Abstract: Background: After long-term analysis of the JALSG-APL204 study we recently reported that maintenance therapy with tamibarotene was more effective than all-trans retinoic acid (ATRA) by reducing relapse in APL patients. Here, the clinical significance of other important prognostic factors was evaluated with multivariate analyses. Patients and Methods: Newly diagnosed acute promyelocytic leukemia (APL) patients were registered with the study. Induction was composed of ATRA and chemotherapy. Patients who achieved molecular remission after consolidation were randomly assigned to maintenance with tamibarotene or ATRA. Results: Of the 344 eligible patients, 319 (93%) achieved complete remission (CR). After completing consolidation, 269 patients underwent maintenance random assignment—135 to ATRA, and 134 to tamibarotene. By multivariate analysis, overexpression of CD56 in blast was an independent unfavorable prognostic factor for relapse-free survival (RFS) (p = 0.006) together with more than 10.0 × 109/L WBC counts (p = 0.001) and the ATRA arm in maintenance (p = 0.028). Of all phenotypes, CD56 was related most clearly to an unfavorable prognosis. The CR rate, mortality rate during induction and overall survival of CD56+ APL were not significantly different compared with CD56− APL. CD56 is continuously an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy.

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.

Abstract: Background: Recent advance in genetic analysis has revealed that many mutations are associated with the development, progression and/or prognosis of core-binding factor acute myeloid leukemia (CBF-AML). Although KIT mutation is the most frequently identified in CBF-AML, its prognostic relevance remains controversial. We conducted the prospective, multicenter cooperative study (JALSG CBF-AML209-KIT, UMIN Clinical Trials Registry UMIN000003434, http://www.umin.ac.jp/ctr/) to evaluate the prognostic impact of KIT mutation, the incidence and clinical relevance of the other gene mutations and prognostic impact of the minimal residual disease (MRD) in CBF-AML. Methods: A total of 199 patients 16 to 64 years of age with newly diagnosed de novo AML were enrolled in this study if they had a RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received 3 courses of high-dose cytarabine therapy (2 g/m2 by 3-hour infusion every 12 hours for 5 days) and no further chemotherapy until relapse. MRD level was evaluated in BM after the completion of the 3-course of consolidation therapy by the quantitation of RUNX1-RUNX1T or CBFB-MYH11 transcript in 112 patients. Target sequencing of 56 genes frequently identified in myeloid malignancies including exons 8, 10, 11 and 17 of the KIT gene were analyzed using the preserved DNA extracted from AML cells at diagnosis. Results: A total of 68 KIT mutations were identified in 63 of 199 patients (31.7%); 42 of 132 (31.8%) and 21 of 67 (31.3%) patients with RUNX1-RUNX1T1 and CBFB-MYH11, respectively. Mutation in exon 17 was the most frequently identified (73.5%), followed by in exon 8 (20.6%) and in exon 10-11 (5.9%). Mutation in exon 8 was more frequent in AML with CBFB-MYH11 (37.5%) than that with RUNX1-RUNX1T1 (11.4%, P=0.014). Although mutation at N822 residue in exon 17 was identified in 13/44 (29.5%) KIT mutations of the patients with RUNX1-RUNX1T1, no patient with CBFB-MYH11 had this mutation (P=0.008); however, mutation at the D816 residue was equally identified in patients with RUNX1-RUNX1T1 (21/44, 47.7%) and CBFB-MYH11 (13/24, 54.1%). The median BM blast percentage of the KIT mutation positive-patients (73.5%) was significantly higher than that of negative-patients (53.8%, P 〈 0.0001). The median follow-up time was 1556 days (range, 356 - 2453 days). There was no significant difference in RFS and OS between the patients with RUNX1-RUNX1T1 and CBFB-MYH11. The 2-year RFS rate was 67.1% in KIT mutation negative-patients and 48.6% in positive-patients (P=0.0033). The 2-year OS rate was 91.0% in KIT mutation negative-patients and 74.6% in positive-patients (P=0.0005). In the patients with CBFB-MYH11, KIT mutations did not affect either RFS or OS. However, in the patients with RUNX1-RUNX1T1, KIT mutations had a strong impact both on 2-year RFS (72.8% vs. 39.5%, P 〈 0.0001) and OS rates (89.7% vs. 63.5%, P 〈 0.0001) in KIT mutation negative- and positive-patients, respectively. Among 3-types of KIT mutations, only the mutation in exon 17 had a worse prognostic impact on CBF-AML, which was also observed in the patients with RUNX1-RUNX1T1 (P 〈 0.001), but not in those with CBFB-MYH11 (P=0.724). Furthermore, mutations at the D816 and N822 residues showed a worse prognostic impact (P 〈 0.0001). In addition to KIT mutations, NRAS (21.7%), FLT3 (12.1%) and ASXL2 (12.0%) genes were frequently identified in CBF-AML. ASXL1 mutation was a favorable factor for RFS in RUNX1-RUNX1T1 and NRAS mutation was a poor prognostic factor for RFS in CBFB-MYH11. The 2-year RFS rate of the patients without MRD was significantly higher than that of those with MRD (81.3% vs. 55.4%, P=0.0075). Notably, the presence of the MRD was associated with worse RFS in the patients with CBFB-MYH11 (P=0.0144), but not in those with RUNX1-RUNX1T1 (P=0.1018). Conclusions: This large-scale prospective study demonstrated that KIT mutation has an adverse effect for OS and RFS only on AML with RUNX1-RUNX1T1 but not on AML with CBFB-MYH11. Notably, we demonstrated that only mutations in the exon 17 of KIT gene had an adverse effect both on the RFS and OS of the patients with RUNX1-RUNX1T1, and the presence of MRD was a poor factor for RFS in AML with CBFB-MYH11. Figure 1 Figure 1. Disclosures 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:Pfizer Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Celgene Co.: Research Funding; Sysmex Co.: Research Funding. Asou:Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Yakult Honsha Co., Ltd.: Speakers Bureau; SRL Inc.: Consultancy; Eisai Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Naoe:Pfizer Japan Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding. Kiyoi:Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Celgene Corporation: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Phizer Japan Inc.: Research Funding; FUJIFILM Corporation: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding.

