Abstract: MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR‐142) is frequently mutated in patients with follicular lymphoma, diffuse large B‐cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR‐142 mutation in blood cancers, the CRISPR‐Cas9 system was utilized to successfully generate miR‐142‐55A 〉 G mutant knock‐in (Ki) mice, simulating the most frequent mutation in patients with miR‐142 mutated AML/MDS. Bone marrow cells from miR‐142 mutant heterozygous Ki mice were transplanted, and we found that the miR‐142 mutant/wild‐type cells were sufficient for the development of CD8 + T‐cell leukemia in mice post‐transplantation. RNA‐sequencing analysis in hematopoietic stem/progenitor cells and CD8 + T‐cells revealed that miR‐142‐Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild‐type miR‐142‐3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt–mTOR pathway was suppressed in miR‐142‐55A 〉 G heterozygous cells, indicating that these genes are repressed by the mutant miR‐142‐3p. Thus, in addition to the loss of function due to the halving of wild‐type miR‐142‐3p alleles, mutated miR‐142‐3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.

Abstract: [Background] Allogeneic hematopoietic stem cell transplantation (HSCT) is a potent treatment to cure in patients with aplastic anemia (AA). However, an optimal pre-transplant conditioning remains unclear. The combination of high-dose cyclophosphamide (CY) and anti-thymocyte globulin (ATG) has been used as an effective conditioning, but cardiotoxity due to high-dose CY has been a major concern especially in patients with iron overload by excessive transfusion. In addition, the appropriate dose and timing of ATG use is another unsolved topic in HSCT for AA. Therefore, we performed a prospective study to assess the safety and efficacy of a conditioning regimen using fludarabine (Flu), reduced-dose CY, and low-dose thymoglobulin in HSCT for AA. [Methods] Patients with severe AA, aged between 16 and 65 years, who have an HLA-matched or 1-locus mismatched, related or unrelated donor were prospectively included. A conditioning regimen consisted of Flu 30mg/m2 for 4 days, CY 25mg/kg for 4 days, and thymoglobulin 1.25mg/kg for 2 days (days -4, and -3). In patients who underwent transplantation from unrelated and/or HLA-mismatched donor, 2 Gy of total body irradiation was added. Cyclosporine for an HLA-matched related donor or tacrolimus for the other donors, together with short-term methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Granulocyte-colony stimulating factor was used from 1 day after transplantation. Primary outcome measure was an overall survival at 1 year after HSCT. This study was approved by the Institutional Review Board of all the participating institutions. [Results] Twenty-eight patients were enrolled between 2011 and 2017, and their median age was 36 years (range: 18 - 61y). Sixteen patients were male. A median time from diagnosis to transplantation was 1858 days in patients who had previously received immunosuppressive therapy (IST) using ATG (n = 16) and 121 days in those who had not received IST (n = 12). Sixteen patients received graft form related donors including 1 HLA-mismatched donor, and 12 patients did from unrelated donors including 3 mismatched donors. Stem cell source was bone marrow in 27 out of 28 patients. All patients but one, who died early due to infection, achieved neutrophil engraftment at a median of 19 days after HSCT. Mixed chimerism (MC) was observed in 6 patients at day 30, and 3 out of those 6 patients achieved complete donor chimerism by day 90. On the other hand, MC was newly observed in additional 2 patients at day 90. Only one patient experienced secondary engraftment failure, and which developed with complete donor-type chimerism at day 99. No patients developed grade 2-4 acute GVHD. However, the cumulative incidence of chronic GVHD was 39.9 % at 1 year, and one third of them had extensive type. With a median follow-up period of 1727 days for survivors, overall survival rates (OS) were 96.4 % at 1 year and 82.8 % at 5 years (Figure 1). Cytomegalovirus (CMV) antigenemia was detected in 17 patients, but no patients developed CMV disease. A high Epstein-Barr virus (EBV)-DNA load (more than 1×104 copies/mL) was detected in 2 patients at day 60 and 1 patient at day 90. Neither developed EBV-lymphoproliferative disorder (LPD) within a year. However, another patient, in whom high EBV-DNA load was not detected within 90days after HSCT, developed EBV-LPD and died at three and a half years after HSCT. [Conclusion] HSCT for AA using Flu, reduced-dose CY, and low-dose thymoglobulin as a conditioning regimen was safe and effective. Relatively high incidences of MC and chronic GVHD need further improvement. (This study is registered with www.umin.ac.jp as UMIN000006071.) Disclosures Kako: Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Tanabe-Mitsubishi: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Taiho: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Otsuka: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria. Usuki:Ono Pharmaceutical: Speakers Bureau; GlaxoSmithKline K.K.: Research Funding; Janssen Pharmaceutical K.K: Research Funding; Sanofi K.K.: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Takeda Pharmaceutical: Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Mori:Astella Pharma: Honoraria; Shire Japan: Honoraria; Janssen: Honoraria; SHIONOGI: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Novartis Pharma: Honoraria; Celgene: Honoraria; Japan Blood Products Organization: Honoraria; Pfizer: Honoraria; CHUGAI: Honoraria; MSD: Honoraria; Eisai: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; MSD: Research Funding; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria.

