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AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome


Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0–72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20–70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

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Fig. 1: Flowchart of the study.
Fig. 2: Epidemiologic characteristics, blast counts, and bone marrow cellularity at initial the diagnosis of AML patients with mutant DDX41.
Fig. 3: Pathologic characteristics of bone marrow aspirates and biopsies from DDX41-mutant AML patients.
Fig. 4: Integrated molecular and cytogenetic characteristics of the 28 DDX41-mutant AML patients.
Fig. 5: Treatment response and overall survival (OS) of 28 DDX41-mutant AML patients.


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Author information




PL designed the study and drafted the manuscript. TW, WX, WC, DP, GZ, H-YW, MW, and SB collected patients’ clinical and family history, morphologic, cytogenetic, and molecular data. JV and TK examined patients and performed DDX41 germline testing. PL, TW, WX, WC, DP, GZ, H-YW, and SB interpreted and classified all variants by NGS testing. PL, MW, and JLP reviewed the bone marrow examination. All authors reviewed and approved the final manuscript.

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Correspondence to Peng Li.

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Li, P., White, T., Xie, W. et al. AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome. Leukemia (2021).

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