TY - JOUR
T1 - DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system
T2 - a multicenter, retrospective study
AU - Gurnari, Carmelo
AU - Makishima, Hideki
AU - Durmaz, Arda
AU - Attardi, Enrico
AU - Saiki, Ryunosuke
AU - Bataller, Alex
AU - Sapinho, Guilherme
AU - Gondek, Lukasz
AU - Nannya, Yasuhito
AU - Best, Steve
AU - Krishnamurthy, Pramila
AU - Kong, Kar Lok
AU - Atsuta, Yoshiko
AU - Kasahara, Senji
AU - Ohyashiki, Kazuma
AU - Miyazaki, Yasushi
AU - Kanemura, Nobuhiro
AU - Hiramoto, Nobuhiro
AU - Versino, Francesco
AU - Montoro, Maria Julia
AU - Torres-Esquius, Sara
AU - Jerez Cayuela, Andres
AU - López-Esteban, Miguel
AU - Martínez-Laperche, Carolina
AU - Awada, Hussein
AU - Visconte, Valeria
AU - DiNardo, Courtney D.
AU - Voso, Maria Teresa
AU - DeZern, Amy E.
AU - Garcia-Manero, Guillermo
AU - Kulasekararaj, Austin G.
AU - Maciejewski, Jaroslaw P.
AU - Ogawa, Seishi
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2026/1
Y1 - 2026/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105023981184
UR - https://www.scopus.com/pages/publications/105023981184#tab=citedBy
U2 - 10.1038/s41375-025-02814-0
DO - 10.1038/s41375-025-02814-0
M3 - Article
C2 - 41339477
AN - SCOPUS:105023981184
SN - 0887-6924
VL - 40
SP - 178
EP - 187
JO - Leukemia
JF - Leukemia
IS - 1
ER -