Abstract: Background Therapy-related myeloid neoplasms (t-MN) have a poor prognosis with conventional chemotherapy and a median survival of ≤1 year. Allogeneic stem cell transplantation (HCT) is considered the only effective treatment. EBMT and CIBMTR analyzed their registry data on HCT against t-MN and reported its outcome and developed scoring systems using identified risk factors in HCT. This study aimed to investigate outcome and risk factors in adult patients with t-MN who underwent HCT in Japan. Methods Data source For this retrospective observational study, recipients' clinical data were provided by the Transplant Registry Unified Management Program of Japan society for Hematopoietic Cell Transplantation. Definition Therapy-related myeloid neoplasms include therapy-related AML (t-AML), t-MDS, and t-MDS/MPN occurring as late complications of cytotoxic chemotherapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Cases with past history of MDS or MPN were excluded because it was not possible to clearly distinguish their neoplasms from an original myeloid neoplasm or therapy-related neoplasm. The primary outcome of the analysis was overall survival (OS), whereas the secondary endpoints included incidence of relapse and transplantation-related mortality (TRM). Cytogenetic risk groups in AML were classified according to the MRC (2010). In MDS, three risk groups were defined using the revised International Scoring System: favorable (very good and good), intermediate (intermediate), poor (poor and very poor). HLA mismatch was defined as incompatibility between the recipient and donor when at least a single allele mismatch was detected at HLA-A, -B, and -DR in related and unrelated donors. In cord blood, HLA mismatch was defined as at least two antigen mismatches detected at HLA-A, -B, and -DR. Statistical analysis OS was estimated using the Kaplan-Meier method and was compared using the log-rank test. Cox's proportional-hazards regression model was used for multivariate analysis of prognostic factors. Cumulative incidence curves were used in a competing-risk setting to calculate the probability of relapse and TRM. Relapse and therapy-related deaths were considered a competing risk event for each other and were compared using Gray's test. Results Between 1992 and 2012, 641 adult patients who had undergone HCTs for confirmed t-MN (not de novo myeloid neoplasms) were identified. Median age at HCT was 53 (range; 16-80) years, with a female proportion of 49%. In total, 414 (64.6%) patients had AML, 215 (33.5%) had MDS, and 12 (1.9%) had MPN. Approximately 50% of patients had a prior history of lymphoma, 14.6% had acute leukemia, and 13.3% had breast cancer. Karyotype was available in 310 cases. Favorable karyotypes were detected in 11 (3.5%) cases, whereas intermediate and poor karyotypes were detected in 122 (39.4%) and in 177 (57.1%) cases, respectively. HLA mismatched HCT was 25.7%. Bone marrow or peripheral HCT from related donors was used in 189 (28.7%) cases, whereas bone marrow HCT from unrelated donor was used in 228 (35.7%) cases, and cord blood HCT was used in 229 (35.6%) cases. Approximately 30% of patients were in remission at HCT. Overall survival was 45.3% [95% confident interval (CI) 45-48], 33% (CI 29-37), and 28% (CI 24-32) at 1, 3, and 5 years, respectively. In multivariate analysis, the significant factors for poor survival were ECOG Performance Status (PS) 2-4 (HR 1.99; CI 1.45-2.72), disease status of non-remission at the time of HCT (HR 1.82; CI 1.33-2.50), patient age of 〉 55 years (HR 1.72; CI 1.32-2.24), and poor karyotype (HR 1.54; CI 1.15-2.05). The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 36%, respectively. In a multivariate analysis, the significant factor for non-relapse mortality was patient age of 〉 55 years (HR 1.48; CI 1.09-2.02). For relapse, poor karyotype (HR 2.29; CI 1.65-3.18) was a significant factor. Conclusions PS 2-4, non-remission, higher patient age, and poor cytogenetics were predictive of poor survival. The outcome of HCT against therapy-related myeloid neoplasms in Japan was comparable to those of EBMT and CIBMTR. Disclosures Usuki: Novartis: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Fuji Film RI Pharma: Other: personal fees; Chugai Pharmaceutical: Other: personal fees; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; Shionogi: Other: personal fees; Sanofi: Other: personal fees, Research Funding; MSD: Other: personal fees, Research Funding; SymBio Pharmaceutical: Other: personal fees, Research Funding; Eisai: Research Funding; Otsuka Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Other: personal fees, Research Funding; Shire: Research Funding; Takeda Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Research Funding; Bristol-Myers Squibb: Other; Astellas: Research Funding. Miyazaki:Chugai: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria; Celgene Japan: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Shin-bio: Honoraria.

