Abstract: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. Methods We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. Results Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9] ) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p  〈  0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p  〈  0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. Conclusions We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

Abstract: Next‐generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)‐SCREEN‐Japan 01 is a multicenter study to detect actionable mutations using paraffin‐embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R‐AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High‐quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1 ‐ RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R‐AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP5 3 mutations had a poor prognosis. As for the detection of actionable mutations, 38% ( n  = 69) of patients had useful genetic mutation ( FLT3 ‐ ITD / TKD , IDH1 / 2 , and DNMT3A R822 ) for treatment selection. Comprehensive genomic profiling using paraffin‐embedded BM clot specimens successfully identified leukemic‐associated genes that can be used as therapeutic targets.

Abstract: Background and Methods: NPM1 mutation and KMT2A(MLL)-rearrangement/amplification are present in approximately 27% and 8.5% patients with acute myeloid leukemia (AML), respectively (data from cBioPortal). Although they have different clinical features and prognostic impact, recent studies suggest that the MLL co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). However, the real-world epidemiology of these mutations and co-existing gene alterations have not been thoroughly investigated in Japan. We launched an actionable mutation profiling multicenter study entitled Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233). In this study, a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who are ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: One-hundred-eighty-two patients were recruited in this study and the F1H report was successfully returned in 177 patients (97.3%). Median age of 68 patients with ND-AML was 73 [63-79] years and those of 109 patients with R/R-AML was 50 [40-68.5] years. Median turn-around time was 13 days (minimum 8 days).We found 32 patients (18.1%) with NPM1 mutation and 23 patients (13.0%) of KMT2A(MLL)-rearrangement/amplification out of the 177 patients. These two alterations were mutually exclusive in this study. The median age of patients with NPM1 mutation (NPM1 mt.) and KMT2A-rearrangement (KMT2A-r) were 56.5 [43.5-73.8] and 62 [45-71] years, respectively. Three quarters or more patients were R/R-AML in both groups. WT1 expression levels were much higher in patients with NPM1 mt. than the other group (6,000 [77-110,000] vs. 93 [34-5,800] copies/mcgRNA). The major amino acid alteration of NPM1 was a frameshift mutation at the 288 th histidine (W288fs*12). Patterns of KMT2A(MLL)-rearrangement included MLL fusion (e.g., MLL-MLLT3) and partial tandem duplication (PTD) in ten patients each. MLL amplification was observed in three patients. Frequently co-occurring mutations with NPM1 mt. included FLT3 (56.3%), DNMT3A (46.9%), TET2 (34.4%), WT1 (18.8%), IDH1 (18.8%), and IDH2 (15.6%). Those with KMT2A-r included FLT3 (39.1%), TP53 (26.1%), PTPN11 (21.7%), DNMT3A (17.4%), and IDH2 (17.4%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS, PTPN11, and NF1) were observed in five patients with NPM1 mt. (15.6%) and 11 patients (47.8%) with KMT2A-r. None of the six patients with TP53 mutation had NPM1 mutation. The prognostic impact of each genes is currently being analyzed. Conclusions: Approximately three in ten patients with AML had NPM1 mutation and/or KMT2A(MLL)-rearrangement/amplification. No single patient had both the alterations. FLT3 and DNA methylation-associated genes (e.g., DNMT3A and TET2) were frequently seen in patients with NPM1 mt. In contrast, TP53 and RAS pathway-related gene alterations (e.g., NRAS, KRAS, PTPT11 and NF1) were relatively dominant in patients with KMT2A-r. TP53 mutation seemed unlikely to occur along with NPM1 mutation. Figure 1 Figure 1. Disclosures Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Fujishima: Pfizer: Speakers Bureau. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

Abstract: Background: Acute myeloid leukemias with KMT2A (formerly known as MLL-1) fusion genes (MLL-AML) and those with NPM1 mutations (NPM1-AML) are distinct subtypes as defined by the WHO classification. Although they have different clinical features and prognostic impact , recent studies suggest that the MLL1 co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). New targeted strategies for these AML subtypes are expected as preliminary data suggest that menin-MLL1 inhibition may inhibit malignancy. In addition to classical chromosomal analysis and prefixed fusion gene screening, next-generation sequencing (NGS) should help in identifying the precise prevalence of these alterations and understanding the relationship with other pathological mutations. We launched the HM-SCREEN-JAPAN01 study (UMIN000035233) in which gene alterations are analyzed by FoundationOne Heme® in patients with AML who are relapsed/refractory to, or ineligible for standard therapies. Aiming for 200 registrations, recruitment has reached approximately 100. The interim results are described here. Methods: HM-SCREEN-JAPAN01 is an observational study and conducted by 17 participating institutions. The eligibility criteria are as follows: 1) histological diagnosis of AML must be made by bone marrow testing; 2) one of the following conditions must be fulfilled: i) a patient with newly diagnosed AML and is ineligible for standard treatment, or ii) a patient with AML who has relapsed or is refractory to prior therapy; 3) sufficient amount of bone marrow sample must be available; 4) age at registration must be 20 or more; and 5) written informed consent must be taken. All samples were analyzed by FoundationOne Heme®. Results:Nine patients (9.9%) with MLL-AML and seventeen patients (18.7%) with NPM1-AML were found among 91 available cases (either one found in 28.6%). No patients demonstrated MLL-rearrangement and NPM1-mutation simultaneously. Median age of patients with MLL-AML (42-68 y) was a decade less than that of patients with NPM1-AML (55-74 y), and the majority of cases had a clinical relapse or were refractory to prior therapies. Translocations involving chromosome 11q23.3 (e.g. t(9;11)(p21.3;q23.3)) were found in 5 of 8 patients (62.5%) with MLL-AML (data not available due to insufficient cell count in one case) and no chromosomal abnormalities were detected in 10 of 16 patients (62.5%) with NPM1-AML (chromosomal analysis was not performed in one case). In patients with MLL-AML (see Figure), FLT3 mutations were found in 3 of 9 cases (33.3%), all of which were point mutations within the tyrosine kinase domain (FLT3-TKD). PTPN11 mutations were also found simultaneously in these three cases. Co-existing NRAS and TP53 mutations with high allele-frequency (32-50%) were also seen in two different cases. A targetable mutation of IDH2 was seen in one patient (11.1%) who had an FLT3 mutation with low allele-frequency (2%). In patients with NPM1-AML (see Figure), allele-frequency of mutated NPM1 ranged from 10 to 44%. Relatively common co-existing mutations were TET2 (7 of 17; 41.2%), DNMT3A (9 of 17; 52.9%), and FLT3 (9 of 17; 52.9%). Unlike in MLL-AML patients, all FLT3 alterations