Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML

Venetoclax plus azacitidine (VEN + AZA) is widely used in acute myeloid leukemia (AML). This study explored the role of static and dynamic profiles of mutational clonal burden to predict outcomes by analyzing marrow samples from 228 VEN + AZA treated AML cases at "Pre-treatment" (n = 228), "Best-response" (n = 105), and "Relapse" (n = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, TP53 mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while BCORL1 mutation predicted longer OS. Notably, myelodysplasia-related gene mutations, which constitute adverse factors in ELN 2022, predicted favorable survival. Achieving composite complete remission (CRc) significantly predicted longer OS (P < 0.001) but showed residual mutations in 76.2% of the cases. Among CRc cases, relapse-free survival was stratified by molecular clearance of mutations other than DNMT3A, ASXL1, and TET2 (P = 0.04). In addition, 37% of relapsed cases showed a change of major clones, with 40% having potential targets of molecular-targeting treatment. This study revealed the novel prognostic role of myelodysplasia-related gene mutations and established the importance of molecular response assessment in CRc phase.

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Publication Details

Journal
Leukemia
Published
2025-04-21
DOI
https://doi.org/10.1038/s41375-025-02625-3
Citations
6
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
10.62

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article

Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML

Nobuhiro Kanemura, Yoshikazu Ikoma, Mitsumasa Watanabe, Tomokazu Seki et al.
6 citations
Leukemia
Acute Myeloid Leukemia Research
10.62
article

Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML

Nobuhiro Kanemura, Yoshikazu Ikoma, Mitsumasa Watanabe, Tomokazu Seki, Masakatsu Hishizawa, Nobuhiko Nakamura, Akifumi Takaori‐Kondo, Hiroyuki Takamori, Yasuko Miyahara, Yotaro Ochi, Yuto Kaneda, Mizuki Watanabe, Nobuhiro Hiramoto, Tadakazu Kondo, Kazunori Imada, Yoshitomo Maesako, Tetsuji Morishita, Seishi Ogawa, Nana Sasaki, Yasuhiro Tanaka, Nobuo Sezaki, Toshiyuki Kitano, Senji Kasahara, Yasuhito Nannya, Shigeru Chiba, Junya Kanda, Michiko Ichii, Satoshi Yoshihara, Masaaki Tsuji, Satoko Oka, Kei Fujita, Yasunori Ueda, Junichi Kitagawa, Kinuko Mitani
article en
6 citations

Abstract

Venetoclax plus azacitidine (VEN + AZA) is widely used in acute myeloid leukemia (AML). This study explored the role of static and dynamic profiles of mutational clonal burden to predict outcomes by analyzing marrow samples from 228 VEN + AZA treated AML cases at "Pre-treatment" (n = 228), "Best-response" (n = 105), and "Relapse" (n = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, TP53 mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while BCORL1 mutation predicted longer OS. Notably, myelodysplasia-related gene mutations, which constitute adverse factors in ELN 2022, predicted favorable survival. Achieving composite complete remission (CRc) significantly predicted longer OS (P < 0.001) but showed residual mutations in 76.2% of the cases. Among CRc cases, relapse-free survival was stratified by molecular clearance of mutations other than DNMT3A, ASXL1, and TET2 (P = 0.04). In addition, 37% of relapsed cases showed a change of major clones, with 40% having potential targets of molecular-targeting treatment. This study revealed the novel prognostic role of myelodysplasia-related gene mutations and established the importance of molecular response assessment in CRc phase.

LeukemiaVol. 39(6)
University of Tsukuba (JP), Gifu Pharmaceutical University (JP), Kyoto University (JP), Kurashiki Central Hospital (JP), Mito Saiseikai General Hospital (JP), Gifu Municipal Hospital (JP), Kyoto City Hospital (JP), Matsunami General Hospital (JP), Gifu University Hospital (JP), Chugoku Central Hospital (JP), Osaka Hospital (JP), Takatsuki Red Cross Hospital (JP), Otsu Red Cross Hospital (JP), Hyogo Prefectural Amagasaki General Medical Center (JP), Shinko Hospital (JP), Kyoto Katsura Hospital (JP), Japanese Red Cross Society Kyoto Daini Hospital (JP), Japanese Red Cross Society Wakayama Medical Center (JP), Tokyo National Hospital (JP), Kitano Hospital (JP), Kobe City Medical Center General Hospital (JP), The University of Tokyo (JP), Dokkyo Medical University (JP), Hyogo University (JP), The University of Osaka (JP)
Japan Agency for Medical Research and Development, University of Tokyo, Japan Society for the Promotion of Science, Institute of Medical Science, University of Tokyo
Good health and well-being
Openalex Percentile: Top 2%
Acute Myeloid Leukemia Research
10.62
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