TP53 Gene allelic State in Myelodysplastic Syndromes (MDS) with Isolated 5q Deletion

Background & aim: The mutational status of TP53 gene is a significant prognostic factor in MDS, with two-thirds of patients harboring TP53 multihit alterations which are associated with poor outcomes. Approximately 20% of patients with MDS with isolated 5q deletion (MDS-del5q) exhibit TP53 aberrations, though their characteristics and prognostic impact have not been fully elucidated. In this study, we aimed to analyze the characteristics and impact of TP53 allelic state in patients with MDS-del5q.

Methods: We conducted an international multicenter study in de novo MDS-del5q patients according to WHO 2017 classification. Clinical and biological characteristics, including the genetic profile were collected at diagnosis. Genetic profiling included conventional G-banding, TP53 deletion by FISH and/or SNP-arrays (for TP53 deletion and copy number neutral loss of heterozygosity). Also, the presence of mutations in myeloid-related genes was assessed by NGS or Sanger. Variant filtering and categorization were performed according to the Spanish Guidelines. Patients were classified as TP53 wild-type (TP53-wt), TP53-monoallelic, and TP53-multihit as proposed by Bernard et al. 2020. Clinical and molecular variables were evaluated for associations with acute myeloid leukemia (AML) evolution and overall survival (OS). In addition, a prognostic model to predict risk of AML evolution was developed using variables selected by the LASSO-cox method with minimum lambda. To calculate the points for each variable, a multivariate competitive risk model (Fine-Gray model) was fitted. Evolution to AML was used as the event and death as the competitive event. Statistical analysis was performed by R (4.2.2).

Results: We included 682 patients with MDS-del5q (Table 1). Median follow-up was 66.8 months (CI95% 61.6-75.2). TP53 mutations were evaluated by NGS in 92.2% (n=629) and by Sanger in 7.8% (n=53) of patients. Overall, 18.7% (n=128) of MDS-del5q presented TP53 mutations. After integrating mutational data (FISH and SNP-arrays), 72.7% (n=93) of TP53-mutated patients were classified as TP53-monoallelic, whereas 27.3% (n=31) as TP53-multihit (4.5% of the whole cohort). Other recurrent mutations were SF3B1 (21%), DNMT3A (18%), TP53 (18%), TET2 (14%), ASXL1 (10%), CSNK1A1 (6%) and JAK2 (6%). Only bone marrow blasts differ between the TP53-wt and TP53-mutated groups ( p=0.031). Furthermore, only gender and VAF were different between TP53-monoallelic and TP53-multihit, being the number and type of co-occurring mutations similar among all subgroups (Table 1).

Median OS of the whole cohort was 73.8 months (CI95% 63.7-83.4), and 77.3 months (CI95% 66.5-85.3) for MDS-del5q TP53-wt and 104 months (CI95% 56.9-89.4) for MDS-del5q TP53-mutated ( p=0.3). Similarly, there was no significant differences in the risk to AML evolution between TP53-wt and TP53-mutated patients (AML evolution at 60 months of 19.9% and 29.7%, respectively; p=0.307). Of note, however, the TP53-multihit group presented worse prognosis compared to TP53-monoallelic and TP53-wt patients (median OS of 55.2, 73.2 and 77.3 months, and AML evolution at 60 months of 40.4%, 25.5% and 19.9% in TP53-multihit, TP53-monoallelic and TP53-wt MDS-del5q) [Figure 1]. Interestingly, TP53-monoallelic MDS with a TP53 VAF >20% showed similar prognosis to TP53-multihit patients (median OS of 43.7 and 55.2 months, and AML evolution at 60 months of 36.7% and 40.4%, respectively).

Finally, a risk score (MDS-del5q score) for AML evolution was developed with five variables, each assigned a different weight based on the regression coefficients: additional chromosomal abnormality, 2 points; TP53-multihit, 2 points; BM blast >2%, 2 points; platelets ≤ 100x10 ⁹/L, 3 points, and SF3B1-mutation, 1 point. Three risk-groups were defined: Low, intermediate, and high-risk for ≤1, 2, or ≥3 points, respectively, with an AML evolution at 60 months of 11.5%, 23.3% and 43.7%, respectively; p <0.05)

Conclusions: In contrast to previous findings in MDS without del5q, our series of MDS-del5q, the longest described to date, reveals that multihit TP53 status is uncommon in MDS-del5q. However, multihit alterations have prognostic significance in this subgroup. Finally, the MDS-del5q score allows to stratify patients into three distinct risk groups for AML evolution. These findings could hold considerable implications for guiding treatment decisions.