Single-Hit TP53mut Is Associated with Poor Outcomes in Therapy-Related but Not De Novo Myelodysplastic Syndromes: Importance of Clinical History

BACKGROUND: Recent World Health Organization (WHO) classifications (5^th edition), International Consensus Classification (ICC) recognized TP53-mutated (TP53^mut) myeloid neoplasms (MNs) as a distinct subcategory, acknowledging their uniformly poor outcomes. However, there are critical differences between the two guidelines in how TP53 allelic status is assigned. Both WHO-5 and ICC acknowledged the poor outcome of multi-hit TP53^mut but excluded single-hit TP53^mut. These changes are driven by a pivotal study demonstrating favourable outcome of single-hit TP53^mut, however this study predominantly included de novo myelodysplastic syndromes (MDS) cases (Bernard et al. Nat Med 2020). In contrast, we previously reported poor outcome of TP53^mut therapy-related myeloid neoplasm (t-MN) irrespective of the allelic status of TP53 (Hiwase et al Blood 2022 and Shah et al BCJ 2023). Finally, the ICC removed the subcategory of “therapy-related,” substituting it with diagnostic qualifiers instead. The WHO has grouped t-MN with secondary MN and renamed it as “myeloid neoplasm post cytotoxic therapy,” with the assertion that only multi-hit TP53^mut MDS occurring post–cytotoxic therapy have poor outcome compared with single-hit.

METHODS: We analyzed one of the largest international cohorts of TP53^mut MN (n=544) with full characterization of TP53^mut allele status utilizing uniform ICC criteria and similar large numbers of de novo and t-MN cases managed at Mayo Clinic Enterprise (USA) and South Australian MDS Registry, Adelaide (Australia) with clinical, integrated genomic profiling, and long-term follow-up.

RESULTS: In our cohort of TP53^mut MN (n=544), 475 (87.3%) MN had TP53^mut variant allele frequency (VAF) of ≥10% and thus satisfied ICC criteria for TP53^mut MN. Majority of TP53^mut t-MN presented with MDS (bone marrow (BM) blasts 0-9%) compared de novo MN (62% vs. 48%; P=0.0012). While acute myeloid leukemia (AML) (BM blasts ≥20%) were more prevalent in TP53^mut de novo MN compared to t-MN (38% vs. 24%; P= 0.001) and there was no difference in frequency of MDS/AML (BM blasts 10-19%) between the two cohorts (14% vs. 14%; P=0.8) (Figure 1A).

Majority of TP53^mut were observed in the DNA-binding domain in t-MN and de novo MN (95% vs. 96.2%; P=0.48). However, mutations in Tetramer Domain were more frequent in t-MN (4.3% vs. 0.3%; P=0.002), whereas those in the TAD2 domain were more frequent in de novo TP53^mut MN (2.4 vs. 0%; P =0.006).

Integrating the mutation, conventional G-banding cytogenetic, copy number variation (CNV), FISH, and SNP array analysis, TP53^mut MDS (BM blast 0-9%; n=260) were classified as multi-hit (n=179, 68.9%) or multi-equivalent (n=35, 13.5%) and single-hit (n=46, 17.7%) (Arber et al. Blood 2022). Striking enrichment of multi-hit/multi-hit equivalent was observed in TP53^mut t-MDS compared to de novo MDS (91% vs. 72%; P<0.0001). While single-hit TP53^mut were prevalent in de novo MDS compared to t-MDS (28% vs. 9%; P<0.0001). Importantly, median overall survival (OS) of single-hit was significantly longer than multi-hit de novo MDS (25.4 vs. 7.2 months; P=0.0002). In contrast to this we did not observe OS difference between single-hit and multi-hit TP53^mut t-MDS (11.6 vs. 10.9 months; P =0.73) (Figure 1B).

CONCLUSION: Our study based on a large international cohort of T53^mut MN provides compelling evidence that in contrast to de novo MDS, single hit TP53^mut t-MDS is associated with poor outcome. Our data supports the consideration of single hit t-MDS as a multi-hit equivalent.