AML-Mrg Mutation Spectrum and Its Prognosis: A Japanese Multicenter Study HM01-02 Analysis with Full Analysis Sets

Background

Acute myeloid leukemia (AML) is a genetically heterogeneous clonal disease characterized by acquired somatic gene alterations in hematopoietic progenitor cells. The ICC classification in 2022 classifies cases lacking TP53 mutations but with mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2 as AML with myelodysplasia-associated gene mutations (AML-MRG). These consist of the characteristic genetic variants of secondary AML (sAML) and the previous provisional category of AML with RUNX1 mutations. In Japan, a multicenter study of targeted sequencing was performed on 365 AML patients (HM-SCREEN-Japan 01 and 02 studies). These data were comprehensively to evaluate AML-MRG frequency, co-mutated genes, and prognosis, and to explore the profiles of sAML-type gene mutations and RUNX1 mutations in AML-MRG.

Methods

Between 2016 and 2023, the HM-01 and HM-02 studies were conducted, based on mutation analysis and clinical data of 365 AML patients who participated in the studies. Of these, 34 underwent sequential mutation analysis. Genetic mutations were detected using Foundation One HEM in the HM-01 study and the Amoy panel in the HM-02 study.

Results

A total of 365 AML patients participated in the study, with a median age of 64 years, 87 (23.8%) of whom possessed MRG mutations. Among the MRG mutations, RUNX1 (n=30, 34%), ASXL1 (n=29, 33%), and SRSF2 (n=16, 18%) were observed most frequently, followed by BCOR mutations (n=15, 17%). Chromosome analysis showed normal karyotype in half (n=41) of the AML-MRG cases. Sequential analysis of AML-MRG was performed in three patients, two of whom did not lose their MRG mutations and were found to persist during AML treatment. Prognosis analysis of 211 newly diagnosed AML patients showed that the AML-MRG had a favorable prognosis, with a median survival time that was not reached, as well as AML with recurrent genetic abnormalities (RGA) and AML not otherwise specified (NOS). There was no difference in OS in the AML-MRG group with or without RUNX1 mutation (p=0.93). On the other hand, the median survival of AML-MRC was 9.5 months and that of TP53 mutation was 9.0 months, which is an inferior prognosis as previously reported. By treatment intensity, AML-RGA patients treated with intensive chemotherapy had a better prognosis than those treated with venetoclax (VEN) combination. Still, there was no significant difference between intensive chemotherapy and VEN combination therapy in AML-MRG patients (p=0.23). Regarding treatment intensity of the RUNX1 mutation status, AML-MRG patients with RUNX1 mutation had longer survival with intensive chemotherapy than with VEN combination therapy. On the other hand, AML-MRG patients without RUNX1 mutations showed no difference in OS by treatment intensity.

Conclusion

Our study found MRG mutations in 24% of newly diagnosed AML patients. Although there was no difference in OS between patients with AML-MRG treated with intensive chemotherapy and those treated with VEN combination therapy, intensive chemotherapy tended to have better OS in patients with AML-MRG with RUNX1 mutations. Although sample size is small, patients with AML-MRG with RUNX1 mutation may benefit from intensive chemotherapy compared with VEN combination therapy.

