Abstract Body

TP53 mutations in MDS are associated with the most inferior outcomes across independent studies with a median OS of 6-12 months^1,2. As we and others have previously shown that the VAF and/or allelic status of TP53 to be strongly concordant with disease phenotype and further stratifies survival over binary mutation analysis alone, we have investigated the importance of serial TP53 NGS analysis^1,3-5. Importantly, clearance of TP53 (i.e. VAF <5%) predicted for improved OS whereas clonal expansion significantly predicted for inferior OS which remained predictive in multivariate analysis. Importantly, clearance of TP53 in the setting of HMA therapy or allogeneic stem cell transplantation has also been identified to be a positive predictor of outcomes⁶.

APR-246, eprenetapopt, is a novel small molecule anti-cancer compound that reactivates mutated and non-functional p53 and targets the cellular redox balance, two Achilles heels of cancer cells. Additionally, APR-246 has p53 independent activity via an increase in reactive oxygen species as well as more recent data identifying early cell death by APR-246 is mediated via ferroptosis^7,8. Parallel studies in US and GFR showed good safety and robust CR rates in phase 2 studies^9,10. These data supported the phase 3 study of APR-246 in combination with azacitidine versus azacitidine alone (NCT03745716). Unfortunately, the trial has failed to meet its primary endpoint of increase CR (33.3% in combination vs 22.4% in control arm; P=0.13) although these data are yet to be formally presented.

Magrolimab is a humanized IgG4 anti-CD47 antibody that blocks the interaction of CD47 with SIRPα and enhances the phagocytosis of tumor cells in human primary AML cell lines and xenograft models. We have reported the phase Ib study combining magrolimab with azacitidine in treatment-naïve higher risk MDS patients (26% with TP53 mutations) with the most recent data update at EHA 2022¹¹. This combo was well tolerated with 7% ORR and 33% CR (40% in TP53 mutant). The median OS was not reached overall and was 16.3 months in TP53 mutant. These observations support the ongoing randomized double-blind phase III study comparing magrolimab plus azacitidine versus azacitidine plus placebo in treatment-naïve higher risk MDS patients (n=520) with a co-primary endpoint of CR and OS (ENHANCE-1, NCT04313881). Additionally, the ENHANCE-2 study is for TP53 mutant AML versus HMA + venetoclax with OS as the primary endpoint, which is critical given recent studies showing uniform outcomes in TP53 mutant MDS-EB and AML populations¹².

Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors¹³. Although the ORR/CR rates are not substantially different then single agent HMA, the durability of response has been very encouraging (19 months for CR), including in adverse populations such as TP53 (DOR of 21.5 months). Unfortunately, the recently presented STIMULUS-MDS1 study was negative, including for TP53 mutant MDS patients¹⁴. However, we await the phase 3 STIMULUS-MDS2 study (NCT04266301) with a primary endpoint of OS.

Lastly, venetoclax is an oral BCL-2 inhibitor with promising synergy with azacitidine and is a standard of care for elderly AML patients¹⁵. Although a reduced schedule is needed for safety in HR-MDS patients (14 days), synergy has been robust with an ORR of 80% and CR rate of 40% include a high degree of molecular remissions¹⁶. Unfortunately, outcomes in TP53 mutant populations, at least in AML, have not been improved with no difference in CR rates in TP53 mutant MDS patients¹⁷.

TP53 mutant MDS/AML patients represent a molecular cohort with very poor outcomes and lack of disease modifying therapy. Ideally, future translational data will further elucidate the underpinnings driving the poor outcomes for this molecular subgroup to lead to additional novel therapeutic strategies.