Abstract: The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph−) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

Abstract: Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndromes (MDS). Several studies have addressed the efficacy of bridging therapy before allo-SCT including hypomethylating agents, combination chemotherapy (e.g. induction chemotherapy regimen for acute myeloid leukemia [AML]), and low-dose chemotherapy. However, these studies were retrospective, so selection bias was unavoidable, and the optimal bridging therapy prior to allo-SCT remains unclear. We analyzed the bridging therapy and outcomes of patients with MDS registered in a prospective observational study, the JALSG-AML/MDS/CMML Clinical Observational Study-11 (CS-11). Methods: We studied 393 patients with MDS-refractory anemia with excess blasts (MDS-EB) ≤70 years old at registration for CS-11 between 2011 and 2016. We collected new data using an online survey software program (Survey Monkey ®) and analyzed these data following their integration into the CS-11 data. This study was approved by the ethical committee of Kanazawa University (No. 2018-227) and all participating institutions. Results: A total of 371 patients (94.4%) had additional data available and who were included in this study. The median age of the patients at registration of CS-11 was 64 (range: 16-70) years, and 279 (75.2%) were male. The patients' cytogenetic subgroups were divided into very good (n=3 [0.8%] ), good (n=117 [31.5%]), intermediate (n=60 [16.2%] ), poor (n=35 [9.4%]), very poor (n=148 [39.9%] ), and missing data (n=8 [2.1%]), according to Revised International Prognostic Scoring System (IPSS-R). A total of 188 patients (50.7%) were considered for allo-SCT at the diagnosis of MDS-EB, and 141 patients (75.0%) underwent allo-SCT, whereas 181 (48.9%) patients were not considered for allo-SCT at their diagnosis. The overall survival (OS) of the patients considered for allo-SCT at their diagnosis was significantly higher than that of the patients who were not considered for allo-SCT (3-year OS, 33.7% vs. 13.9%, P & lt;0.001). The Cox regression analysis identified consideration for allo-SCT at the diagnosis, performance status, and cytogenetic subgroup according to IPSS-R as independent factors that affect the OS. In an intention-to-treat analysis, bridging therapy included azacytidine (n=90 [50%]), combination chemotherapy such as induction chemotherapy regimen for AML (n=33, [18%] ), and low-dose chemotherapy (n=12 [7%]), while 32 patients (18%) received allo-SCT without bridging therapy. There was no correlation between the various bridging therapies and the transplantation rates or OS in patients considered for allo-SCT. The reasons for discontinuing allo-SCT included cancellation of transplant request (n=12 [30%] ), complications or comorbidity developed during bridging therapy (n=10 [25%]), and uncontrolled MDS (n=7 [17%] ). Conclusion: Transplant-eligible patients with MDS-EB should be considered for allo-SCT. Further studies will be required to determine the optimal bridging therapy prior to allo-SCT. Disclosures Usuki: MSD K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Amgen-Astellas Biopharma K.K.: Research Funding; Mundipharma K.K.: Research Funding; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Handa: Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Suehiro: Amgen BioPharma: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Research Funding; Ono Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding. Maeda: Bayer Yakuhin, Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Novartis Pharmaceuticals: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding. Yamamoto: Bristol-Myers Squibb Company: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; NIPPON SINYAKU CO., LTD: Honoraria; Novartis Pharma: Honoraria; ONO PHARMACEUTICAL CO.: Honoraria; Otsuka Pharmaceutical: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Kiyoi: Astellas: Honoraria; celgene: Honoraria; Daiichi Sankyo: Honoraria; Dainippon Sumitomo: Honoraria; Eisai: Honoraria; Fijifilm: Honoraria; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Perseus Proteomics: Honoraria; Pfizer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Zenyaku Kogyo: Honoraria. Matsumura: Ono: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shionogi: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Sumitomo Dainippon: Research Funding; Nihon Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; AYUMI Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Novartis: Research Funding, Speakers Bureau; Nippon Shinyaku: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding; Amgen: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Janssen: Speakers Bureau; Kyowa Kirin: Research Funding; Eisai: Research Funding; Chugai: Research Funding; Astellas: Speakers Bureau; Asahi Kasei: Research Funding; Addvie: Research Funding. Miyazaki: Pfizer: Honoraria; Kyowa-Kirin: Honoraria; Abbvie: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Janssen: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Chugai: Honoraria; Sanofi: Honoraria.