Funding; Nippon-Shinyaku: Honoraria; Ohtsuka: Honoraria, Research Funding.

*signifies non-member of ASH