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<p><i>DDX41</i>-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how <i>DDX41</i> mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of <i>DDX41</i>-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for <i>DDX41</i>-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to <i>DDX41</i>-mutant MN when compared to wild-type counterparts. Dissecting all possible <i>DDX41</i> configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in <i>DDX41-</i>specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in <i>DDX41</i>-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.</p>

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DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system: a multicenter, retrospective study

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Carmelo Gurnari,
  • Hideki Makishima,
  • Arda Durmaz,
  • Enrico Attardi,
  • Ryunosuke Saiki,
  • Alex Bataller,
  • Guilherme Sapinho,
  • Lukasz Gondek,
  • Yasuhito Nannya,
  • Steve Best,
  • Pramila Krishnamurthy,
  • Kar Lok Kong,
  • Yoshiko Atsuta,
  • Senji Kasahara,
  • Kazuma Ohyashiki,
  • Yasushi Miyazaki,
  • Nobuhiro Kanemura,
  • Nobuhiro Hiramoto,
  • Francesco Versino,
  • Maria Julia Montoro,
  • Sara Torres-Esquius,
  • Andres Jerez Cayuela,
  • Miguel López-Esteban,
  • Carolina Martínez-Laperche,
  • Hussein Awada,
  • Valeria Visconte,
  • Courtney D. DiNardo,
  • Maria Teresa Voso,
  • Amy E. DeZern,
  • Guillermo Garcia-Manero,
  • Austin G. Kulasekararaj,
  • Jaroslaw P. Maciejewski,
  • Seishi Ogawa

摘要

DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.