Abstract: In this phase II multicenter study (JALSG AML209‐FLT3‐SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1) for FLT3 ‐internal tandem duplication (ITD)‐positive AML. Newly diagnosed de novo AML patients with FLT3 ‐ITD were enrolled at the achievement of CR1 and received allo‐HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17‐49) years, 36 (75%) received allo‐HSCT at a median of 108 days after CR1. The median follow‐up was 1726 days. The primary end‐point, 3‐year disease‐free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%‐57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3‐year overall survival, post‐transplant DFS, and non‐relapse mortality rates were 54.2% (95% CI, 39%‐67%), 58.3% (95% CI, 41%‐72%), and 25.0% (95% CI, 12%‐40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006‐4.099). Neither FLT3 ‐ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo‐HSCT for FLT3‐ ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Abstract: KIT exon 17 mutation is a poor prognostic factor in AML patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11. NRAS mutation is a poor prognostic factor in AML patients with CBFB-MYH11.

Abstract: Background: Since FLT3-ITD is a poor prognostic factor for acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is practically performed. However, clinical usefulness of allo-HSCT at the first remission (CR1) has not been fully evaluated by the prospective study. To prospectively elucidate the role of allo-HSCT at CR1 in younger adult patients with FLT3-ITD positive AML and explore the prognostic impacts of clinical and genetic features, we conducted a phase II multicenter study (JALSG AML209-FLT3-SCT, UMIN Clinical Trials Registry UMIN000003433, http://www.umin.ac.jp/ctr/). Methods: A total of 49 patients 16 to 49 years of age with newly diagnosed de novo AML were enrolled in this study if they had a FLT3-ITD mutation and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received allo-HSCT as soon as possible while continuing 4 courses of consolidation therapy combining cytarabine plus mitoxantrone, daunorubicin, aclarubicin or etoposide, vincristine, and vindesine. Patients received no further chemotherapy until allo-HSCT or relapse. Conditioning was selected according to each institutional standard from myeloablative regimens except for reduced intensity conditioning only in patients older than 40 years old or with higher HCT-CI than 1 point. GvHD prophylaxis was according to each institutional standard based on cyclosporine A or tacrolimus combined with short-term MTX. Targeted sequencing of 57 genes frequently identified in myeloid malignancies were analyzed using the preserved DNA extracted from AML cells at diagnosis. FLT3-ITD allelic ratio (AR) was quantified using DNA fragment analysis. Primary endpoint was 3-year disease-free survival (DFS). Results: Among 48 eligible patients with the median age of 38.5 (range, 17-49) years, 36 (75%) maintained CR1 to receive allo-HSCT at the median of 108 (range, 54-228) days after the achievement of CR1. Median follow-up was 1,726 (range, 983-2,974) days. The 3-year DFS rate was 43.8% (95% confidence interval [CI], 30-57%, Figure 1). The lower limit of 95% CI exceeded threshold response rate of 20%, concluding the treatment was effective. The 3-year overall survival, post-transplant DFS and non-relapse mortality rates were 54.2% (95%CI, 39-67%), 58.3 % (95%CI, 41-72%) and 25.0% (95%CI, 12-40%), respectively. There was no significant difference in DFS post allo-HSCT according to donor sources (related BM 64.6% vs. related PB 50.0% vs. unrelated BM 63.6% vs. UCB 60.0% at 3 years, P= .881). Neutrophil recovery was achieved in 94.3%. Cumulative incidences of grade II to IV and III to IV acute GvHD at day 100 were 21.2% (95%CI, 9-37%) and 9.1% (95%CI, 2-22%), respectively. Cumulative incidence of chronic GvHD at 1 year was 25.0% (95%CI, 12-40%). Mutations in NPM1 gene (65%) and genes associated with DNA methylation were frequently identified including DNMT3A (36%), IDH1 (6%), IDH2 (17%) and TET2 (17%, Figure 2). Median ITD AR was 0.344 (range, 0.006-4.099). There was no significant overlap of genetic alterations with high ITD-AR (≥ 0.5). No significant impact on DFS was observed by high ITD AR (≥0.5) (Hazard ratio [HR], 1.53; 95%CI, 0.58-4.06; P= .39) or other co-occurring genetic alterations including NPM1 mutations (HR, 0.78; 95%CI, 0.28-2.20; P= .64). Conclusions: This prospective study demonstrated the efficacy and safety of proceeding faster to allo-HSCT in CR1 for younger adult patients with FLT3-ITD positive AML, whose graft sources were not limited to HLA identical donors and the first available donor should be considered. Beyond FLT3-ITD mutations, no significant prognostic factor was identified in their genetic background or high ITD AR. Further study is required to improve the prognosis of AML patients with FLT3-ITD by establishment of an adequate therapeutic strategy using FLT3 inhibitors and allo-HSCT. Disclosures Atsuta: Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Sawa:Asahi-Kasei: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Shire: Honoraria; Mundi Pharma: Honoraria. Ozawa:Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria. Tomita:Taiho Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Maeda:Nippon Shinyaku Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K..: Honoraria. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Matsuoka:Takeda Pharmaceutical: Research Funding; Novartis: Research Funding; Astellas Amgen Biopharma: Consultancy. Asou:SRL Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharm Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Novartis Pharmaceuticals: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Chugai: Research Funding; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria. Kiyoi:Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding.

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.