Researchers Identify Prognostic Factors in TP53-Mutated MDS

A retrospective study finds karyotypic complexity and TP53 variant allele frequency can define prognostic subgroups in TP53-mutated MDS and TP53 variant allele frequency (VAF) helps predict survival outcomes to treatment (Blood Adv. 2020 Feb 11. 4(3):482-495).

“Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS,” explained Guillermo Montalban-Bravo, MD, and coinvestigators.

Thus, investigators evaluated 261 patients with MDS and TP53 mutations for clinicopathologic characteristics, outcomes and response rates. The median patient age was 68 years.  In total, 83% of patients (n = 217) had a complex karyotype and most patients (n = 175, 67%) had 1 TP53 mutation. 

The median VAF where TP53mutations were detected was 0.39. A lower overall response rate was associated with TP53 deletion. Overall, 24% of patients experienced transformation to acute myeloid leukemia (AML). 

Notably, at time of transformation, 13 patients experienced an increase in TP53VAF, and previously undetectable mutations were observed in 15 patients.

Lower TP53 VAF correlated with higher overall response rate and relapse-free survival in TP53-mutated MDS. Higher TP53VAF correlated with worse prognosis. 

Investigators were able to determine prognostic subgroups within patients with TP53-mutant MDS by integrating TP53VAF and karyotypic complexity, which clearly stratified patients with MDS into distinct subgroups. The 4 subgroups had median survival times of not reached, 42.2 months, 21.9 months, and 9.2 months.

A complex karyotype was associated with presence of a TP53mutation (78.3% vs 6.7% for non-complex karyotype). In patients with a non-complex karyotype, TP53 VAF was significantly lower (5.1%) than with complex karyotype (33.9%).

Researchers stated that by studying this cohort, they observedthe clonal size of TP53 mutations influences response to therapy with hypomethylating agents, risk of transformation to AML, and overall survival.

“…Our data suggest that outcomes of patients with MDS and TP53 mutations are not uniform and that their response and prognosis may differ on the basis of mutation burden and genomic context, even when correcting by clinical characteristics,” stated Dr. Montalban-Bravo et al.

Additionally, they found that transformation to AML in TP53-mutated MDS is not always associated with TP53 clone expansion and that available or emerging treatment agents could potentially target acquired or emerging clones at transformation. 

“Incorporation of this data at the time of diagnosis may allow the definition of specific subgroups of patients with TP53-mutated MDS and may help define the optimal therapeutic approach and timing of transplantation,” Dr. Montalban-Bravo et all concluded.—Kaitlyn Manasterski