Posttransplant MRD monitoring by TP53 duplex sequencing with APR-246 + azacitidine maintenance predicts outcomes

Area of Science:

• Hematology
• Oncology
• Molecular Diagnostics

Background:

• Outcomes for TP53 mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are generally poor.
• Limited data exist regarding the impact of TP53 minimal residual disease (MRD) monitoring after allo-HSCT in these high-risk patient populations.

Purpose of the Study:

• To evaluate the clinical utility of duplex TP53 MRD sequencing in patients with TP53 mutant MDS/AML receiving maintenance therapy post-allo-HSCT.
• To determine the correlation between TP53 MRD status and clinical outcomes, including overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS).

Main Methods:

• Prospective study of 14 patients with TP53 mutant MDS/AML on an eprenetapopt (APR-246) + azacitidine maintenance protocol.
• Duplex TP53 MRD sequencing performed on bone marrow aspirates pre-allo-HSCT, pre-maintenance therapy, and post-cycles 3 and 12.
• Custom-targeted sequencing panel with high duplex coverage (30,000-70,000X) to detect variants down to 0.005% allele frequency; MRD negativity defined as <0.01%.

Main Results:

• All patients exhibited TP53 positivity pre-allo-HSCT, with 57% remaining positive post-HSCT.
• TP53 MRD status after 12 cycles of maintenance therapy was the strongest predictor of outcomes.
• MRD negativity after cycle 12 significantly correlated with improved OS (33.9 vs 20.4 months, P=.005) and EFS (33.9 vs 10.1 months, P=.004), with a trend for RFS (32.6 vs 13.5 months, P=.06).

Conclusions:

• TP53 MRD monitoring post-allo-HSCT is a powerful predictive tool for clinical outcomes in patients with TP53 mutant MDS/AML.
• The findings support the integration of TP53 MRD assessment into future therapeutic strategies and clinical trials for this patient group.