Not All TP53-Mutated Myeloid Neoplasms Are Created Equal

BOSTON — A unique genetic signature, dubbed SIG4, observed in patients with high-risk TP53-mutated myeloid neoplasms is associated with improved survival outcomes potentially leading to important treatment implications, according to the results of a new study.

“Our findings suggest that the SIG4 genetic signature could serve as an important prognostic and potentially predictive biomarker in TP53-mutated myeloid neoplasms,” said first author Madhavi Pandiri, MD, of The University of Chicago, Chicago.

“We know that the TP53 mutation is high-risk, but we wanted to determine whether this is a monolithic group, or if we can further slice the pie to better stratify the risk,” said Pandiri, who presented the study at the United States and Canadian Academy of Pathology (USCAP) 2025 Annual Meeting.

Patients with high-risk TP53-mutated myeloid neoplasms (with at least 10% blasts) typically do not see a significant survival benefit from current therapies with the exception of allogeneic stem cell transplantation in a small proportion of patients who achieve a complete response to first-line therapy.

In research published last year, Pandiri’s team identified key reliable genetic predictors of a poor response to first-line therapy and inferior survival within a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥ 10% blasts.

That genetic signature, named EPI6, was determined to identify patients who are likely ineligible for transplant, due to their higher risk.

“This reinforces the idea that co-mutations do matter, even in a cohort already defined by poor prognosis,” Pandiri said.

SIG4 Genetic Signature

To dig deeper and explore pre-therapy mutations that may predict better outcomes, the authors expanded the cohort of patients with TP53-mutated myelodysplastic syndrome and acute myeloid leukemia to 324 individuals.

The study included evaluation of genes shared among patients across 10 centers. Patients in the study had a median age at diagnosis of 68.6 years.

In identifying genes that were present in more than 2% of the high-risk cohort, they detected a four-gene co-mutation signature — SIG4 — consisting ofpathogenic mutations in BCOR, IDH1, IDH2, or DDX41.

The SIG4 signature was observed in11.1% of the cohort. There was no significant difference in baseline characteristics based on SIG4 status.

Among those who were SIG4-positive, complex karyotypes were less common (60.6% vs 81.1%; P = .007) and TP53 variant allele frequency over 25% was marginally less frequent (69.4% vs 81.9%; P = .08) compared with those who were not carriers of the four-gene signature.

Seventy-eight percent of all patients (253/324) had data available on first-line therapy responses; 28.5% of these achieved a frontline composite complete response (cCR1).

The only factors predicting an inferior complete first response among these patients included a monosomal karyotype (22.2% with vs 39.5% without achieved cCR1; P = .005) and positivity of theEPI6 signature described in the previous study (16.4% with vs 31.8% without achieved cCR1; P = .025).

SIG4 positivity was not a significant predictor (P = .94) of an inferior complete first response but instead was associated with a marginally favorable association with achieving cCR1 among patients who were treated with venetoclax — 61.5% in SIG4-positive patients vs 35.1% in SIG4-absent patients (P = .07).

Better Survival Outcomes 

Importantly, SIG4 positivity was associated with improved survival outcomes at 24 months compared with negative SIG4 in the entire cohort (13.7 vs 6.9 months; P = .004) and in subsets including patients with single TP53 mutations (14.2 months vs 6.9 months; P = .007), patients treated with venetoclax (14.9 months vs 6.9 months; P = .015), and patients receiving intensive chemotherapy (not reached vs 10.0 months; P = .008).

In a group of 51 allo-transplanted patients, SIG4-positive patients showed a trend toward a superior overall survival (not reached vs 15.3 months; P = .06).

“The main takeaway is that not all TP53-mutated myeloid neoplasms carry the same poorprognosis,” Pandiri told Medscape Medical News.

Further commenting on the study, senior author Girish Venkataraman, MD, also of The University of Chicago, cautioned that “not all SIG4-positive patients represent a single uniform group of patients with the same [acute myeloid leukemia] diagnosis,” adding that he believed the effect is likely the result of “an interplay of mutations.”

In general, however, SIG4-positive patients may have simpler cases and be “more likely to respond to venetoclax,” he said.

“So if you see this signature,” said Venkataraman, it suggests that patients may be able to get a stem cell transplant down the line, if they’re fit for it.

The authors had no disclosures to report.