NPM1-mutated AML-MRC diagnosed on the basis of history of MDS or MDS/MPN frequently harbours secondary-type mutations and confers inferior outcome compared to AML with mutated NPM1

Davidson Zhao; Mojgan Zarif; Entsar Eladl; José-Mario Capo-Chichi; Adam C Smith; Eshetu G Atenafu; Anne Tierens; Mark D Minden; Andre Schuh; Hong Chang

doi:10.1016/j.leukres.2022.106869

NPM1-mutated AML-MRC diagnosed on the basis of history of MDS or MDS/MPN frequently harbours secondary-type mutations and confers inferior outcome compared to AML with mutated NPM1

Leuk Res. 2022 Jul:118:106869. doi: 10.1016/j.leukres.2022.106869. Epub 2022 May 22.

Authors

Affiliations

¹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Haematology, University Health Network, Toronto, ON, Canada. Electronic address: davidson.zhao@mail.utoronto.ca.
² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Haematology, University Health Network, Toronto, ON, Canada. Electronic address: mojgan.zarif@uhnresearch.ca.
³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt. Electronic address: entsar.eladl@uhn.ca.
⁴ Clinical Lab Genetics Division, Laboratory of Molecular Pathology, Toronto General Hospital, University Health Network, Toronto, ON, Canada. Electronic address: jose-mario.capo-chichi@uhn.ca.
⁵ Clinical Lab Genetics Division, Laboratory of Molecular Pathology, Toronto General Hospital, University Health Network, Toronto, ON, Canada. Electronic address: adam.smith@uhn.ca.
⁶ Department of Biostatistics, University Health Network, Toronto, ON, Canada. Electronic address: eshetu.atenafu@uhnresearch.ca.
⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Haematology, University Health Network, Toronto, ON, Canada. Electronic address: anne.tierens@uhn.ca.
⁸ Department of Haematology and Oncology, University Health Network, Toronto, ON, Canada. Electronic address: mark.minden@uhn.ca.
⁹ Department of Haematology and Oncology, University Health Network, Toronto, ON, Canada. Electronic address: andre.schuh@uhn.ca.
¹⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Haematology, University Health Network, Toronto, ON, Canada. Electronic address: Hong.Chang@uhn.on.ca.

PMID: 35636054
DOI: 10.1016/j.leukres.2022.106869

Abstract

Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a prognostically diverse disease. Owing to its favourable prognosis, AML-MRC with mutated NPM1 (NPM1^MUT) diagnosed on the basis of multi-lineage dysplasia has been reclassified into "AML with mutated NPM1". However, it remains unclear if NPM1^MUT AML with antecedent MDS or MDS/MPN (AML-MRC-H) should also be reclassified into this subentity. The mutational landscape of NPM1^MUT AML-MRC-H remains poorly defined.

Methods: The clinicopathological features, molecular profiles and outcomes of 241 AML-MRC-H and 332 normal karyotype (NK)-AML with mutated NPM1 patients were retrospectively analyzed. Fisher's exact test, chi-square test and Wilcoxon rank-sum test were used to compare clinicopathological and molecular features. Overall survival and event-free survival were compared using the log-rank test. Multivariable survival analysis was performed using Cox proportional hazards regression.

Results: 33 (14%) AML-MRC-H patients had an NPM1 mutation. By NGS, NPM1^MUT AML-MRC-H patients had a significantly higher frequency of secondary-type mutations in U2AF1 and ASXL1 compared to NK-AML with mutated NPM1. NPM1^MUT AML-MRC-H was significantly associated with inferior outcomes compared to NK-AML with mutated NPM1. Bone marrow transplantation had a favourable prognostic impact in NPM1^MUT AML-MRC-H.

Conclusions: NPM1^MUT AML-MRC-H has inferior prognosis compared to NK-AML with mutated NPM1, likely due to the higher frequency of secondary-type mutations, and thus should still be included in the high-risk subentity of AML-MRC. NPM1^MUT AML-MRC patients may benefit from bone marrow transplantation.

Keywords: AML risk stratification; AML with mutated NPM1; AML-MRC-H; NPM1 mutation; Next-generation sequencing; Secondary-type mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Leukemia, Myeloid, Acute* / diagnosis
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / therapy
Mutation
Nuclear Proteins* / genetics
Nucleophosmin
Prognosis
Retrospective Studies

Substances

Nuclear Proteins
Nucleophosmin