Abstract: Background: Although introduction of pediatric-type Berlin-Frankfurt-Munster (BFM) chemotherapy has markedly improved the prognosis of adolescent and young adult (AYA) patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL), their higher toxicity has become an emerging issue with an increased post-remission mortality in AYA patients than pediatric patients. Allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning (MAC) regimens containing total body irradiation (TBI) is recognized as an important treatment option for patients with higher risk diseases. However, safety and efficacy of allo-SCT with TBI-MAC have not been fully investigated among AYA patients who received pediatric-type chemotherapy. Patients and methods: AYA was defined as 16 to 39 years old. Of the 143 AYA patients with Ph-negative ALL who underwent the first allo-SCT in the first remission between 2007 and 2016 at the 20 institutions, 106 patients who were treated with one BFM chemotherapy regimen before transplant and were conditioned with MAC regimens containing more than or equal to 8 Gy of TBI dose. The reasons for the transplant were surveyed with a multi-answer questionnaire. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p & lt; 0.20) in univariate analyses were subjected to multivariate analysis. The Fine-Gray and Cox proportional hazard model were used for multivariate analysis of risk factors and prognostic factors, respectively. Values of p & lt; 0.05 were considered to indicate statistical significance. Results: Of the 106 patients included in this study, 61 were male, and 45 were female. The median age at transplant was 29 years (range, 16-39 years). Donor types were related, unrelated, and cord blood in 47 (44%), 47 (44%), and 12 (12%) patients, respectively. The difficulty of continuing chemotherapy due to side effects as the reason for transplant was included in 13 patients (12%). As chemotherapy before transplant, pediatric-type and adult-type regimens were used in 56 (53%) and 50 patients (47%), respectively. There was no significant difference in baseline characteristics and transplant procedures between the pediatric-type group and the adult-type group, except for proportion of patients over 30 years (14% vs. 64%, respectively; p & lt; 0.01), those with more than or equal to 2 of hematopoietic cell transplant comorbidity index (13% vs. 36%, respectively; p & lt; 0.01), and transplant between 2007 and 2011 (36% vs. 64%, respectively; p & lt; 0.01). The CI of NRM, the OS rates, and the CI of relapse were not significantly different between two groups (NRM: 4% vs. 12% at three years after transplant, respectively; p = 0.26), (OS: 86% vs. 70%, respectively; p = 0.14), and (relapse: 16% vs. 24%, respectively; p = 0.32), respectively. Multivariate analysis for NRM revealed that more than or equal to 1 of performance status at transplant (hazard ratio [HR] = 4.8; p & lt; 0.01) and transplant due to side effects of chemotherapy (HR = 3.5; p = 0.04) were identified as independent risk factors, but not pediatric-type chemotherapy (HR = 0.48; p = 0.23). The proportions of transplant due to side effects of chemotherapy were similar between two groups (13% vs. 12%, respectively; p = 1). No independent prognostic factor for OS was found, while transplant between 2007 and 2011 (HR = 2.5; p = 0.04) was extracted as an independent risk factor of relapse. Regarding transplant complications, significant differences were not shown in CI of grade II to IV acute graft-versus-host disease (GVHD), chronic GVHD, bacteremia, cytomegalovirus reactivation, hemorrhagic cystitis, and avascular necrosis between two groups. No characteristic cause of NRM was found in the pediatric-type group. Conclusion: These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric-type chemotherapy. Disclosures Kimura: MSD: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Nippon Kayaku: Honoraria; Takeda Pharmaceutical: Honoraria; SymBio Pharmaceutical: Honoraria. Usuki: MSD: Speakers Bureau; Alexion: Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Eisai: Speakers Bureau; Nippon shinyaku: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Mundipharma: Research Funding; Yakult: Speakers Bureau; PharmaEssentia: Speakers Bureau. