TP53 Mutational Status in Myelodysplastic Neoplasm and Acute Myeloid Leukemia: Impact of Reclassification By Who 2022 and ICC Criteria – a Korean Multi-Center Study

Introduction: The WHO 2022 classification (WHO 2022) introduced the category of myelodysplastic neoplasm (MDS) with biallelic TP53 inactivation (MDS-biTP53), while the international consensus classification (ICC) included the categories of MDS, MDS/acute myeloid leukemia (AML), and AML with mutated TP53. Particularly in MDS, multi-hit TP53 mutations are clinically important, but there were differences in the criteria defining multi-hit TP53 mutations between the WHO 2022 and ICC classifications. In this study, we investigated the TP53 mutational status in Korean adult patients with MDS and AML and evaluated the impact of TP53 mutation-related criteria of WHO 2022 and ICC on the reclassification of MDS.

Methods: This study included patients aged 18 years or older who were diagnosed with MDS and AML from January 2017 to December 2022 at six institutions. The results of bone marrow examination, chromosome analysis, TP53 fluorescence in situ hybridization, and targeted next-generation sequencing including TP53 were analyzed in 1264 patients with MDS and 2112 patients with AML. Multi-hit TP53 mutation was defined based on WHO 2022 and ICC criteria as having any of the following: one TP53 mutation with variant allele frequency (VAF) ≥ 50%, one TP53 mutation with VAF ≥ 10% with 17p deletion, one TP53 mutation with VAF ≥ 10% with complex karyotype (only for ICC), two TP53 mutations with VAF ≥ 10% (only for ICC), or two TP53 mutations (only for WHO 2022).

Results: TP53 mutations were observed in 9.3% (118/1264) and 9.1% (192/2112) of patients with MDS and AML, respectively. Among these, 90% of patients had a single TP53 mutation and multiple TP53 mutations were observed in 10% of patients. There was no difference according to MDS or AML (P=0.478), and 91% of patients with a single TP53 mutation had a VAF of ≥ 10%. Median VAFs of TP53 mutations were 42.7% and 44.4% in MDS and AML, respectively (P=0.899), and complex karyotype was observed in 76.1% (236/310) of all patients with TP53 mutations without differences between MDS and AML (P=0.534). In contrast, 17p deletion was identified in 40.3% of AML patients, significantly higher than in MDS (27.4%, P=0.02). Within MDS, 17p deletion was observed in 46.7% in MDS with 10-19% blasts (MDS-H), significantly higher than in MDS with 0-9% blasts (MDS-L, 20.7%, P=0.008), but similar to AML (P=0.514). When each TP53 mutation-related criterion based on WHO 2022 and ICC criteria were applied to MDS, 55.7% (49/88) and 75% (66/88) of MDS-L met the criteria for multi-hit TP53 mutation and were classified as MDS-biTP53 (WHO 2022) and MDS with mutated TP53 (ICC), respectively. Notably, more patients were classified into this category based on ICC criteria (P<0.001), all due to the complex karyotype-related criterion included only in the ICC. Among MDS-H, 63.3% (19/30) of patients were classified as MDS-biTP53 (WHO 2022) based on multi-hit TP53 mutation criteria, whereas 86.7% (26/30) of patients were classified as MDS/AML with mutated TP53 (ICC) based on the single TP53 mutation criterion with VAF ≥ 10%. Overall, 57.6% (68/118) and 78% (92/118) of patients with MDS and TP53 mutations were reclassified into the TP53 mutation-related MDS or MDS/AML subgroup according to WHO 2022 and ICC, respectively.

Conclusions: TP53 mutation status was not different between MDS and AML, but 17p deletion was observed at approximately 40% in MDS-H and AML, much higher than in MDS-L. Multi-hit TP53 mutation based on WHO 2022 and ICC was present at a relatively high frequency at 60-80% in MDS and AML with TP53 mutations. In particular, when ICC criteria were applied to MDS, 20% more patients were reclassified into TP53 mutation-related MDS or MDS/AML subgroup than when WHO 2022 criteria were applied.