-Author name in bold denotes the presenting author
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4328 Prognostic Impact of Chromosomal Abnormalities in TP53-Mutated Acute Myeloid Leukemia and High-Risk Myelodysplastic SyndromesClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

June Takeda, MD1,2*, Makoto Iwasaki, MD, PhD3*, Junya Kanda, MD, PhD4*, Yasuhito Nannya, MD, PhD2,5, Nobuhiro Hiramoto, MD6*, Tadakazu Kondo, MD6, Takayuki Ishikawa, MD7, Mitsumasa Watanabe, MD, PhD8, Takahito Kawata, MD, PhD8*, Takeshi Maeda, MD, PhD9*, Yasunori Ueda, MD, PhD10, Kazunori Imada11*, Toshiyuki Kitano, MD, PhD12*, Masaaki Tsuji13*, Yoshitomo Maesako14*, Satoko Oka15*, Yasuhiro Tanaka16*, Takashi Miyoshi17*, Kosuke Asagoe18*, Mitsuru Itoh, MD, PhD19, Hirokazu Hirata, MD, PhD20*, Hiroshi Kawabata, MD, PhD21, Masakatsu Hishizawa, MD22*, Akinori Maeda23*, Kazuhiro Yago, MD24*, Nana Sasaki25*, Nobuhiko Uoshima, MD, PhD25*, Seishi Ogawa26,27,28 and Akifumi Takaori-Kondo, MD, PhD1

1Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Nara, NAR, Japan
4Department of Hematology / Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
5Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
6Department of Hematology, Kobe City Hospital Organization Kobe City Medical Center General Hospital, Kobe, Japan
7Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
8Department of Hematology, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
9Kurashiki Central Hospital, Kurashiki, Japan
10Department of Hematology/Oncology, Transfusion and Hemapheresis Center, Kurashiki Central Hospital, Kurashiki, Japan
11Osaka Red Cross Hospital, Osaka, Japan
12Deptartment of Hematology., Kitano Hospital, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
13Japan Red Cross Otsu Hospital, Otsu, Japan
14Department of Hematology, Takatsuki Red Cross Hospital, Osaka, Japan
15Department of Hematology, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan
16Department of Hematology, Shinko Hospital, Hyogo, Japan
17Uji Tokushukai Medical Center, Uji, Japan
18Shiga General Hospital, Moriyama, Japan
19Department of Hematology, Kyoto City Hospital, Kyoto, Japan
20Department of Hematology, Kansai Electric Power Hospital, Osaka, Japan
21Department of Hematology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
22Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan
23Department of Hematology, Shizuoka City Shizuoka Hospital, Shizuoka, Japan
24Department of Hematology, Shizuoka General Hospital, Shizuoka, Japan
25Department of Hematology, Red Cross Kyoto Daini Hospital, Kyoto, Japan
26Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
27Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Sakyoku, KYO, Japan
28Center for Hematology and Regenerative Medicine, Department of Medicine (MedH), Karolinska Institutet, Huddinge, Sweden


Background: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) exhibit clinical heterogeneity, and genomic profiles play a crucial role in disease characteristics and survival outcomes. Elli Papaemmanuil et al. classified AML into 11 genomic subgroups (NEJM, 2016), where TP53 mutations and aneuploidy predicted dismal survival. Cases with TP53 mutations are often accompanied by complex chromosomal abnormalities (CAs), but the prognostic impact and target genes of CAs have not been fully studied.


To clarify this issue, specimens of AML and MDS with excess blasts (MDS-EB) were collected from 1,001 patients enrolled at collaborating institutes of Kyoto Hematology Study Group between July 2017 and January 2023. Targeted capture sequencing with 1,216 single nucleotide polymorphism sites was used to analyze primary samples, allowing assessment of copy number alteration (CNA) profiles. The target gene panel included common mutations in myeloid neoplasms. Mutation calling was performed using the established pipeline Genomon 2. Prognostic impact of CNA, single nucleotide variants, and insertion/deletion with 10% or more frequency was evaluated, and the frequencies of CNA were calculated for the short and long arms of chromosomes 1-22 and the X chromosome. Univariate and multivariate analyses were conducted using statistical significance criteria of p < 0.05.


