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4019 Mutational Analysis of DNMT3A Improves the Prognostic Stratification Using NPM1/FLT3-ITD Genotypes in Patients with Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, survivorship, Myeloid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Atsushi Marumo, MD1*, Satoshi Wakita, MD, PhD1*, Kaoru Morita, MD, PhD2*, Shinichi Kako3, Takashi Toya4, Yuho Najima5, Noriko Doki6*, Junya Kanda, MD, PhD7, Junya Kuroda, MD, PhD8, Shin-Ichiro Mori, MD9*, Atsushi Satake, MD, PhD10, Kensuke Usuki, MD, PhD11, Toshimitsu Ueki, MD12*, Nobuhiko Uoshima, MD, PhD13*, Yutaka Kobayashi, MD, PhD14*, Eri Kawata, MD, PhD15, Kazutaka Nakayama16*, Yuhei Nagao17*, Katsuhiro Shono, MD, PhD17*, Motoharu Shibusawa18*, Jiro Tadokoro19*, Masao Hagihara, MD20*, Hitoji Uchiyama, MD, PhD21*, Naoyuki Uchida, MD, PhD22, Yasushi Kubota, MD, PhD23*, Shinya Kimura, MD, PhD24*, Hisao Nagoshi25*, Tatsuo Ichinohe26, Saiko Kurosawa27*, Sayuri Motomura, MD, PhD28, Hashimoto Akiko, MD29*, Hideharu Muto, MD, PhD30*, Eriko Sato, MD, PhD31*, Masao Ogata, MD, PhD32*, Kenjiro Mitsuhashi33*, Jun Ando, MD, PhD34*, Haruko Tashiro, M.D., Ph.D.35*, Masahiro Sakaguchi1*, Shunsuke Yui1*, Kunihito Arai1*, Tomoaki Kitano1*, Miho Miyata36*, Takahiro Fukuda37*, Yoshinobu Kanda, MD, PhD38 and Hiroki Yamaguchi, MD, PhD1

1Department of Hematology, Nippon Medical School, Tokyo, Japan
2Division of Hematology, Jichi Medical University, Tochigi, Japan
3Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
4Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
5Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Tokyo, TKY, Japan
6Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
7Department of Hematology and Oncology, Kyoto University, Kyoto, Japan
8Division of Hematology and Oncology, Deparment of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
9St. Luke's International Hospital, Chuo-Ku, TKY, JPN
10Kansai Medical University, Osaka, Japan
11Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan
12Nagano Redcross Hospital, Nagano, JPN
13Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
14Department of Hematology, Japan Red Cross Kyoto Daini Hospital, Kyoto, Japan
15Department of Hematology, Panasonic Health Insurance Organization, Matsushita Memorial Hospital, Osaka, KYO, Japan
16Yokohama Minami Kyousai Hospital, Kanagawa, Japan
17Department of Hematology, Chiba Aoba Municipal Hospital, Chiba, Japan
18Department of Hematology, IMS group Shinmatsudo Central General Hospital, Chiba, Japan
19Shinmatsudo Central General Hospital, Matsudo-Shi, Chiba-Ken, JPN
20Department of Hematology, EIJU GENERAL HOSPITAL, Taito-Ku, Japan
21Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
22Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Tokyo, Japan
23Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
24Saga University, Saga, Japan
25Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
26Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
27Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
28Tokyo Metropoloitan Tama-Hokubu Medical Center, Higashimurayama-shi, JPN
29Kobe City Nishi-Kobe Medical Center,, Hyogo, Japan
30Division of hematology, Tokyo Metropolitan Otsuka Hospital, Tokyo, Japan
31Department of Hematology, Juntendo University Nerima Hospital, Tokyo, Japan
32Department of Hematology, Oita University, Yufu, Japan
33Saitama Red Cross Hospital, Saitama, Japan
34Department of Hematology, Juntendo University of Medicine, Tokyo, Japan
35Department of Hematology/Oncology, Teikyo University School of Medicine, Itabashi-ku, Japan
36Department of Hematology, Nippon Medical School, Tokyo, JPN
37Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan
38Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama City, Japan

Background: Nucleophosmin 1 (NPM1) mutations are considered a favorable factor of acute myeloid leukemia (AML). However, their clinical significance in non-European regions remains unclear. DNA methyltransferase 3A (DNMT3A) mutations have been reported as a factor for poor prognosis in many cohort analyses. However, they were excluded among major prognostic factors even in the European Leukemia Net 2017 (ELN2017) classification. In this study, we analyzed the effects of NPM1 and concurrent mutations, particularly DNMT3A mutations, on prognosis.