were internal tandem duplication (FLT-ITD) with one case of dual FLT3-ITD and -TKD mutation. IDH1 and IDH2 mutations were found in two (11.8%) and four (23.5%) separate cases, respectively. A rare fusion gene ETV6-NTRK3 (one of primary targets of NTRK inhibitors) was detected in one patient (5.9%) who had IDH1 mutation with moderate allele-frequency (17%). Conclusion: MLL-rearrangements and NPM1-mutations were found in approximately a quarter of the 91 AML patient (mostly relapsed or refractory) bone marrow samples analyzed. These alterations appeared to be mutually exclusive. FLT3 alterations were seen in a third of the MLL-AML cases and half of the NPM1-AML cases, seemingly more frequent than that previously reported. Interestingly, FLT3-TKDs were dominant in MLL-AML cases, whereas NPM1-AML cases carried FLT3-ITD. IDH1 and IDH2 mutations commonly co-existed in both groups. This HM-SCREEN-Japan01 study is now recruiting patients, and a further understanding of genomic distribution and correlation is expected. Figure Disclosures Yamauchi: Otsuka:Research Funding;Astellas:Research Funding;Daiichi Sankyo:Research Funding;Chugai:Honoraria;Pfizer:Honoraria, Research Funding;Abbie:Research Funding;Solasia Pharma:Research Funding;Ono Pharmaceutical:Honoraria.Shibayama:AstraZeneca:Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria;Pfizer:Honoraria;Fujimoto:Honoraria;Janssen:Honoraria, Research Funding;Teijin:Research Funding;Novartis:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Daiichi Sankyo:Honoraria;Chugai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sumitomo Dainippon:Honoraria, Research Funding;Merck Sharp & Dohme:Research Funding;Shionogi:Research Funding;Astellas:Research Funding;Taiho:Research Funding;Otsuka:Honoraria;Bristol-Myers Squibb:Honoraria;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Eisai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kyowa Kirin:Honoraria;Ono:Honoraria, Research Funding;Mundi Pharma:Honoraria.Yamamoto:Stemline Therapeutics:Consultancy;Meiji Seika Pharma:Consultancy, Honoraria;MSD:Consultancy, Honoraria, Research Funding;Chugai:Consultancy, Honoraria, Research Funding;Eisai:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy;IQIVA/HUYA:Honoraria;HUYA:Consultancy;IQIVA/Incyte:Research Funding;Mundipharma:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria;Mochida:Honoraria;Gilead Sciences:Research Funding;Solasia Pharma:Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Ono:Consultancy, Honoraria, Research Funding;Aichi Cancer Center:Current Employment;AbbVie:Consultancy, Honoraria, Research Funding;Astra-Zeneca:Consultancy, Research Funding;Bayer:Research Funding;Bristol-Myers Squibb:Honoraria;Celgene:Consultancy, Honoraria, Research Funding;Zenyaku:Research Funding;Takeda:Consultancy, Honoraria, Research Funding;Yakult:Research Funding;SymBio:Research Funding;Pfizer:Honoraria;Otsuka:Consultancy, Honoraria, Research Funding;Sanofi:Honoraria;Sumitomo Dainippon:Honoraria;Janssen:Honoraria.Fujishima:Pfizer:Speakers Bureau.Takahashi:Pfizer Japan Inc.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria, Research Funding;Bristol-Myers Squibb Company:Honoraria.Usuki:Alexion:Speakers Bureau;Pfizer:Research Funding;Nippon Boehringer Ingelheim:Research Funding;Mundipharma:Research Funding;Astellas-Amgen-Biopharma:Research Funding;Nippon shinyaku:Research Funding, Speakers Bureau;Eisai:Speakers Bureau;MSD:Speakers Bureau;Takeda:Speakers Bureau;PharmaEssentia:Speakers Bureau;Yakult:Speakers Bureau;Symbio:Research Funding, Speakers Bureau;Daiichi Sankyo:Research Funding, Speakers Bureau;Sumitomo Dainippon:Research Funding;Otsuka:Research Funding, Speakers Bureau;Novartis:Research Funding, Speakers Bureau;Brisol-Myers Squibb:Research Funding, Speakers Bureau;Kyowa