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<p>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” (<i>n</i> = 228), “Best-response” (<i>n</i> = 105), and “Relapse” (<i>n</i> = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, <i>TP53</i> mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while <i>BCORL1</i> 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 (<i>P</i> &lt; 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 <i>DNMT3A</i>, <i>ASXL1</i>, and <i>TET2</i> (<i>P</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月21日

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

摘要

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.