Methods: All patients in this analysis were enrolled and selected by the gene sequencing of Japanese AML (GS-JAML) conducted by Nippon Medical School. We targeted only patients aged 70 years or younger who were diagnosed after 2010 and who received standard induction therapy consisting of 7 days of standard-dose cytarabine (100–200 mg/m2 continuous infusion) and 3 days of an anthracycline antibiotic infusion (idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2). Mutation screening were performed with target-captured sequencing for the AML gene panel. We also conducted agarose gel electrophoresis for the FMS-like tyrosine kinase 3 (FLT3-ITD) mutations and used the Sanger method to screen for CEBPA and NPM1 mutations. This study was reviewed and approved by the Human Subjects Institutional Review Board (project approval number 29-07-783) of the Nippon Medical School (Tokyo, Japan). Informed consent was obtained in accordance with the Declaration of Helsinki from all participants.

Results: We retrospectively analyzed the prognosis in 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated, 125 patients with DNMT3A-mutated and 127 patients with FLT3-ITD mutated AML. NPM1 mutation was not a prognostic factor either overall or in subgroups based on NPM1/tandem duplication in FLT3-ITD genotypes. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNMT3A (DNMT3AR882) were a strong factor of poor prognosis for AML overall and NPM1-mutated AML. Furthermore, multivariate analysis of all AML showed that DNMT3AR882 mutations and the cooccurrence of FLT3-ITD, NPM1 mutations, and DNMT3AR882 mutations (triple mutation) were independent factors for poor prognosis related to overall survival, with NPM1 mutations being an independent factor for favorable prognosis (hazard ratio: DNMT3AR882 mutations, 1.946; triple mutation, 1.992, NPM1 mutations, 0.548). Furthermore, we evaluated the prognostic impacts of DNMT3AR882 and triple mutation and demonstrated that NPM1-mutated AML patients could be more clearly stratified into three risk groups based on DNMT3AR882/FLT3-ITD genotypes than the ELN 2017 classification.

Conclusion: Our study showed that the addition of DNMT3AR882 mutations to existing prognostic models allowed for further stratification of NPM1-mutated AML. This new prognostic model might provide important clinical guidance.

Disclosures: Kanda: asclepia: Honoraria; ASAHI KASEI PHARMA CORPORATION: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co: Honoraria; Novartis Pharma K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMITED.: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Sanofi K.K.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Amgen Pharma Inc.: Honoraria; AbbVie Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Consultancy, Honoraria; MSD K.K.: Honoraria; CSL Behring K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; NIPPON KAYAKU CO．，LTD．: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Eisai: Research Funding. Kuroda: Kyowa Kirin: Research Funding, Speakers Bureau; Chugai Phamaceutical: Research Funding, Speakers Bureau; Japan Blood Products Organization: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Taiho Phamaceutical: Research Funding; Sumitomo Pharmaceutical: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Asahikasei: Research Funding, Speakers Bureau; Takeda Pharmaceutical: Research Funding, Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; CLS Behring: Research Funding; Bristol Myers Squibb: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Fujimoto Pharmaceutical: Research Funding, Speakers Bureau; Sysmex cooporation: Research Funding. Usuki: Bristo-Myers Squibb: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Sanofi: Consultancy, Honoraria; Sumitomo-Dainippon: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Eisai: Honoraria, Research Funding; Mundi: Research Funding; Yakult: Honoraria, Research Funding; Janssen: Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Research Funding; MSD: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; SymBio: Consultancy, Research Funding; SynBio: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Nippon Shinyaku: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Research Funding. Kanda: Mundipharma Pharmaceuticals: Research Funding.

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