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Molecular Taxonomy of MDS May Help Guide Clinical Decisions, Trials Free

August 15, 2024

September 2024

Katie Robinson

Katie Robinson is a medical writer based in New York.

In patients with myelodysplastic syndromes/neoplasms (MDS), genomic profiling identified molecular subgroups associated with specific clinical phenotypes and disease courses. This is according to a study published in Blood, which suggested that this molecular taxonomy will help develop a broader genetically informed MDS classification that benefits clinical decisions and therapeutic trials.

“The definition of molecular groups is key to identifying determinants of disease progression and treatment response,” said lead author Elsa Bernard, PhD, of Memorial Sloan Kettering Cancer Center in New York.

MDS are caused by genetic abnormalities, but their classifications rely mainly on bone marrow morphology. Dr. Bernard and colleagues examined how genetic alterations define specific disease subtypes and their clinical implications.

The researchers performed genomic profiling on bone marrow or blood samples from 3,233 patients (median age = 72 years) with MDS or related neoplasms who were included in the development of the International Prognostic Scoring System Molecular. The study excluded patients with acute myeloid leukemia with recurrent genetic abnormalities. The researchers performed sequencing with a 152-gene panel to define gene mutations, copy-​number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) events.

For gene mutations, CNAs, and cnLOH events, abnormalities were identified in 91%, 43%, and 11% of patients, respectively. When the patients were grouped based on their molecular profiles, the researchers identified 16 molecular groups and two residual groups. The 16 molecular groups comprised 86% of the patients, using information from 21 genes, six cytogenetic events, and LOH at the TP53 and TET2 loci. The two residual groups comprised 14% of patients and included the molecularly not-otherwise-specified group (defined as the presence of other cytogenetic abnormalities and/or mutations in 51 other recurrently mutated genes) and the no-event category (defined as the absence of any recurrent drivers evaluated in the study).

The 18 groups varied both in size, ranging from 0.5% to 14% of patients, and molecular complexity, with zero to five mutated genes per patient. The groups were associated with distinct demographics, clinical presentations, and patient outcomes. Across the groups, the median age of diagnosis ranged from 64 years to 75 years; the median bone marrow blast ranged from 1.5% to 10%; the median overall survival ranged from 11 months to 8.2 years; and the two-year leukemic transformation rate ranged from 0% to 40%. Of the 16 molecular groups, five validated established (TP53-complex, del(5q), SF3B1) or well-characterized subsets (DDX41, AML-like); three supported previously reported subgroups (bi-TET2, der(1;7), CCUS-like); and eight were new (-7/SETBP1, EZH2-ASXL1, IDH-STAG2, BCOR/L1, U2AF157, U2AF134, SRSF2, ZRSR2).

The percentage of bone marrow blasts did not stratify patient outcomes in several groups as it did for groups enriched for lower-risk disease. “Specific genetic subtype outweighs blast count as a predictor of outcomes, which should be considered in a future MDS classification,” the authors wrote. The clinical and outcome profiles were like primary MDS within the several genetic subgroups, accounting for more than 5% of patients with therapy-related MDS or myeloproliferative neoplasms.

Limitations to the study included the use of targeted sequencing, potentially omitting relevant biomarkers, the lack of germline control tissues, and the absence of analysis with related morphologic features.

“This molecular taxonomy should be a useful tool for future correlative studies and exploratory analyses within clinical trials evaluating the efficacy of therapeutic compounds and for the development of targeted therapies,” the authors concluded.

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

Reference

Bernard E, Hasserjian R, Greenberg PL, et al. Molecular taxonomy of myelodysplastic syndromes and its clinical implications [published online ahead of print, 2024 July 3]. Blood. doi: 10.1182/blood.2023023727.

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