New Guidelines Clarify MDS Classification, Highlight Diagnostic Nuances

A revised guideline and a new guideline set in diagnostic criteria for myelodysplastic neoplasms were published in 2022, and clinicians have been experiencing some classification confusion, according to new research. In Annals of Laboratory Medicine, authors shed light on the distinctions between the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO 2022) and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias (ICC 2022).^1-3 For instance, myelodysplastic neoplasms were called myelodysplastic syndromes (MDS) in the previous 2017 WHO classification and remain so named in ICC 2022.

The authors recommend using WHO 2022 and ICC 2022 complementarily when classifying and diagnosing MDS, especially SF3B1- and TP53-mutated MDS, to offer better survival prediction.

The 2 syndrome criteria sets have value, despite their similarities and differences, the authors of this study acknowledge. | Image Credit: tashatuvango-stock.adobe.com

New Terminology, New Refinements

First, the team examined how the revised diagnostic criteria influenced MDS classification in a large population, comprising 2454 patients with MDS from a well-validated, open-source dataset from cBioPortal. Then, to examine potential diagnostic differences, they used WHO 2022 criteria to reclassify patients previously classified using WHO 2017. Additionally, they compared the WHO 2022 and ICC 2022 diagnostic criteria in classifying 2 genetics-based MDS subtypes, SF3B1- and TP53-mutated MDS; definitions of these newly introduced subtypes differ between the 2 criteria sets.

Based on WHO 2022 criteria, they found, 1.4% of patients with MDS would be reclassified as having acute myeloid leukemia (AML). The diagnosis of another small subset changed to clonal cytopenia of undetermined significance with WHO 2022. MDS unclassifiable, part of WHO 2017, has been removed from WHO 2022, with those patients allocated to specific MDS subtypes.

For classifying MDS with low blast counts and SF3B1 mutation, a variant allele frequency (VAF) cutoff of 5% (WHO 2022) and the absence of RUNX1 comutation (ICC 2022) are diagnostically relevant. The VAF cutoff for SF3B1 mutation for the diagnosis of MDS-SF3B1 is higher in ICC 2022 (10%) than in WHO 2022 (5%), the investigators pointed out. Additionally, according to ICC 2022, the RUNX1 comutation should be absent for this diagnosis, they said.

The VAF cutoff of 5% and the absence of RUNX1 comutation are clinically relevant, wrote the team. The SF3B1 variant type doesn’t influence prognosis, however.

For classifying MDS with mutated TP53, a blast count cutoff of 10% (ICC 2022) and multihit TP53 (WHO 2022) are independent risk factors in cases with 10% or greater blasts.

WHO 2022 “specifies MDS-biTP53 when the blast count is less than 20%, and AML with mutated TP53 is not specified as a disease entity,” explained the authors. “In contrast, the ICC defines a category termed ‘myeloid neoplasms with mutated TP53,’ which includes MDS (less than 10% blasts), MDS/AML (10%-19% blasts), and AML (20% or greater blasts).”

They added that in ICC 2022, the TP53 mutation status should be biallelic in MDS with mutated TP53, but it can be monoallelic or biallelic in MDS/AML with mutated TP53 and AML with mutated TP53. WHO 2022 does not specify a VAF threshold, they continued, but ICC 2022 mandates that the VAF for TP53 mutations should be greater than 10%.

In their work, the authors went on, it was prognostically valuable to use a blast cutoff of 10% (ICC 2022) to distinguish MDS and MDS/AML when classifying TP53-mutated MDS. They found that in MDS cases with blast counts of 10% or more, TP53 multihit (WHO 2022) was an independent risk factor compared with wild-type TP53. On the other hand, the TP53 variant type within TP53 multihit and a TP53 VAF cutoff of 10% within myeloid neoplasms with mutated TP53-ICC were not prognostic indicators, they wrote.

References

1. Yun J, Kim HR. Reclassification of myelodysplastic neoplasms according to the 2022 World Health Organization classification and the 2022 International Consensus Classification using open-source data: focus on SF3B1- andTP53-mutated myelodysplastic neoplasms. Ann Lab Med. Published online July 24, 2024. doi:10.3343/alm.2024.0079

2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

3. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850