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Peer-reviewedCC BY 4.0PLOS One

Genomic and clinical determinants of response to Azacitidine plus venetoclax in acute myeloid leukemia: Results from the HM-SCREEN-Japan 02 study

  • Tomoaki Ueda1
  • Kentaro Fukushima2
  • Sunggi Chi3
  • Hiroshi Haeno4
  • Goichi Yoshimoto5
  • Hironori Arai6
  • Daisuke Ikeda7
  • Motoshi Ichikawa8
  • Naoto Takahashi9
  • Naoko Hosono10
  • Takahiro Yamauchi11
  • Takeshi Kondo12
3 more authors
  • Shigeru Kusumoto
  • Junya Kuroda
  • Yosuke Minami
12 affiliations
  1. 1Department of Hematology and Oncology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan
  2. 2Department of Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
  3. 3Division of Integrated Research Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
  4. 4Department of Hematology, Saga-ken Medical Centre Koseikan, Kasemachi, Saga, Japan
  5. 5Division of Hematology, Japanese Red Cross Narita Hospital, Narita, Chiba, Japan
  6. 6Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan
  7. 7Department of Hematology, NTT Medical Center Tokyo, Shinagawa-ku, Tokyo, Japan
  8. 8Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Hondo, Akita, Japan
  9. 9Department of Hematology and Oncology, University of Fukui, Yoshida-gun, Fukui, Japan
  10. 10Blood Disorders Center, Aiiku Hospital, Sapporo, Hokkaido, Japan
  11. 11Department of Hematology and Cell Therapy, Aichi Cancer Center, Chikusa-ku, Nagoya, Japan
  12. 12Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
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Abstract

The combination of azacitidine and venetoclax (Aza/Ven) is an effective treatment for acute myeloid leukemia (AML); however, biological factors underlying heterogeneous treatment responses across diverse genetic backgrounds remain incompletely defined. We analyzed 97 AML patients treated with Aza/Ven in the prospective HM-SCREEN-Japan 02 study using targeted next-generation sequencing (NGS) of 53 genes, cytogenetic analyses, and clinical variables. Somatic mutations were categorized into type 1 (FLT3, PTPN11, WT1, IDH1/2, NPM1, NRAS) and type 2 (GATA2, KRAS, TP53, RUNX1, STAG2, ASXL1, ZRSR2, TET2) groups based on a previously proposed framework describing clonal characteristics. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 53.8%, 52.1%, and 50.0% of patients treated in the first-, second-, and ≥third-line settings, respectively. Among 53 first-line patients with pre-treatment NGS data, type 1–only mutations were more frequently observed in responders (CR/CRi 72%), whereas type 2–only mutations were enriched in non-responders (CR/CRi 33%). In the first-line setting, achievement of CR/CRi following Aza/Ven was associated with improved overall survival. In addition, an exploratory mathematical model integrating baseline clinical variables demonstrated strong discriminatory performance for treatment response, including in cases without established prognostic mutations. In conclusion, Aza/Ven demonstrated consistent clinical activity across treatment lines in this real-world cohort. Mutational patterns classified by a type 1/type 2 framework were associated with differential response patterns in the first-line setting. Integrative modeling approaches may support the interpretation of response heterogeneity, particularly in genetically uninformative AML.

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Cite

BibTeXRIS
BibTeX
@article{ueda2026genomic,
  title = {{Genomic and clinical determinants of response to Azacitidine plus venetoclax in acute myeloid leukemia: Results from the HM-SCREEN-Japan 02 study}},
  author = {Tomoaki Ueda and Kentaro Fukushima and Sunggi Chi and Hiroshi Haeno and Goichi Yoshimoto and Hironori Arai and Daisuke Ikeda and Motoshi Ichikawa and Naoto Takahashi and Naoko Hosono and Takahiro Yamauchi and Takeshi Kondo and Shigeru Kusumoto and Junya Kuroda and Yosuke Minami},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0357898},
  url = {https://doi.org/10.1371/journal.pone.0357898},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Genomic and clinical determinants of response to Azacitidine plus venetoclax in acute myeloid leukemia: Results from the HM-SCREEN-Japan 02 study
AU  - Tomoaki Ueda
AU  - Kentaro Fukushima
AU  - Sunggi Chi
AU  - Hiroshi Haeno
AU  - Goichi Yoshimoto
AU  - Hironori Arai
AU  - Daisuke Ikeda
AU  - Motoshi Ichikawa
AU  - Naoto Takahashi
AU  - Naoko Hosono
AU  - Takahiro Yamauchi
AU  - Takeshi Kondo
AU  - Shigeru Kusumoto
AU  - Junya Kuroda
AU  - Yosuke Minami
PY  - 2026
DA  - 2026/10/01
JO  - PLOS One
DO  - 10.1371/journal.pone.0357898
UR  - https://doi.org/10.1371/journal.pone.0357898
AB  - The combination of azacitidine and venetoclax (Aza/Ven) is an effective treatment for acute myeloid leukemia (AML); however, biological factors underlying heterogeneous treatment responses across diverse genetic backgrounds remain incompletely defined. We analyzed 97 AML patients treated with Aza/Ven in the prospective HM-SCREEN-Japan 02 study using targeted next-generation sequencing (NGS) of 53 genes, cytogenetic analyses, and clinical variables. Somatic mutations were categorized into type 1 (FLT3, PTPN11, WT1, IDH1/2, NPM1, NRAS) and type 2 (GATA2, KRAS, TP53, RUNX1, STAG2, ASXL1, ZRSR2, TET2) groups based on a previously proposed framework describing clonal characteristics. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 53.8%, 52.1%, and 50.0% of patients treated in the first-, second-, and ≥third-line settings, respectively. Among 53 first-line patients with pre-treatment NGS data, type 1–only mutations were more frequently observed in responders (CR/CRi 72%), whereas type 2–only mutations were enriched in non-responders (CR/CRi 33%). In the first-line setting, achievement of CR/CRi following Aza/Ven was associated with improved overall survival. In addition, an exploratory mathematical model integrating baseline clinical variables demonstrated strong discriminatory performance for treatment response, including in cases without established prognostic mutations. In conclusion, Aza/Ven demonstrated consistent clinical activity across treatment lines in this real-world cohort. Mutational patterns classified by a type 1/type 2 framework were associated with differential response patterns in the first-line setting. Integrative modeling approaches may support the interpretation of response heterogeneity, particularly in genetically uninformative AML.
SN  - 1932-6203
ER  -