1272 A 4-Gene Co-Alteration Signature (SIG4) Predictive of Favorable Outcomes in High-Grade TP53 Mutated Myeloid Neoplasms: An International TP53 Investigators Network (iTIN) Study
Recommended Citation
Pandiri M, Kaur A, Rojek A, Symes E, Velmurugan S, Arber D, Badar T, Chang H, Ghosh S, Menon M, Nawas M, Pan Z, Patel J, Patel A, Sojitra P, Tariq H, Tjota M, Stock W, Wang P, Wiredja D, Zhang J, Bell R, Perry A, Venkataraman G. 1272 A 4-Gene Co-Alteration Signature (SIG4) Predictive of Favorable Outcomes in High-Grade TP53 Mutated Myeloid Neoplasms: An International TP53 Investigators Network (iTIN) Study. Lab Invest 2025; 105(3).
Document Type
Conference Proceeding
Publication Date
3-24-2025
Publication Title
Lab Invest
Keywords
biological marker, venetoclax, aged, bone marrow tumor, cohort analysis, conference abstract, controlled study, diagnosis, drug therapy, female, gene, high risk population, human, human tissue, karyotype, major clinical study, male, monosomy, multicenter study, overall survival
Abstract
Disclosures: Madhavi Pandiri: None; Amandeep Kaur: None; Alexandra Rojek: None; Emily Symes: None; Sinthujaa Velmurugan: None; Daniel Arber: None; Talha Badar: None; Hong Chang: None; Sharmila Ghosh: None; Madhu Menon: None; Mariam Nawas: None; Zenggang Pan: None; Jay Patel: None; Ami Patel: None; Payal Sojitra: None; Hamza Tariq: None; Melissa Tjota: None; Wendy Stock: None; Peng Wang: None; Danica Wiredja: None; Jingjing Zhang: None; Robert Bell: None; Anamarija Perry: None; Girish Venkataraman: None Background: We recently proposed an adverse EPI6 6-gene co-mutation signature (CUX1, U2AF1, EZH2, TET2, CBL, or KRAS) in high-grade TP53-mutated myeloid neoplasms (≥ 10% blasts). In this expanded cohort of 324 individuals with TP53-mutated MDS/AML and AML, we asked if there are any pre-therapy molecular determinants of better outcomes. Design: All participating centers collected clinical, pathological, somatic genetic, and cytogenetic information. Genes shared across ten centers were examined to identify potential gene sets capable of delineating a favorable risk group. The primary outcome was 24-month overall survival (OS24) from the time of diagnosis, with a secondary focus on assessing frontline composite complete response (cCR1; see Table 1). Results: We included 324 patients with a median age at diagnosis of 68.6 years (range: 13.5–92.6 years). A 4-gene co-mutation signature (termed 'SIG’) with pathogenic mutations in BCOR, IDH1, IDH2, or DDX41 was identified in 11.1% (36/324) of the cohort with no significant difference in baseline characteristics stratified by SIG4 status (Table 1). SIG4+ individuals had less frequent complex karyotype (60.6% vs. 81.1%; P = .007) as well as marginally infrequent TP53 VAF >25% (69.4% vs. 81.9%; P = .08). First-line response was evaluable in 253 patients with 28.5% (72/253) achieving a cCR1. In the response-evaluable subgroup, only a monosomal karyotype (22.2% vs. 39.5% CR1 in 0-1 Monosomy; P = .005) and EPI6 (16.4% vs. 31.8% CR1 in Absent EPI6; P = .025) predicted inferior CR1 but not SIG4 (P = .94) although SIG4 showed a marginally favorable cCR1 in venetoclax-treated patients (61.5% vs. 35.1% CR1 in SIG4 Absent; P = .07). In age-adjusted OS24 analysis, SIG4 was favorable (HR = 0.5 [0.3–0.8]; P = .005) while EPI6 predicted inferior OS24 (HR = 1.7 [1.3–2.3]; P < .001); See Figure 1 for subset analysis by blast counts and therapy groups. Among the 51(15.7%) allo-transplanted patients, SIG4+ patients experienced a trend towards superior overall survival (not reached vs. 15.3 mos.; PLog-rank = .06). In a forward stepwise multivariable Cox model including both signatures (EPI6 & SIG4), were retained in the final model (P = .0001). [Formula presented] [Formula presented] Conclusions: Our work highlights the prognostic value of the novel SIG4 signature in this high-risk cohort. When combined with the adverse EPI6, it offers a powerful tool for accurately identifying individuals who could benefit from personalized frontline treatment strategies.
Volume
105
Issue
3
