Abstract: Introduction: The outcome of BCR–ABL positive acute lymphoblastic leukemia (ALL) has drastically improved since the introduction of imatinib. We recently reported the clinical results of the Japan Adult Leukemia Study Group (JALSG) ALL-202 study at the 51th ASH Annual Meeting. Most patients (97.1%) achieved complete remission (CR) and 9% of them relapsed within 100 days after CR. In addition, 60% of patients received allogeneic stem cell transplantation during their first CR, and the 3-year overall survival (OS) rate was 57%. We now present the data of the subsequent JALSG Ph+ALL208 study, where we have modified a part of consolidation therapy to prevent early relapse after achieving CR. Methods: The JALSG Ph+ALL208 study was a phase 2 trial for patients newly diagnosed with BCR–ABL positive ALL. Imatinib at a dose of 600 mg/day was administered from day 8 to day 42 combined with daunorubicine (DNR), cyclophosphamide (CPM), vincristine (VCR) and prednisolone (PSL) for induction therapy. Consolidation therapy comprised course 1 (C1: high-dose methotrexate and high-dose cytarabine with imatinib for 18 days) and course 2 (C2: DNR, CPM, VCR, and PSL with imatinib for 20 days). C1 and C2 were repeated alternately for 4 cycles. After consolidation therapy, allogeneic stem cell transplantation (allo-SCT) was recommended if a suitable stem cell donor was identified. Those ineligible for allo-SCT, due to the lack of a suitable donor and/or comorbidity, received maintenance therapy comprising VCR, PSL and imatinib for 2 years from the date they achieved CR. Seventy patients were enrolled between October 2008 and December 2010. Of these, two patients were excluded because they were diagnosed with chronic myeloid leukemia blast phase. Therefore, 68 patients newly diagnosed with BCR–ABL positive ALL were included in this study. The median age was 49 years (18–64 years) and 41% were 〉 54 years. Results: With this treatment regimen, 65 patients achieved CR (95.6%) and only 1% of them relapsed within 100 days after CR. Finally, 35/40 patients (81%) 〈 55 years-old="" and="" 8="" 28="" 19="" 〉 54 years-old were able to receive allo-SCT in their first CR (13 from a sibling donor, 23 from an unrelated bone marrow donor, and 7 from unrelated cord blood). The 3-year OS and disease-free survival (DFS) rates were estimated at 62% and 52%, respectively. Three early deaths occurred during the induction course. One patient (51 years) died of pulmonary bleeding on day 9, another patient (59 years) died of sepsis on day 15, and the third patient (62 years) died of cerebral hemorrhage on day 15. Grade 3 or 4 non-hematologic adverse events including febrile neutropenia and liver dysfunction was reported in 60.3% and 11.8% of the patients, respectively. Twelve patients relapsed after achieving CR with a median time of 307 (64–1053) days. Moreover, 6/43 patients who received allo-SCT relapsed with a median time of 346 (149–602) days. The probability of DFS at 3 years was 72% for patients who underwent allo-SCT in CR compared to only 21% for patients without allo-SCT (p = 0.0004)(Figure.1). Conclusion: We conclude that imatinib-based chemotherapy produced a very high CR rate, thus allowing a high proportion of patients to prepare for allo-SCT, particularly patients 55 years. Moreover, the intensified consolidation therapy reduced the rate of early relapse after induction therapy and resulted in a higher rate of DFS after allo-SCT. Figure 1 Figure 1. Disclosures Hatta: Bristol Myers Squibb: Honoraria. Miyazaki:Novartis: Honoraria. Ohnishi:Novartis: Honoraria.

Abstract: This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib‐combined chemotherapy for newly diagnosed BCR‐ABL‐positive ALL in adults. Sixty‐eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients 〉 55 years of age. Sixty‐five patients achieved CR (95.6%). The estimated 2‐year event‐free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo‐SCT) at initial CR was performed in 43 patients. Thirty‐five of 39 patients 〈 55 years and 8 of 26 patients 〉 55 years underwent allo‐SCT at first CR. The 3‐year OS in patients 〈 55 years receiving allo‐SCT at first CR, patients 〉 55 years receiving allo‐SCT at first CR, patients 〈 55 years not receiving allo‐SCT at first CR, and patients 〉 55 years not receiving allo‐SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively ( P  =   0.058). The three‐year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively ( P  =   0.150). A high CR rate was observed with imatinib‐based chemotherapy allowing allo‐SCT in a high proportion of patients, particularly those 〈 55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo‐SCT. This trial was registered with the UMIN (000001226).