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Handa: Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; 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. Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

Abstract: Abstract 2281 Poster Board II-258 Background: A decision analysis using the Markov process is a flexible and convenient analytical method that tracks the clinical events that occur after a certain decision with different probabilities and utilities over time. To address the role of allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) in CR1, we performed a Markov decision analysis using newly collected clinical data from 2029 patients. Methods: Probabilities and other outcome data were derived from a database of adult AML patients that was constructed from case report files collected for this study. We included patients who were diagnosed with AML other than M3 between 1999 and 2006, aged 16 to 70 years, and who had achieved CR1 after 1 or 2 courses of induction chemotherapy. Using the software package TreeAge Pro 2009, we constructed a Markov decision model that compared 2 strategies: allo-HCT in CR1 (HCT group) and no allo-HCT in CR1 (CTx group). Possible health states considered in each decision included, for the HCT group, 1) no relapse without chronic GVHD, 2) no relapse with chronic GVHD, 3) relapse, and 4) dead, and, for the CTx group, 1) no relapse, 2) relapse, 3) second remission, 4) after salvage allo-HCT, and 5) dead. Quality-of-life (QOL) adjustments were made by incorporating time trade-off utilities that were derived from a questionnaire to 12 physicians who were familiar with the treatment of AML. The cycle length between state transitions was set at 3 months. Results: A total of 2029 patients were eligible for this analysis. The median age was 50 years, and the median follow-up of the surviving patients was 4.10 years. The proportions of patients with favorable, intermediate, unfavorable and unknown cytogenetic risk by SWOG criteria were 20%, 54%, 17% and 9%, respectively. Therapies performed at CR1 were allo-HCT in 494 patients (24%) and chemotherapy in 1535 patients (76%). Among 1076 patients whose HLA typing was performed for allo-HCT in CR1, 431 had HLA-matched or 1-antigen-mismatched related donors. Life expectancy and quality-adjusted life expectancy for the HCT and CTx groups in each risk category are summarized in Table 1. Life expectancy of the HCT group was longer than that of the CTx group (4.96 years vs. 4.44 years). However, quality-adjusted life expectancy of the HCT group was comparable to that of the CTx group (4.06 years vs. 3.98 years) due to a larger reduction of expected life length in the HCT group after QOL adjustment. In a subset analysis of the CTx group, patients with more favorable cytogenetic risk had a longer life expectancy. Whereas allo-HCT in CR1 was associated with a shorter life expectancy in patients with favorable-risk AML, allo-HCT in CR1 was associated with a longer life expectancy in those with intermediate-risk or unfavorable-risk AML. Adjustment for QOL did not change the preferred decision in the intermediate- and unfavorable-risk groups, although the survival advantages for allo-HCT in CR1 were less than those without QOL adjustment. In a subset of patients who had related donors, both life expectancy and quality-adjusted life expectancy were longer in the HCT group. Conclusion: The results of our decision analysis using the Markov process indicated that patients with intermediate- or unfavorable-risk AML have a longer life expectancy and quality-adjusted life expectancy with a decision of allo-HCT in CR1. Our results also showed that a Markov decision analysis that incorporates QOL may be useful as a decision-making tool for patients who might be candidates for allo-HCT. Disclosures: No relevant conflicts of interest to declare.