Post-transplant MRD Monitoring by TP53 Duplex Sequencing with APR-246 + Azacitidine Maintenance Predicts Outcomes Open Access

• Many TP53 mutant MDS/AML patients are MRD+ before and after allo-HSCT, supporting the need for novel strategies to decrease relapse.

• Following completion of maintenance therapy with eprenetapopt and azacitidine, TP53 MRD was strongly predictive of outcomes.

Outcomes are poor for TP53 mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who undergo allo-HSCT. Notably, minimal data exist on the impact of TP53 MRD monitoring post allo-HSCT. Thus, we completed duplex TP53 MRD sequencing for all patients on our prospective eprenetapopt (APR-246) + azacitidine maintenance study (n=14). Bone marrow aspirates were obtained prior to allo-HSCT, prior to the start of investigational therapy (day +30 to day +100) and after cycle 3 and cycle 12 of therapy. To assess low allele frequency mutations in TP53, a custom-targeted sequencing panel was used with duplex sequencing, targeting 30,000-70,000X duplex coverage to detect variants at a frequency as low as .005%. For all analyses, TP53 MRD negativity cutoff was 0.01%. All study patients had significant TP53 positivity prior to allo-HSCT and 57% post-HSCT. MRD evaluation after end of maintenance (12 cycles) was the strongest predictor of outcomes. Specifically, MRD negativity after cycle 12 strongly predicted 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). TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies.