Abstract: 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. Figure. Figure. 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.

Abstract: Background: Tamibarotene, a new synthetic retinoid, displays (i) approximately 10-fold increased potency over ATRA at inducing in vitro differentiation of NB-4 cells (ii) enhanced chemical stability compared with ATRA (iii) low affinity for cellular RA-binding protein. The clinical efficacy of tamibarotene for the treatment of acute promyelocytic leukemia (APL) has also been reported. A prospective randomized controlled study to evaluate tamibarotene by comparison to ATRA was carried out for maintenance therapy of APL in JALSG APL204 (Shinagawa et al, 2014). The 4-year-relapse free survival (RFS) did not differ between patients treated with ATRA or tamibarotene. However, an improved efficacy of tamibarotene in high-risk patients was suggested, which warrants further investigation. Here, we evaluate the long-term outcome of the study. Patients and Methods: Patients enrolled in this study were newly diagnosed with APL and documented cytogenetic and/or molecular evidence of t(15;17)/ PML-RARA . The age of the patients ranged between 15 and 70 years and the ECOG performance status was between 0 and 3. For remission induction therapy, ATRA was administered to all patients at a daily dose of 45 mg/m2 until complete remission (CR). The chemotherapy protocol varied depending on the initial leukocyte count and blast count in the peripheral blood. In brief, patient groups were defined as: leukocytes & lt; 3,000/µl (Group A: ATRA alone), 3,000/µl ≤ leukocytes & lt; 10,000/µl (Group B: ATRA plus IDA/Ara-C: 2+5), and leukocytes ≥ 10,000/µl (Group C: ATRA plus IDA/Ara-C: 3+5). Those patients who experienced leukocytosis received additional chemotherapy (Group D). Patients who achieved molecular remission after consolidation chemotherapy were randomly assigned to 2 groups of maintenance therapy, and administered tamibarotene at a daily dose of 6 mg/m2 divided into 2 doses for 14 days or ATRA at a daily dose of 45 mg/m2 divided into 3 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years. The primary endpoint was hematological or molecular relapse-free survival (RFS) during the maintenance and follow up period. This study is registered at the University Hospital Medical Information Network Clinical Trials Registry as C000000154. Results: A total of 347 patients were enrolled in the study. Of the 344 eligible patients, 319 (93%) achieved CR. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment; 135 patients were assigned to ATRA, and 134 patients were assigned to tamibarotene. The mean follow-up of patients alive and relapse-free at the date of last contact was 7 years. The 7-year RFS rate was 84% for the ATRA arm and 93% for the tamibarotene arm (p=0.031) (Fig.1). When the analysis was restricted to 52 high-risk patients with an initial leukocyte count ≥ 10,000/µl, the difference was more prominent (62% vs 89%, p=0.034) (Fig.2). The 7-year RFS of induction treatment for Group A (92 cases) was 91%, Group B (38 cases) 92%, Group C (52 cases) 75% and Group D (87 cases) 91% (p=0.005). Both treatments were generally well tolerated. Secondary hematopoietic disorders were observed in 12 cases, malignancies in 9 cases, late cardiac complications (grade 3 or more) in 5 cases. However, there was no significant difference in terms of these complications between the two treatment groups. Conclusions: Maintenance therapy with tamibarotene was effective at decreasing the relapse rate in APL patients by comparison to ATRA at the 7-year observation point. In particular, tamibarotene was significantly more effective than ATRA for high risk patients with leukocytes ≧10,000/μl. These results could lead to a new strategy for the treatment of high risk patients, which is one of the recent priority issues in the treatment of APL. Disclosures Takeshita: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co Ltd: Research Funding. Asou: Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Ueda: KAINOS LABORATORIES INC: Membership on an entity's Board of Directors or advisory committees; Abrynx nv: Membership on an entity's Board of Directors or advisory committees; Elli LiLLY Japan KK: Other: Clinical Trial; Takeda PharmaceuticalCompany Limited: Other: Clinical TRial; Otsuka Pharmaceutical Co Ltd: Other: Clinical Trial; Celgene KK: Other: Clinical Trial; Symbio Pharmaceutical Limited: Other: Clinical Trial; AstellasPharma Inc: Other: Clinical Trial; Eisai Co. Ltd: Other: Clinical Trial. Fujita: Chugai Pharmaceutical: Honoraria. Usui: Nippon Shinyaku Pharmaceutical Co: Research Funding. Kobayashi: Pfizer, Ohtsuka, Astellas, Ariad: Research Funding. Kiyoi: Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Meiji Seika Pharma Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Eisai Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; MSD K.K.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding. Atsuta: Otsuka Pharmaceutical Co., Ltd.: Honoraria. Naoe: Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Nippon Boehringer Ingelheim Co.: Honoraria, Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Dainippon Sumitomo Pharma Co.,LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding. Miyazaki: Nippon Shinyaku: Honoraria.