Evidence-based risk stratification of myeloid neoplasms harboring TP53 mutations

• Hierarchical risk-stratification acknowledges poor survival of 92% of TP53-mutated MN compared to 36.5% by WHO-5 and 80.7% by ICC

• MDS-EB1 and EB2 share biological characteristics and have equally poor survival, regardless of allelic status, supporting their integration

This retrospective analysis aimed to provide evidence-based risk-stratification of TP53-mutated (TP53mut) myeloid neoplasms (MN). Of 580 MN harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), MDS with low blasts (MDS-LB), MDS excess blasts (MDS-EB)-2, and -EB1 according to the revised 4th edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified four risk groups with distinct survival: (i) MDS-LB, (ii) MDS-EB1/EB2/AML VAF <10%, (iii) MDS-EB1/EB2 VAF ≥10%, and (iv) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with <5% blasts and not for blasts 5-9%, as proposed by the International Consensus Classification (ICC), or 5-19%, as proposed by the 5th edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs. 7.2 months, P=0.12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF <10% and CK had poor survival compared to those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs. 26.2 vs. 6.3 months, P=0.003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, utilizing ICC or WHO-5 may underestimate prognosis of MDS with blasts 5-19% and 5-9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared to 36.5% and 80.7% by WHO-5 and ICC, respectively.