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Data-Driven Analysis Harmonizes 2022 WHO, ICC Classifications of Myelodysplastic Syndromes

December 14, 2023

January 2024

Lara C. Pullen, PhD

Lara C. Pullen, PhD, is a freelance medical writer in Chicago, Illinois.

In 2022, the World Health Organization (WHO) and the International Consensus Classification (ICC) introduced gene mutations and chromosomal abnormalities into their distinct classifications of myelodysplastic syndromes (MDS). Now, new results demonstrate that a data-driven approach based on advanced statistical methods can generate a harmonization of the two systems. Luca Lanino, MD, of Humanitas Clinical and Research Center in Milan, Italy, presented the resulting provisional hierarchical classification algorithm at the 65th ASH Annual Meeting and Exposition.

“We know that gene sequencing techniques have radically changed our understanding of MDS,” Dr. Lanino said. He and his colleagues thus analyzed retrospective international cohorts of patients annotated with molecular and cytogenetic data who, according to WHO 2016 criteria, had a diagnosis of MDS (n=7,017) and acute myeloid leukemia (AML; n=1,002). Although the discordance between the WHO and ICC classification criteria was not calculated, Dr. Lanino estimated there was approximately a 10% discordance between the two criteria. He then emphasized that the effort was not designed to determine new classification entities, but rather to harmonize the two classification criteria.

The team applied Hierarchical Dirichlet Processes to capture broad dependencies among all gene mutations and cytogenic abnormalities and was able to define nine classification clusters. The first three clusters were based on genomic features. Cluster one had the highest hierarchical importance and included MDS with TP53 mutation. The major genomic feature contributing to this cluster was the presence of biallelic TP53 (biTP53) inactivation. Dr. Lanino reported that most patients assigned to the biTP53 cluster had TP53 variant allele frequency (VAF) of greater than 10% (77.9%) and a complex karyotype (70.1%). Cluster two contained patients with MDS with isolated del(5q); most (88.1%) of these patients had blast counts of less than 5%. Cluster three consisted of patients with MDS with isolated SF3B1 mutations in the absence of concurrent del(7q), abn3q26.2, complex karyotype, or RUNX mutation. Most patients (94.2%) with MDS and SF3B1 mutation had less than 5% blasts. Common co-mutated variants in this cluster included mutant DNMT31 (25.2%) and TET2 (38.3%).

The researchers used morphologic features to define the MDS cases that did not fit into the above clusters and, based on those features, assigned patients to the following additional clusters:

  • SF3B1 and concurrent higher-risk mutations
  • SRSF2 and concomitant TET2 mutations
  • U2AF1 mutations with del(20q), del(7q), or -7
  • SRSF2 with TET2 mutations and co- mutational patterns including RUNX1 and ASXL1
  • AML-like genomic signatures

The analysis indicated that morphologically defined MDS is characterized by a large heterogeneity in terms of maturation profiles and that this heterogeneity is not entirely captured by the presence of unilineage versus multilineage dysplasia. The investigators did, however, identify similarities between the AML-like MDS clusters and selected AML genomic signatures such that the overlap in genomic signatures was 29%. Dr. Lanino described the modified Delphi Consensus process that involved 71 experts from 11 countries who were tasked with identifying morphologically defined MDS. He concluded his presentation with a description of the hierarchical harmonized MDS classification determined by the Consensus process.

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Lanino L, Ball S, Bewersdorf JP, et al. Data-driven harmonization of 2022 WHO and ICC classifications of myelodysplastic syndromes/neoplasms (MDS): a study by the International Consortium for MDS (icMDS). Abstract 998. Presented at the 65th American Society of Hematology Annual Meeting and Exposition; December 11, 2023; San Diego, California.

 

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