Implications of the 5th Edition of the World Health Organization Classification and International Consensus Classification of Myeloid Neoplasm in Myelodysplastic Syndrome With Excess Blasts and Acute Myeloid Leukemia

Abstract

The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We reviewed the changes in the diagnosis distribution in patients with MDS with excess blasts (MDS-EB) or AML using both classifications. Forty-seven patients previously diagnosed as having AML or MDS-EB with available mutation analysis data, including targeted next-generation and RNA-sequencing data, were included. We reclassified 15 (31.9%) and 27 (57.4%) patients based on the 2022 WHO and 2022 ICC, respectively. One patient was reclassified as having a translocation categorized as a rare recurring translocation in both classifications. Reclassification was mostly due to the addition of mutation-based diagnostic criteria (i.e., AML, myelodysplasia-related) or a new entity associated with TP53 mutation. In both classifications, MDS diagnosis required the confirmation of multi-hit TP53 alterations. Among 14 patients with TP53 mutations, 11 harbored multi-hit TP53 alterations, including four with TP53 mutations and loss of heterozygosity. Adverse prognosis was associated with multi-hit TP53 alterations (P=0.009) in patients with MDS-EB, emphasizing the importance of detecting the mutations at diagnosis. The implementation of these classifications may lead to the identification of different subtypes from previously heterogeneous diagnostic categories based on genetic characteristics.

Keywords: Acute myeloid leukemia; Mutation; Myelodysplastic syndrome; Prognosis; TP53; World Health Organization.

Fig. 1

Summary of the reclassification of the study population according to the 2022 WHO and 2022 ICC classifications. *A case diagnosed as therapy-related myeloid neoplasm according to the 2016 WHO classification is not included in the above figure. It was reclassified as AML, MR post cytotoxic therapy and AML with mutated TP53, therapy-related according to the 2022 WHO and 2022 ICC classifications, respectively. Abbreviations: MDS-EB, MDS with excess blasts; ICC, International Consensus Classification; IB, increased blasts; MR, myelodysplasia-related; MRC, myelodysplasia-related changes; NOS, not otherwise specified.

Fig. 2

Relationships between subtypes in the study population classified according to the 2016 WHO, 2022 WHO, and 2022 ICC classifications. Reclassification based on the (A) 2022 WHO and (B) 2022 ICC classifications. *AML with recurrent genetic abnormalities is not a valid category in the 2022 ICC classification. The term was adopted from the WHO to characterize eight AML cases with mutated NPM1, three AML cases with in-frame bZIP-mutated CEBPA, and one AML case with other rare recurring translocations. Abbreviations: MDS-EB, MDS with excess blasts; MRC, myelodysplasia-related changes; NOS, not otherwise specified; t-MN, therapy-related myeloid neoplasms; IB, increased blasts; MR, myelodysplasia-related; ICC, International Consensus Classification.

Fig. 3

Boxplots showing TP53 VAF levels stratified by TP53 mutation states. (A) Comparison of VAF levels between the single TP53 mutation (1mut) and multi-hit TP53 alteration groups. (B) Comparison of VAF levels between single TP53 mutation and various subtypes of multi-hit TP53 alterations. Multi-hit TP53 alterations comprise two TP53 mutations (2mut), a single TP53 mutation with copy number loss of TP53 (Mut+del), and a single TP53 mutation with cnLOH (Mut+cnLOH). *P<0.1, Wilcoxon–Mann–Whitney test; each multi-hit TP53 alteration subgroup was compared to the single TP53 mutation group. Abbreviations: VAF, variant allele fraction; cnLOH, copy number neutral loss of heterozygosity.