Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, MDS, Clinical Practice (Health Services and Quality), Genomics, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Biological Processes, Technology and Procedures, Molecular testing
Deletions (del) 5q in MDS typically occur either in MDS with low blasts and del(5q) (MDS-5q according to WHO) or in MDS with complex karyotype (CK). While MDS-5q are generally associated with a favorable prognosis and harbor TP53 alterations (alt) in 10-20% of these cases (most commonly single-hit), MDS with CK are associated with an unfavorable outcome, harbor additional cytogenetic abnormalities such as monosomy 7 or del(7q) and del(17p) and frequently show TP53 alt which are multi-hit in 80-90% of cases.
Aims:
To clarify based on hierarchy analysis whether MDS with CK arises from MDS-5q cases with del(5q) as primary abnormality.
Methods:
729 MDS patients harboring a del(5q) (median age: 76 years [32-98]; female: 58%) were collected between 2005 and 2023 and included in this study. All samples were analyzed by cytomorphology, cytogenetics, FISH and a targeted NGS panel. Diagnoses were established following WHO classification valid at time of sampling. We analyzed the clonal composition at initial diagnoses. Follow-up samples were available in 150/729 patients. To compare the variant allele frequencies (VAF) of mutations (mut) to those of cytogenetic abnormalities, the number of cells with aberrant nuclei were divided by two (CA-VAF). VAF estimates were used to evaluate clonal hierarchy of TP53 and del(5q) using a VAF difference cut-off of ≥5% in samples that harbored no del(17p) by FISH and had TP53 VAF <55%, i.e. presumably unaffected by copy-neutral loss of heterozygosity (CN-LOH). TP53 multi-hit was defined as either ≥2 TP53 mut, one TP53 mut with VAF ≥55% or one TP53 mut accompanied by del(17p). For progression analysis only patients with a minimum follow-up time of 90 days were considered.
Results:
Of all del(5q) patients, 42% (308/729) had MDS-5q (median age: 77 years; female: 72%), 50% (365/729) had CK (median age: 74 years; female: 46%) and 8% (56/729) neither fulfilled criteria for MDS-5q or CK. Both age (p=0.001) and sex ratio (p<0.0001) differed significantly between MDS-5q and CK.
The most frequently co-occurring somatic mut in cases with del(5q) was TP53, detected in 54% (397/729) of cases, out of which TP53 was the sole mutated gene in 63% (252/397). Notably, TP53 mut were more frequent in MDS with CK than in MDS-5q (87% vs 20%; p<0.0001) and were also more commonly multi-hit in MDS with CK compared to MDS-5q (79% vs. 27% of TP53 alt cases; p<0.0001).
Clonal hierarchy analysis of TP53 mut cases that neither harbored del(17p) nor CN-LOH showed that for MDS-5q (n=23) the median CA-VAF of del(5q) was higher than the VAF of TP53 mut (25% vs. 20%, p=0.48), while in CK cases (n=90) this was reversed (19% vs. 29%, p<0.0001). Congruently, in MDS-5q the clear primary event (determined by CA-VAF del(5q) to VAF TP53 mut comparison in each case) was del(5q) in 43% (10/23) of cases compared to TP53 mut in 26% (6/23) of cases. For MDS with CK del(5q) was the clear primary event in 7% (6/90) and TP53 mut in 50% (45/90) of cases. In CK cases with del(17p) (n=104), del(5q) preferably occurred before del(17p) (27% vs. 13%; 60% hierarchy not determinable).
For a subset of patients data on karyotype and TP53 status was available from different time points (median follow-up time: 2.8 years). Out of 84 patients initially diagnosed with MDS-5q 4% (3/84) presented with normal karyotype following transplantation or therapy with lenalidomide, 4% (3/84) showed clonal evolution (acquisition of one additional cytogenetic alt), 24% (20/84) developed CK (acquisition of two or more additional cytogenetic alt) and 69% (58/84) showed a stable karyotype.
Out of the 20 cases acquiring CK during progression, 13 harbored TP53 alt (nine multi-hit, four single-hit), of these only six patients showed TP53 alt already in the MDS-5q phase (two multi-hit, four single-hit). TP53 alt were significantly more common at final follow-up in patients progressing to CK (13/20; 65%) than in those retaining a stable karyotype (22/58; 38%), as were multi-hit TP53 alt which were found in 45% (9/20) of CK acquiring patients and only in 19% (11/58) of stable MDS-5q patients (for both p=0.04).
Conclusion:
Clonal hierarchy analysis and serial genetic assessment suggest two separate routes to complex karyotypes in MDS: 1) deriving from MDS-5q which mainly harbor del(5q) within the ancestral clone and acquire TP53 alterations during the course of the disease, 2) more commonly arise from clones with a TP53 mutation as the primary abnormality acquiring del(5q) later.
Disclosures: Haferlach: Abbvie: Consultancy, Honoraria. Hoermann: Cogent: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees.
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