Abstract: The standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

Abstract: The treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has been changed dramatically since the introduction of imatinib. We previously reported a 96% complete remission (CR) rate in newly diagnosed patients treated with imatinib-combined chemotherapy (Yanada et al. J Clin Oncol2006;24:460–466), and showed that the combination therapy is useful in terms of providing patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation (HSCT) in first CR. However, little is known about the outcome after allogeneic HSCT in such patients. To address this issue, we analyzed detailed data from 60 patients who underwent allogeneic HSCT in first CR following a uniform treatment protocol consisting of imatinib and chemotherapy. The median age of the studied patients was 37 years (range, 15–64 years), with 32 males and 28 females. Donors were HLA-matched related (n=24), matched unrelated (n=21), mismatched cord blood (n=9), and mismatched related (n=6). All 52 patients aged less than 55 years received a myeloablative conditioning regimen, whereas 6 of 8 patients aged 55 years or older received a reduced intensity conditioning (RIC) regimen. Grade 2–4 acute graft-versus-host disease (GVHD) was recorded in 20 patients, and chronic GVHD was recorded in 32 patients, 17 of whom had the extensive form. During a median follow-up of 2.6 years (maximum, 4.6 years) after transplantation, relapse and death in first CR occurred in 9 and 15 patients. The probabilities for overall survival (OS) and relapse-free survival (RFS) were 64% and 53%, respectively, at 3 years. Patients younger than 40 years had a trend toward better RFS than those at 40 to 54 years (60% vs. 38% at 3 years, p=0.16). Unexpectedly, all of the 8 patients aged 55 years or older remained alive in first CR. In relation to the donor type, RFS did not differ among patients allografted from a matched related donor, a matched unrelated donor, and mismatched cord blood (52% vs. 59% vs. 56% at 3 years, p=0.92). For risk factor analysis, the following variables were examined: donor type (sibling vs. unrelated vs. cord blood), age group ( & lt;40 years vs. 40–54 years vs. ≥55 years), minimal residual disease status at time of HSCT (quantitative real-time PCR negative vs. positive), type of conditioning regimen (RIC vs. myeloablative conditioning), performance status at time of HSCT, and bcr/abl isotype (major vs. minor). Multivariate analysis revealed that only the presence of major bcr/abl was significantly associated with inferior RFS (HR, 3.70; 95% CI, 1.34–10.2; p=0.012). Conclusion: In patients with Ph+ ALL who were initially treated with imatinibcombined chemotherapy, the outcome after allogeneic HSCT in first CR was favorable irrespective of the donor type. Cord blood transplantation and RIC transplantation might be attractive options for those without a suitable donor and for those unfit for conventional myeloablative conditioning, respectively. Prospective studies are warranted to confirm the roles of these forms of transplantation, especially RIC for patients between 40 and 54 years of age.

Abstract: Background Copy-number alterations (CNAs) and gene mutations are hallmarks of cancer genomes, and they are implicated in the development of myeloid neoplasm. However, their relationships have not been fully examined. To address this issue, we have recently developed a novel, next-generation sequencing-based platform for copy-number analysis, which enabled us to detect mutations and CNAs simultaneously. We applied this platform to around 2,000 cases with myeloid neoplasms. Aims We aimed at delineating the landscape of CNAs and their relationships with gene mutations in myeloid neoplasms. Methods We examined 2,101 cases with myeloid neoplasms by whole-exome sequencing (WES) or targeted deep sequencing. Excluding 116 samples showing low qualities of copy-number signals, we performed subsequent analysis on the remaining 1,985 cases with myelodysplastic syndromes (MDS, n = 1,102), myelodysplastic/myeloproliferative neoplasms (MDS/MPN, n = 140), de novo acute myeloid leukemia (de novo AML, n = 448), and secondary AML (sAML, n = 295). In copy-number analysis, total copy numbers and allele-specific copy numbers (ASCNs) were quantified based on sequencing depths and allelic ratios on genome-wide probes. Copy-number signals were corrected for multiple biases (e.g. GC content, ASCN, and fragment length). We also validated the performance of this platform through comparison with SNP-array karyotyping data in 115 de novo AML cases. CNAs longer than 5 Mb were regarded as arm-level CNAs, and those shorter than 5 Mb were regarded as focal CNAs. Results In total, we identified 4,141 CNAs (52.9 % of cases with at least one CNA), and 3,863 mutations (73.9 % of cases with at least one mutation). Most frequent alterations included -7/del(7q) (13.2 %), del(5q) (11.4 %), trisomy 8 (7.2 %), and del(20q) (5.2 %), and mutations of TET2 (12 .3 %), TP53 (11.3 %), ASXL1 (10.1%), and DNMT3A (9.9 %). To evaluate the difference of copy-number landscapes between de novo AML and myelodysplasia (MDS, MDS/MPN, and sAML), we compared the frequencies of CNAs between them. Uni-parental disomy (UPD) of 13q (FLT3) and 11p (WT1), and amplifications of 11q, 13q, and 21q (ERG) were more enriched in de novo AML, while der(1;7), UPD of 11q (CBL), and del(20q) were enriched in myelodysplasia, suggesting differential involvements of CNAs. We next analyzed the correlations between CNA profiles and prognosis in cases with myelodysplasia. Since TP53 status implies a large impact on both patients' prognosis and CNA profiles, we separately analyzed TP53-positive (n = 53) and negative (n = 686) cases with available survival data. In TP53-negative cases, -7/7qLOH (Hazard ratio(HR): 2.28, q 〈 0.001), and UPD of 11q (CBL) (HR: 2.60, q = 0.0034) significantly correlated with shorter overall survivals (OS), while, in TP53-positive cases, amp(11q), +19, and amp(21q) were marginally associated with shorter OS. To delineate the relationships between CNAs and mutations, we interrogated correlations between both lesions among MDS cases without TP53 alterations (n = 937). A number of significant correlations were detected, such as those between trisomy 8 and del(20q) with U2AF1 mutations (q 〈 0.05, for each), and monosomy 7 and amp(21q) with mutations of RUNX1 and NRAS (q 〈 0.01, for each). These correlations were also revealed in clustering analysis based on CNA and mutation profiles, which identified 5 unique clusters: Cluster 1 (n = 171) with trisomy 8, del(20q), and mutations of U2AF1 and ETV6, Cluster 2 (n = 43) with monosomy 7, amp(21q), and mutations of NRAS, SETBP1, and RUNX1, Cluster 3 (n = 19) with amp(1q) and amp(3q), Cluster 4 (n = 127) with those of SF3B1, TET2, and DNMT3A, and Cluster 5 (n = 50) with those of SRSF2, STAG2, ASXL1, and RUNX1. The remaining 527 cases were not assigned into any cluster due to lack of significantly correlated alterations. Finally, the temporal relationships of coexisting alterations were estimated based on their cell fractions; monosomy 7 had significantly greater cell fractions (P = 0.031) and is predicted to precede NRAS mutations, while the cell fractions of U2AF1 mutations tended to be greater than those of trisomy 8 (P = 0.063), suggesting their implications in different stages of disease progression. Conclusion An integrated analysis of CNAs and mutations in 〉 2,000 cases revealed the impacts of CNAs on disease characteristics and provided novel insight into the interplay between CNAs and mutations in the pathogenesis of MDS. Figure Disclosures Atsuta: CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Kanda:Celgene: Consultancy, Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Taiho: Research Funding; Asahi-Kasei: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Asahi-Kasei: Research Funding; Alexion: Consultancy, Honoraria; CSL Behring: Research Funding; Takara-bio: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Taiho: Research Funding; Celgene: Consultancy, Research Funding; Tanabe Mitsubishi: Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Otsuka: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Usuki:Boehringer-Ingelheim Japan: Other: Received Research ; Daiichi Sankyo: Other: Received Research ; SymBio Pharmaceuticals Limited.,: Other: Received Research ; Novartis: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Takeda Pharmaceutica: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau; Celgene Corporation: Other: Received Research , Speakers Bureau; Sumitomo Dainippon Pharma: Other: Received Research , Speakers Bureau; Pfizer Japan: Other: Received Research ; Stellas Pharma: Other: Received Research ; Otsuka: Other: Received Research ; Kyowa Kirin: Other: Received Research ; GlaxoSmithKline K.K.: Other: Received Research ; Sanofi K.K.: Other: Received Research ; Shire Japan: Other: Received Research ; Janssen Pharmaceutical K.K: Other: Received Research . Imada:Bristol-Meyer Squibb K.K.: Honoraria; Celgene K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria. Takaori-Kondo:Kyowa Kirin: Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Chugai: Research Funding; Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kiguchi:Celltrion, Inc.: Research Funding; Astellas Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; MSD CO., Ltd.: Research Funding; Novartis Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myeres Squibb Co., Ltd.: Research Funding; Janssen Pharmaceutical Co., Ltd.: Research Funding; Celgene Co., Ltd.: Research Funding; SymBio Pharmaceutical Co., Ltd.: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; Tejin Co., Ltd.: Research Funding; Sanofi K.K., Ltd.: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Ogawa:Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; RegCell Corporation: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy.

