Sangmin Lee, MD
Weill Cornell Medicine
For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.
TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) ( Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future.