A Phase I Study of Milademetan (DS3032B) in Combination With Low Dose Cytarabine With or Without Venetoclax in Acute Myeloid Leukemia: Clinical Safety, Efficacy, and Correlative Analysis

Authors

Jayastu Senapati
Muharrem Muftuoglu
Jo Ishizawa
Hussein A Abbas
Sanam Loghavi
Gautam Borthakur
Musa Yilmaz
Ghayas C Issa
Samuel I Dara
Mahesh Basyal
Li Li
Kiran Naqvi
Rasoul Pourebrahim
Elias J Jabbour
Steven M Kornblau
Nicholas J Short
Naveen Pemmaraju
Guillermo Garcia-Manero
Farhad Ravandi
Joseph Khoury
Naval Daver
Hagop M Kantarjian
Michael Andreeff
Courtney D DiNardo

Publication Date

6-29-2023

Journal

Blood Cancer Journal

Abstract

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response.

Keywords

Adult, Humans, Young Adult, Middle Aged, Aged, Aged, 80 and over, Cytarabine, Tumor Suppressor Protein p53, Myeloid Cell Leukemia Sequence 1 Protein, Proteomics, Leukemia, Myeloid, Acute

Comments

Supplementary Materials

PMID: 37386016