The average sequencing depth was 548. Among 1,001 patients, 224 (22.4%) harbored TP53 mutations. TP53-mutated cases had a median age of 70 (24-95) years old at diagnosis, with 117 (52.2%) being AML and 107 (47.8%) MDS-EB. TP53 biallelic mutation, defined by 2 or more mutations in TP53 or loss of heterogeneity of TP53 locus, was present in 200 (89.3%) of cases, more commonly associated with 3 or more CAs or CNA (complex karyotype (CK)-like) than monoallelic mutation (99% vs. 42%, p = 1.9x10-13). The most frequent affected lesions were del(5q), del(7q), del(7p), del(12p), del(18q), gain(11q), and gain(21q) with frequencies of 76%, 59%, 34%, 33%, 28%, 27%, and 26%, respectively.

In survival analysis, gain(21q), gain(19p), del(16q), del(3q), del(19p), del(13q), and del(4q), along with diagnosis of AML (p = 2.0x10-2), TP53 biallelic mutation (p = 6.8x10-3), and CK-like (p = 3.4x10-3), were associated with poor outcomes in univariate analysis. Multivariate analysis revealed gain(19p), del(3q), del(13q), del(4q), diagnosis of AML, and CK-like as independent poor prognostic factors. Here we have defined gain(19p), del(3q), del(13q), and del(4q) as "Risk CNA". A significant difference in outcomes was observed between patients with and without Risk CNA (n = 110 and n = 114, respectively, Hazard ratio = 2.6, p = 6.0x10-8): The 6-month survival rate was 70 (95% Confidence interval [60-79]) % for patients without Risk CNA and 42 [31-52] % for those with Risk CNA. Patients with two or more Risk CNAs had worse prognosis than those with one (p = 2.7x10-2), indicating independent or additive contributions to outcomes. Similar trends were observed when limiting the analysis to TP53-biallelic cases.

Further investigation of Risk CNA target genes was performed by identifying commonly amplified/deleted lesions. Target genes of gain(19p) included DNM2, CARM1, SMARCA4, LDLR, and EPOR, while RB1 and TET2 were potential candidates of del(13q) and del(4q), respectively. Identification of candidate genes for del(3q) was challenging due to broad common deleted lesions.


Chromosomal abnormalities stratify the prognosis of AML and MDS-EB with TP53 mutation. The number of Risk CNA also impacts survival. Investigation of target genes of Risk CNA suggests potential therapeutic targets for TP53-mutated myeloid neoplasms, warranting further study for treatment optimization.

Disclosures: Kanda: Amgen: Ended employment in the past 24 months, Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K.: Honoraria; Sanofi K.K.: Honoraria; AbbVie Pharma: Honoraria; Megakaryon Co.: Honoraria; Eisai Co.: Research Funding. Nannya: Daiichi Sankyo Company Limited: Research Funding; Amelieff Corporation: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd: Speakers Bureau. Kondo: Asahi Kasei Pharmaceutica,Chugai Pharma, MSD Pharmaceutical, Dainippon Sumitomo Pharma, Otsuka Pharmaceutical: Honoraria, Research Funding. Takaori-Kondo: Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Otsuka Pharmaceutical: Honoraria, Other: Subsidies ; Megakaryon: Honoraria; Ono Pharmaceutical: Research Funding; COGNANO: Research Funding; DKS Co. Ltd.: Research Funding; Pharma Essentia Japan: Research Funding; Takeda Pharmaceutical: Other: Subsidies; Kyowa Kirin: Other: Subsidies ; Chugai Pharmaceutical: Other; Eisai: Other; Ohara Pharmaceutical: Other; Kinshikouraininjin: Other; AbbVie: Other; Shionogi Pharma: Other; ASAHI KASEI PHARMA: Other; Nippon Shinyaku Co., Ltd.: Honoraria, Other: Subsidies.

*signifies non-member of ASH