Kirin:Research Funding, Speakers Bureau;Ono:Research Funding, Speakers Bureau;Janssen:Research Funding;Celgene:Research Funding, Speakers Bureau;Takeda:Research Funding;Astellas:Research Funding, Speakers Bureau;Abbvie:Research Funding;Gilead:Research Funding.Ono:Celgene:Honoraria, Research Funding;Kyowa Kirin Co., Ltd.:Honoraria, Research Funding;Chugai Pharmaceutical Co., Ltd.:Honoraria, Research Funding;Novartis Pharma KK:Honoraria;Mundipharma K.K.:Honoraria;TAIHO PHARMACEUTICAL CO., LTD.:Research Funding;Eisai Co., Ltd.:Honoraria;Otsuka Pharmaceutical Co., Ltd.:Honoraria;Astellas Pharma Inc.:Honoraria;Bristol-Myers Squibb Company:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda Pharmaceutical Company Limited.:Honoraria;ONO PHARMACEUTICAL CO., LTD.:Honoraria, Research Funding;DAIICHI SANKYO COMPANY, LIMITED.:Honoraria;Janssen Pharmaceutical K.K:Honoraria.Kuroda:Daiichi Sankyo:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding;Sysmex:Research Funding;Janssen Pharmaceutical K.K:Consultancy;Eisai:Honoraria, Research Funding;Sanofi:Consultancy, Honoraria, Research Funding;Kyowa Kirin:Honoraria, Research Funding;Otsuka Pharmaceutical:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria, Research Funding;Abbvie:Consultancy, Honoraria;MSD:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Dainippon Sumitomo Pharma:Honoraria, Research Funding;Chugai Pharmaceutical:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Bristol-MyersSquibb:Consultancy, Honoraria, Research Funding;Astellas Pharma:Honoraria, Research Funding;Fujimoto Pharmaceutical:Honoraria, Research Funding;Taiho Pharmaceutical:Research Funding;Asahi Kasei:Research Funding;Shionogi:Research Funding;Nippon Shinyaku:Honoraria, Research Funding.Ishitsuka:Celgene:Other: Personal Fees;Kyowa Hakko Kirin:Other: Personal fees, Research Funding;BMS:Other: Personal fees;Chugai Pharmaceutical:Other: Personal fees, Research Funding;Takeda:Other: Personal fees, Research Funding;mundiharma:Other: Personal fees;Taiho Pharmaceuticals:Other: Personal fees, Research Funding;Janssen Pharmaceuticals:Other: Personal fees;Novartis:Other: Personal fees;Pfizer:Other: Personal fees;Astellas Pharma:Other, Research Funding;Genzyme:Other;Sumitomo Dainippon Pharma:Other, Research Funding;Eisai:Other, Research Funding;Mochida:Other, Research Funding;Shire:Other;Otsuka Pharmaceutical:Other;Ono Pharmaceutical:Other, Research Funding;Teijin Pharma:Research Funding;MSD:Research Funding;Asahi kasei:Research Funding;Eli Lilly:Research Funding;Daiichi Sankyo:Other;Huya Japan:Other.Minami:Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria;Pfizer Japan Inc.:Honoraria;Takeda:Honoraria.

Abstract: Background:Recently, whole exome sequencing has been performed for acute myeloid leukemia (AML) by next generation sequencing. The results revealed that certain gene mutations are identified in patients with AML. Among them,FLT3(28%),NPM1(27%),DNMT3A(26%), andIDH1/2(20%) mutations are observed in 20 to 30% of cases, while the frequencies of more than 10 other types of mutations are less than 10%. Some of these low frequency mutations are actionable mutations, which are defined as genetic DNA aberrations that are expected to elicit a response to an approved targeted therapy that is available for off-label treatment or available in clinical trials. Thus, the treatment strategies for leukemia are drastically changing with the rapid development of new drugs. Moving forward, the proper use of new agents is one of the major AML treatment issues. Especially, genome profiling analysis for newly diagnosed patients will be needed to select an optimal first line treatment. The HM-SCREEN-Japan 01 is an actionable mutation profiling multicenter study of patients with newly diagnosed AML who are unsuitable for the first standard treatment or have relapsed/refractory AML. The objective of this study is to evaluate the frequency and characteristics of cancer-related genome alterations in AML using a comprehensive genome profiling assay (FoundationOne®Heme) and determine the quality of specimens that contribute to the gene analysis. Approval was obtained from the Institutional Review Board prior to starting patient accrual at each institution. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000035233. Methods:This study was conducted by 17 participating institutions, with a sample size of 200. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) either of the following conditions fulfilled, i) patients with newly diagnosed AML unfit for standard treatment or ii) patients with relapsed/refractory AML; 3) sufficient sample is collected by bone marrow aspiration; 4) age at registration is 20 years or older; 5) written informed consent is taken. The primary outcome was the frequency of each genomic alteration in leukemia using FoundationOne®Heme (F1H), which is a comprehensive genomic profile that applies next-generation sequencing. The secondary outcomes evaluated the association between each cancer genome alteration and clinicopathological characteristics, prognosis, and quality of the specimens that contributed to the genetic analysis. In this study, we also performed serial genome profiling analyses to evaluate the time-dependent changes in genomic profiles in patients administered FLT3 inhibitors, gilteritinib, and quizartinib for AML. Results:This study commenced in January 2019, and 91 patients were recruited by March 2020. The median turnaround time between sending specimens and receiving results was 15 days (9 to 56 days). Of the 91 patients, 35.2% (32/91) were newly diagnosed with AML and unfit for standard treatment and 64.8% (59/91) had relapsed/refractory AML. Mutations were observed in the following genes in all 91 patients:FLT3(28.6%),RUNX1(25.0%),TP53(20.1%),DNMT3A(19.8%),NPM1(18.7%),IDH1/2(17.6%),CEBPA(16.5%),KMT2A(14.3%),NRAS(13.2%),TET2(12.1%),ASXL1(12.1%), and EZH2(2.2%). In 32 patients with newly diagnosed AML, mutations were observed in the following genes:FLT3(28.6%),RUNX1(20.3%),TP53(18.8%),DNMT3A(15.6%),NPM1(12.5%),IDH1/2(15.6%),CEBPA(15.6%),KMT2A(6.0%),NRAS(12.5%),TET2(9.0%),ASXL1(21.9%), and EZH2(6.3%). In 59 patients with relapsed/refractory AML, mutations were observed in the following genes:FLT3(28.6%),RUNX1(22.0%),TP53(22.0%),DNMT3A(22.0%),NPM1(22.0%),IDH1/2(18.6%),CEBPA(15.3%),KMT2A(18.6%),NRAS(13.6%),TET2(13.6%),ASXL1(6.8%), andEZH2(0%). In the FLT3 positive AML cohort, six patients were registered and one achieved remission by quizartinib after progression on gilteritinib. Conclusions:The evaluation of F1H for its use in HM-SCREEN-Japan 01 facilitates the analysis of leukemia-associated genes that can be used as therapeutic targets, which have rarely been identified in AML thus far. Figure Disclosures Shibayama: Shionogi:Research Funding;Taiho:Research Funding;Eisai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Ono:Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Merck Sharp & Dohme:Research Funding;Sumitomo Dainippon:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Daiichi Sankyo:Honoraria;Novartis:Honoraria, Research Funding;Janssen:Honoraria, Research Funding;Chugai:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Kyowa Kirin:Honoraria;Otsuka:Honoraria;Bristol-Myers Squibb:Honoraria;Pfizer:Honoraria;Fujimoto:Honoraria;AbbVie:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca:Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria;Mundi Pharma:Honoraria;Teijin:Research Funding;Astellas:Research Funding.Yamauchi:Chugai:Honoraria;Pfizer:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria;Otsuka:Research