Abstract: It is known new classification named revised IPSS(IPSS-R) as a prognosis in MDS patients in 2012. To investigate the clinical utility of WT1 mRNA expression level including IPSS-R, we studied of MDS patients who provided consent at 17 medical institutions nationwide from Dec. 2008 to Sep. 2009 were enrolled in Japan. A total of 172 subjects including 115 MDS patients by IPSS (RA:69, RARS:9, RAEB:24, RAEB-t :13 ). 13 patients who developed AML from MDS, and 44 patients with non malignant hematological disorders who provided consent. This study was designed to follow up 82 patients, who gave secondary consent, among 115 MDS patients registered in study ODK-0801 for 5 years up to 2014 to analyze in detail the relationship between the WT1 mRNA expression level and prognosis. WT1 mRNA level in PB and BM were measured using the WT1 mRNA assay kit “OTSUKA” (OTSUKA PHARMACEUTICAL CO., LTD). WT1 mRNA expression levels in peripheral blood (and in bone marrow, if possible) were measured periodically to evaluate the usefulness of the WT1 mRNA expression level as a monitoring marker of MDS and analyze changes in pathology in individual patients by central review and changes in WT1 mRNA expression levels. In this study, value of 50 copies/μgRNA was set as the cut off value for WT-1mRNA expression. The differences in clinical and demographic data were assessed in the chi-square test and logistic regression analysis. The survival data was analyzed using Kaplan-Meier method and compared by the log-rank test. This study presents the results of interim analysis 3 years after the start of the investigation. Results The comparison study between the patients categorized into three groups by the WT1 mRNA level　in BM ,GroupI:less than 102 copies/μgRNA(n=35), Group II: 102 to 104 copies/μgRNA(n=30), and GroupIII: more than 104 copies/μgRNA(n=17) resulted that the survival rates decreased significantly as the WT1 mRNA level increased(GI vs GII P 〈 0.01, GI vs GIII P 〈 0.01, GII vs GIII p 〈 0.067), respectively. In multivariate Cox proportional hazard regression analysis of IPSS, five out of fifteen parameters, which are WBC count (P=0.0001), IPSS score (P=0.0003), blast in PB(P=0.0011), WT1 mRNA level in BM(P=0.0055), sex(P=0.093) were independently associated with survival time, respectively. And we studied same analysis used WPSS. WBC count (P=0.0001), WPSS socre(P=0.0001), blast in PB(P=0.0037), WT1 mRNA level in BM(P=0.0029), sex(P=0.012) were independently associated with survival time, respectively. Also we analyzed using IPSS-R. In multivariate Cox proportional hazard regression analysis, five out of fifteen parameters, WBC count (P=0.0001), IPSS-R score(P=0.0001), blast in PB(P=0.0012), WT1 mRNA level in BM(P=0.01), sex(P=0.01) were independently associated with survival time, but not ANC(both score and absolute number), Hb, platelet, karyotype or other parameters. Using these selected five valiables, we provided the level of WT-1mRNA with 4 risk groups which classified :100, 50100, 100,100, 150,100copies/μRNA). According to increasing of WT-1mRNA level, survival duration shortened the increase with the increase in each risk group. Discussion The WT-1 mRNA level in BM was positively correlated with the prognosis of MDS stage and tended to be correlated with advanced risk of IPSS, WPSS, and IPSS-R. Therefore it was considered to be a useful prognostic marker for MDS. Conclusion We found that the survival time was shortened significantly with an increase in WT1 mRNA expression levels in both peripheral blood and bone marrow, demonstrating that WT1 mRNA expression levels are a highly useful prognostic factor in MDS even if we use any of classification of IPSS, WPSS, IPSS-R. This assay has great possibility to contribute to more appropriate therapeutic decisions in MDS patients as well as diagnosis and to evaluate the timing of allogeneic transplantation. Disclosures: Kurokawa: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding. Usuki:Alexion Pharmaceuticals, Inc.: Speakers Bureau. Ohyashiki:Novartis: Honoraria, 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.

