TP53 Mutations Distinguish a Class of Highly Homogenous Myeloid Neoplasms within MDS and AML in the Context of Complex Karyotype
Authors: Tong Hongyan , Yang Ye , Jiang Lingxu , Zhou Xinping , Ma Liya , Xu Gaixiang , Zhang Yudi , Wang Wei , Liu Xiaozhen , Yu Huchu 
Published: December 2024

Background: In patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the presence of a complex karyotype (CK) consistently indicates a poor prognosis, a low response rate to treatment, a high risk of transition to relapse or refractory disease, and an urgent need for more effective therapeutic options. When TP53 mutations are present in conjunction with CK, the prognosis is further worsened, and treatment becomes more challenging. Consequently, could MDS and AML with complex karyotypes and TP53 mutations be classified into a single category for clinical diagnosis, treatment, and management?
Methods: The clinical characteristics and survival outcomes of 151 patients with MDS or AML with CK who were first diagnosed in our center from January 2021 to December 2022 were collected. Overall survival (OS) was calculated from the date of diagnosis to the date of death or the last date of follow-up. Next generation sequencing (NGS) was used to detect gene mutations. TP53 mutations were considered to be multi-hit if either 2 different TP53 mutations, a single TP53 mutation with VAF≥50%, or a single TP53 mutation with -17/17p- on karyotype were present.
Results: A total of 151 patients with complex karyotypes were included in the study, including 82 MDS and 69 AML. Compared with AML, MDS patients had lower hemoglobin (69.5 g/L vs 75.0 g/L, P=0.012) and higher absolute neutrophil count (1.09×10e9/L vs 0.72×10e9/L, P=0.007). Age and sex ratio were not significantly different between MDS and AML subgroups. Also, there was no significant difference in OS between MDS and AML in the context of complex karyotype.
TP53 mutations were detected in 69.5% (105/151) of the patients, with a median VAF value of 46.1%; The median VAF of TP53 in MDS patients was significantly lower from that in AML patients (43.1% vs 58.1%, P=0.017). However, as for TP53 mutation types, there was no significant difference between MDS and AML (P=0.58). Also, there was no significant difference in OS between MDS and AML in TP53 mutations (MT) (8.8 months vs 4.6 months, P=0.06) or in TP53 wild type (WT) (21.7 months vs NR, P=0.20). However, both the presence of TP53 mutations significantly shortened OS than TP53 WT in MDS and AML patient (MDS: 21.7 months vs 8.8 months, P=0.002; AML: NR vs 4.6 months, P&lt;0.0001). Furthermore, among MDS and AML with CK, there was no statistical difference in OS among the groups according to the proportion of bone marrow (BM) blasts 0-9%, 10-19%, 20-29%, and ≥30% (P=0.07), which indicated that the impact of BM blasts on prognosis would be less important when CK combined with TP53 mutation. COX multivariate regression analysis included age, gender, TP53 mutation, hemoglobin, absolute neutrophil count, platelet, BM blasts, and myelofibrosis as research variables. Results showed that only TP53 mutation was an independent adverse prognostic factor (P＜0.001, HR 4.58, 95% CI 2.24-9.3). These results suggest that patients with TP53 mutations have a worse prognosis in both MDS and AML with complex karyotypes.
Moreover, we compared TP53 mono-hit with multi-hit, and the results showed that the OS of TP53 multi-hit was significantly worse than that of TP53 WT in both MDS and AML (21.7 months vs 8.0 months, P&lt;0.0001; NR vs 5.5 months, P&lt;0.0001). Of note, OS of TP53 mono-hit was not significantly different from that of TP53 WT in MDS (21.7 months vs 12.2 months, P=0.08), while in AML were significantly worse than TP53 WT (NR vs 2.4 months, P=0.0002). This suggests that although patients with TP53 mutations have a poor prognosis for both MDS and AML, TP53 mono-hit has limited prognostic impact in MDS patients.
Conclusions: Our study shows that in the context of complex karyotypes, the presence of TP53 mutations (especially TP53 multi-hit) could distinguish a class of highly homogenous myeloid neoplasms in which the proportion of BM blasts is no longer an independent prognostic factor. This discovery might define a novel category of disease entities that could more precisely guide treatment options.