Discussion
GI toxicities, death, myeloid malignancies, leukemia, AML, leukemic cell apoptosis, leukemic cell death, gastrointestinal toxicity
LEUKEMIA, AML
In this phase I trial of milademetan in combination with LDAC, ±venetoclax for AML, the MTD was determined to be 260 mg/day of milademetan (D 5–7 and D 15–17), 600 mg of venetoclax (D 1–14), and 20 mg of LDAC administered twice daily (D1-10). The treatment combination was associated with noticeable rates of gastrointestinal toxicity (50% patients ≥ grade 3) and only modest clinical responses. Noticeable gastrointestinal toxicity has been also seen in trials with other MDM2i in AML and could be an important adverse class effect of these drugs [Combining BCL2 inhibition with MDM2 inhibition potentiates dual apoptotic pathways [MDM2i in myeloid malignancies harbors the possibility of a clonal selection of Through comprehensive CyTOF analysis we did not detect a substantial or persistent accumulation of p53 in samples assessed at the EOC1 in patients receiving DT, indicating p53 accumulation in response to MDM2i and LDAC is transient which could partly explain the low efficacy of DT. We found that DT downregulated MCL1 levels, which is regulated by p53 through transcriptional regulation and post-translational modification [Our analysis showed that TT consistently downregulates MCL1 and revealed YTHDF2 downregulation as a novel mechanism of cell death induction in AML. This mechanism could further synergize with MCL1 downregulation and BCL2 inhibition. However, leukemic cells may utilize BCL2 and BCL-XL upregulation as potential resistance mechanisms. Overall, our single-cell proteomic analysis of leukemia and immune cell compartments provides insights into mechanisms of action and treatment resistance in AML, which could guide the development of future drug combinations.In conclusion, despite the biological rationale behind the dual inhibition of MDM2 and BCL2 to optimize leukemic cell apoptosis and a promising clinical trial the benefit from this approach was not apparent in the present clinical setting. Our phase 1 trial captured noticeable GI toxicities. In-depth correlative CyTOF analysis revealed that leukemic cell death by the combination therapy was mediated by the downregulation of MCL1 and YTHDF2 and favored by an immune-rich microenvironment.