Hosono:Astellas Pharma: Honoraria; AbbVie: Honoraria. Onodera:Janssen Pharmaceutical: Honoraria; Meiji Seika Pharma: Honoraria; Nippon Shinyaku: Honoraria; Chugai Pharmaceutical: Honoraria; Celgene: Research Funding; BMS: Honoraria; Astellas pharma: Honoraria; Asahi Kasei Pharma: Honoraria; Abbvie: Honoraria, Research Funding; Novartis pharma: Honoraria; Otsuka: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Fukushima:Janssen Pharma: Honoraria; Pfizer Japan Inc.: Honoraria. Iyama:MSD: Research Funding; Otsuka: Research Funding; Chugai Pharmaceutical Co: Research Funding; Kyowa Kirin: Research Funding; Novartis: Research Funding; Alexion: Honoraria; Astellas: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria; Sanofi: Honoraria; SymBio: Honoraria; Asahikasei: Honoraria; KyowaKirin: Honoraria; Chugai: Honoraria. Gotoh:Eisai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Bayer: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Nihon Pharmaceutical: Honoraria, Research Funding; Novartis Pharma: Honoraria; Alexion Pharmaceuticals: Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Otsuka Pharma: Honoraria, Research Funding. Ikezoe:Alexion: Consultancy; AsahiKasei Pharma: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Chugai: Honoraria; Sanofi: Honoraria; AbbVie: Honoraria; Otsuka: Honoraria; Ono: Honoraria; Novartis: Honoraria. Takahashi:Asahi Kasei: Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ono: Research Funding. Kojima:Janssen Pharmaceutical KK: Honoraria; AstraZeneca KK: Honoraria; AbbVie GK: Honoraria. Kanda:Janssen Pharmaceutical K.K.: Consultancy, Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; CSL Behring K.K.: Honoraria; MSD K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Amgen Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Ono Pharma Inc.: Honoraria; ASAHI KASEI PHARMA CORPORATION: Honoraria; Sanofi K.K.: Honoraria; asclepia: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; NIPPON KAYAKU CO．，LTD．: Honoraria; Novartis Pharma K.K.: Consultancy, Honoraria; DAIICHI SANKYO Co., Ltd.: Consultancy, Honoraria; Megakaryon Co: Consultancy; SymBio Pharmaceuticals, Ltd.: Consultancy; AbbVie Inc.: Consultancy, Honoraria; Eisai: Research Funding. Izutsu:Ono Pharma, Symbio, Takeda: Consultancy, Honoraria; MSD, AstraZeneca, Genmab, Chugai, BMS, Kyowa Kirin, Novartis, AbbVie: Consultancy, Honoraria, Research Funding; Incyte, Bayer, O Oncology, Regeneron: Research Funding; Pfizer, Janssen, Gilead, Daiichi Sankyo: Honoraria, Research Funding; Beigene, Yakult, Otsuka: Consultancy, Research Funding; AstraZeneca, Eli Lily, Astellas, Ono Pharmaceuticals, Eisai, Chugai, Janssen, Symbio, Bristol Myers Squibb, Daiichi Sankyo, Otsuka, Abbvie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, MeijiSeika Pharma, Novartis, Nihon Kayaku, Gilead,: Honoraria; MSD, AstraZeneca, Abbvie, Incyte, Bristol Myers Squibb, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, Daiichi Sankyo, Chugai, Beigene, Genmab, LOXO Oncology, Otsuka, Regeneron, Gilead: Research Funding; AstraZeneca, Zenyaku, Ono Pharmaceuticals, Mitsubishi Tanabe Pharma, Eisai, Chugai, Bristol Myers Squibb, Takeda, Otsuka, Abbvie, Zenyaku, Kyowa Kirin, MSD, Carna Biosciences, Novartis, Yakult, Nihon Shinyaku, Abe Pharma, Eisai,Beigene: Consultancy. Fukuhara:Genmab, Abbvie, Janssen, Chugai, Otsuka, Ono, Takeda, Astrazeneca, Amgen, Nippon shinyaku: Honoraria; Chugai, Loxo Oncology, Mitsubishi Tanabe Pharma, AbbVie: Research Funding; Genmab, Otsuka: Consultancy. Kuroda:Bristol Myers Squibb, Pfizer, Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin, Chugai Pharmaceutical, Japan Blood Product Organization, Sumitomo Pharmaceutical, Otsuka Pharmaceutical, Asahikasei, Taiho Pharmaceutical, Mochida Pharmaceutical: Research Funding; Janssen Pharmaceutical, AbbVie, Pfizer, BeiGene, Bristol Myers Squibb: Consultancy; Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Bristol Myers Squibb, Novartis, AbbVie, Pfizer, Astellas Pharmaceutical, Nippon Shinyaku, Genmab, Pharma Essentia Japan: Honoraria. Yamauchi:Chugai Comapny: Research Funding. Usuki:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals, Inc.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Consultancy, Research Funding; Incyte Biosciences Japan G.K.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Consultancy, Honoraria, Research Funding; MSD K.K.: Research Funding; Nippon Shinyaku Co., Ltd.: Consultancy, Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Research Funding; Pfizer Japan Inc.: Honoraria; Sanofi K.K.: Consultancy, Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Yakult Honsha Co., Ltd.: Research Funding; Amgen K.K.: Consultancy, Research Funding; Janssen Pharmaceutical K.K.: Research Funding; AbbVie G.K.: Honoraria, Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Ohara Pharmaceutical Co., Ltd.: Consultancy; Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding; Alnylam Japan K.K.: Consultancy. Minami:Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy; Daiichi-Sankyo: Consultancy, Speakers Bureau; ONO: Research Funding; CMIC: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau.