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<p><i>NPM1</i>-mutated (<i>NPM1</i>-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult <i>NPM1</i>-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in <i>FLT3</i>-ITD, <i>DNMT3A</i>, <i>IDH1/IDH2</i>, and <i>TET2</i> genes, was applied to a training cohort of <i>NPM1</i>-mut AML patients included in clinical trials (<i>n</i> = 1001), an internal validation cohort more representative of real-world settings (<i>n</i> = 762), and an external validation cohort enrolled in UK-NCRI trials (<i>n</i> = 585). The HARMONY classification considered 51.8% of the <i>NPM1</i>-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; <i>p</i> &lt; 0.001), thereby reclassifying 42.7% of <i>NPM1</i>-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the <i>NPM1</i>-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult <i>NPM1</i>-mut AML with potential clinical impact on allo-HSCT decision-making.</p><p></p>

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Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • Alberto Hernández-Sánchez,
  • Ángela Villaverde Ramiro,
  • Eric Sträng,
  • Amin T. Turki,
  • María Abáigar,
  • Jurjen Versluis,
  • Ian Thomas,
  • Marta Sobas,
  • Javier Martínez Elicegui,
  • Gastone Castellani,
  • Axel Benner,
  • Raúl Azibeiro,
  • Jesse M. Tettero,
  • Rabea Mecklenbrauck,
  • Joaquín Martínez-López,
  • Marta Pratcorona,
  • Ken I. Mills,
  • Guillermo Sanz,
  • Maria Teresa Voso,
  • Lehmann Sören,
  • Christoph Röllig,
  • Christian Thiede,
  • Klaus H. Metzeler,
  • Konstanze Döhner,
  • Michael Heuser,
  • Torsten Haferlach,
  • Peter JM Valk,
  • Nigel Russell,
  • Jesús María Hernández-Rivas,
  • Brian Huntly,
  • Gert Ossenkoppele,
  • Hartmut Döhner,
  • Lars Bullinger

摘要

NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.