Abstract: Abstract 3118 Introduction: Elderly patients with myelodysplastic syndromes (MDS) are often lack of suitable human leukocyte antigen (HLA)-matched related donors. Unfortunately, the data on the efficacy of allogeneic transplantation using alternative donor sources are limited. We retrospectively compared the outcomes of HLA 6/6 antigen-matched related bone marrow or peripheral blood progenitor cells (rBM/PBPC) transplantation (6/6rBM/PBPCT), HLA 8/8 allele-matched unrelated bone marrow (uBM) transplantation (8/8uBMT), HLA 7/8 allele-matched uBM transplantation (7/8uBMT), and HLA at least 4/6 antigen-matched single-unit umbilical cord blood (CB) transplantation (sCBT) for elderly patients with MDS. Method: The data were obtained from the Transplant Registry Unified Management Program, which includes data from the Japan Society for Hematopoietic Cell Transplantation, the Japan Marrow Donor Program, and the Japan Cord Blood Bank Network. Patients aged 50–70 years old at transplantation with MDS according to French-American-British (FAB) classification who received first allogeneic transplantation between January 1, 2001 and December 31, 2010 were included. Among 336 rBM/PBPC, 291 uBM, and 215 CB transplantation recipients with complete HLA data, 268 6/6rBM/PBPCT, 147 8/8uBMT, 90 7/8uBMT, and 211 sCBT recipients were included. Cox proportional-hazards regression model was used for adjusted comparisons of the donor sources on overall survival (OS). Fine and Gray proportional-hazards model was used for adjusted comparisons of the donor sources on non-relapse mortality (NRM), relapse, grade 2–4 acute graft-versus-host disease (aGVHD2–4), and neutrophil engraftment. Recipient age at transplantation ( 〉 =60 or 50–59), recipient sex (male or female), performance status (PS) at transplantation (2–4 or 0–1), FAB classification at transplantation (refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), or refractory anemia (RA) and RA with ringed sideroblasts), latest cytogenetics classification according to International Prognostic Scoring System (good, intermediate, poor, or unevaluable), transplant conditioning regimen (reduced-intensity conditioning or myeloablative conditioning), and the year at transplantation (2001–2005 or 2006–2010) were included in the multivariate models. Result: Median follow-up was 2.9 years. The unadjusted 3-year OS rates for recipients of 6/6rBM/PBPCT, 8/8uBMT, 7/8uBMT, and sCBT were 50.7%, 58.2%, 46.2%, and 28.4%, respectively. Multivariate analysis revealed that the OS for sCBT recipients was significantly inferior to those for 6/6rBM/PBPCT (relative risk (RR) [95% confidential interval], 1.9 [1.5–2.5] ; P 〈 0.001), 8/8uBMT (RR, 2.3 [1.7–3.2]; P 〈 0.001), and 7/8uBMT (RR, 1.4 [1.0–2.0]; P=0.047) recipients. The OS for 8/8uBMT and 7/8uBMT recipients were comparable with that for 6/6rBM/PBPCT. Other variables associated with significant inferior OS were recipient age 〉 = 60, male sex, PS 〉 1, FAB classification at transplantation as RAEB/RAEBt, and poor cytogenetics. The risk of relapse for sCBT recipients was comparable with that for 6/6rBM/PBPCT but significantly higher than those for 8/8uBMT (RR, 2.4 [1.5–3.8]; P 〈 0.001) and 7/8uBMT (RR, 2.3 [1.3–4.2]; P=0.005) recipients. The risk of NRM for sCBT recipients was significantly higher than that for 6/6rBM/PBPCT recipients (RR, 1.7 [1.1–2.4] ; P=0.009) but comparable with those for 8/8uBMT and 7/8uBMT recipients. The risk for NRM for 7/8uBMT recipients was significantly higher than that for 6/6rBM/PBPCT (RR, 2.1 [1.4–3.1], P 〈 0.001) and 8/8uBMT (RR, 1.6 [1.1–2.5]; P=0.024) recipients. The risk of aGVHD2–4 for 7/8uBMT recipients was significantly higher than those for 6/6rBM/PBPCT (RR, 1.6 [1.1–2.4] ; P=0.008), 8/8uBMT (RR, 1.7 [1.2–2.6], P=0.008), and sCBT (RR, 1.6 [1.0–2.3] ; P=0.032) recipients. Neutrophil engraftment for sCBT recipients was significantly slower than those for 6/6rBM/PBPCT (RR, 0.26 [0.21–0.33]; P 〈 0.001), 8/8uBMT (RR, 0.35 [0.29–0.43]; P 〈 0.001), and 7/8uBMT (RR, 0.40 [0.31–0.51]; P 〈 0.001) recipients. Conclusion: For elderly patients with MDS, the outcome of sCBT recipient was inferior to those of 6/6rBM/PBPCT, 8/8uBMT, and 7/8uBMT recipients. Decreasing the risk of NRM, which would be brought by improving the neutrophil engraftment, and decreasing the risks of relapse are required to improve the outcome of sCBT. Disclosures: No relevant conflicts of interest to declare.