AML-Mrg Mutation Spectrum and Its Prognosis: A Japanese Multicenter Study HM01-02 Analysis with Full Analysis Sets
Authors: Hosono Naoko , Naito Tomoki , Chi Sunggi , Arai Hironori , Onodera Koichi , Fukushima Kentaro , Ikeda Daisuke , Iyama Satoshi , Gotoh Akihiko , Ikezoe Takayuki , Takahashi Naoto , Kojima Kensuke , Kanda Junya , Izutsu Koji , Fukuhara Suguru , Matsui Hirotaka , Yoshimoto Goichi , Kuroda Junya , Yamauchi Takahiro , Usuki Kensuke , Minami Yosuke 
Published: December 2024

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.