Interim Analysis of Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study of Patients with AML (2020)

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 &amp; 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.