Funding;Astellas:Research Funding;Abbie:Research Funding;Solasia Pharma:Research Funding;Daiichi Sankyo:Research Funding.Gotoh:Alexion pharmaceuticals:Research Funding;Eisai:Honoraria;Ono Pharmaceutical:Honoraria;Taiho pharmaceutical:Honoraria;Takeda pharmaceutical:Honoraria;Nippon Shinyaku:Honoraria;Chugai:Honoraria;Novartis:Research Funding.Yamamoto:Zenyaku:Research Funding;Yakult:Research Funding;Takeda:Consultancy, Honoraria, Research Funding;SymBio:Research Funding;Solasia Pharma:Research Funding;Stemline Therapeutics:Consultancy;Sumitomo Dainippon:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Otsuka:Consultancy, Honoraria, Research Funding;Ono:Consultancy, Honoraria, Research Funding;Novartis:Honoraria, Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Mundipharma:Consultancy, Honoraria, Research Funding;MSD:Consultancy, Honoraria, Research Funding;Mochida:Honoraria;Meiji Seika Pharma:Consultancy, Honoraria;Kyowa Kirin:Honoraria;Janssen:Honoraria;Gilead Sciences:Research Funding;IQIVA/Incyte:Research Funding;HUYA:Consultancy;IQIVA/HUYA:Honoraria;Daiichi Sankyo:Consultancy;Eisai:Consultancy, Honoraria, Research Funding;Chugai:Consultancy, Honoraria, Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb:Honoraria;Bayer:Research Funding;Astra-Zeneca:Consultancy, Research Funding;AbbVie:Consultancy, Honoraria, Research Funding;Aichi Cancer Center:Current Employment.Fujishima:Pfizer:Speakers Bureau.Takahashi:Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria, Research Funding;Pfizer Japan Inc.:Honoraria, Research Funding.Usuki:Novartis:Research Funding, Speakers Bureau;Chugai:Research Funding;Apellis:Research Funding;Alexion:Research Funding, Speakers Bureau.ONO:TAIHO PHARMACEUTICAL CO., LTD.:Research Funding;Mundipharma K.K.:Honoraria;DAIICHI SANKYO COMPANY, LIMITED.:Honoraria;Janssen Pharmaceutical K.K:Honoraria;Eisai Co., Ltd.:Honoraria;Astellas Pharma Inc.:Honoraria;Takeda Pharmaceutical Company Limited.:Honoraria;ONO PHARMACEUTICAL CO., LTD.:Honoraria, Research Funding;Otsuka Pharmaceutical Co., Ltd.:Honoraria;Pfizer Japan Inc.:Honoraria;Bristol-Myers Squibb Company:Honoraria;Novartis Pharma KK:Honoraria;Chugai Pharmaceutical Co., Ltd.:Honoraria, Research Funding;Kyowa Kirin Co., Ltd.:Honoraria, Research Funding;Celgene:Honoraria, Research Funding.Kuroda:Astellas Pharma:Honoraria, Research Funding;Sanofi:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Honoraria, Research Funding;Shionogi:Research Funding;Nippon Shinyaku:Honoraria, Research Funding;Fujimoto Pharmaceutical:Honoraria, Research Funding;Sysmex:Research Funding;Eisai:Honoraria, Research Funding;Ono Pharmaceutical:Honoraria, Research Funding;Abbvie:Consultancy, Honoraria;MSD:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Takeda:Honoraria, Research Funding;Dainippon Sumitomo Pharma:Honoraria, Research Funding;Chugai Pharmaceutical:Honoraria, Research Funding;Bristol-MyersSquibb:Consultancy, Honoraria, Research Funding;Janssen Pharmaceutical K.K:Consultancy;Asahi Kasei:Research Funding;Taiho Pharmaceutical:Research Funding;Kyowa Kirin:Honoraria, Research Funding;Otsuka Pharmaceutical:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding.Izutsu:Sanofi:Research Funding;Symbio:Research Funding;Solasia:Research Funding;Janssen:Research Funding;Yakult:Research Funding;HUYA Japan:Research Funding;Abbvie pharmaceuticals:Research Funding;Incyte:Research Funding;Eisai:Research Funding;AstraZeneca:Research Funding;Daiichi Sankyo:Research Funding;Bayer pharmaceuticals:Research Funding;Ono Pharmaceutical:Research Funding;Novartis:Research Funding;Chugai:Research Funding;Celgene:Research Funding.Minami:Bristol-Myers Squibb Company:Honoraria;Pfizer Japan Inc.:Honoraria;Novartis Pharma KK:Honoraria;Takeda:Honoraria.