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2952 Minimal Residual Disease in Acute Myeloid Leukemia Following Induction Chemotherapy Can be Effectively Eradicated By Targeting Mitochondrial Metabolism

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, apoptosis, Translational Research, Combination therapy, Diseases, Therapies, therapy sequence, metabolism, Myeloid Malignancies, Biological Processes, molecular biology, Technology and Procedures, Study Population, Animal model, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Natalia Baran, MD, PhD, MSc1, Lina Han, MD PhD2*, Lucille Stuani, PhD3*, Antonio Cavazos, MSc4*, Laurie Cooper2*, Cassandra L. Ramage5*, Vinitha MARY Kuruvilla, MSc6*, Qi Zhang, PhD5*, Marie Sabtier7*, Emeline Boet7*, Jason P Gay8*, Ninping Feng8*, Venkata Lokesh Battula, PhD9, Emeline Chu-Van10*, Florence Castelli10*, Martin Carroll11*, Sergej Naumovich Konoplev, MD, PhD12*, Beenu Thakral13*, Naval Daver, MD5, Joseph R Marszalek8*, Yubin Ge, PhD14, Michael Andreeff, MD PhD5, Jean-Emmanuel Sarry, PhD15* and Marina Y. Konopleva5,16

1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2The University of Texas MD Anderson Cancer Center, Houston
3Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, Montpellier, France
4The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6The University of Texas, MD Anderson Cancer Center, Houston
7INSERM, Toulouse, FRA
8TRACTION, The University of Texas MD Anderson Cancer Center, Houston
9Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
10CEA/DSV/iBiTec-S/SPI, Laboratoire d’Etude du Métabolisme des Médicaments, MetaboHUB-Paris, Paris, France
11Department of Medicine, The University of Pennsylvania, Philadelphia, PA
12UT M.D. Anderson Cancer Center, Houston, TX
13Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston
14Karmanos Cancer Institute Wayne State Univ., Detroit, MI
15Inserm, Toulouse, FRA
16Department of Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY

Acute myeloid leukemia (AML) stem cells (AMLSCs) AMLSCs and residual cytarabine (AraC)-resistant AML cells (constituting minimal residual disease, MRD) thought to be responsible for chemoresistance and treatment failure, were shown to be highly dependent on mitochondrial function for survival and thus are vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS) (Farge et al. Cancer Discov, 2017). Efficacy of OXPHOS inhibitor IACS-010759 (OXPHOS-i) was previously reported, demonstrating potent inhibition of mitochondrial complex I, OXPHOS suppression and growth inhibition of AML cells (Molina, et al. Nat Med, 2018). Here we evaluated OXPHOS dependency of AML MRD cells and determined impact of OXPHOS blockade on residual AML cells surviving standard chemotherapy (Doxorubicin/AraC, DA). Our results demonstrated that AML cell lines treated with AraC or DA induced accumulation of reactive oxygen species, mitochondrial superoxides, increased mitochondrial mass and mitochondrial membrane potential. AraC- and DA therapies in vitro were significantly enhanced by OXPHOS-i. OXPHOS dependency shown as a significantly increased basal and maximal oxygen consumption rate after AraC and DA treatment, was fully inhibited by OXPHOS-i, leading to complete mitochondrial collapse. OXPHOS inhibition in combination with DA translated into reduction of viable cell numbers, induction of apoptosis and differentiation in AraC-sensitive and AraC-resistant cell lines models. In vitro efficacy was also observed in engineered p53-mutated MOLM13 model, indicating that combination of OXPHOS-i and DA might successfully overcome p53 mutation-driven chemoresistance. These effects were further validated in a subset of AraC-resistant primary patient samples. Mechanistically, induction of ROS caused by OXPHOS-i addition upon DA contributed to differentiation and cell death, and was partially reversed by ROS scavengers.

Next, the efficacy of IACS-010759 together with DA chemotherapy was evaluated in several chemotherapy-sensitive and -resistant animal models in vivo. DA/IACS-010759 combination significantly reduced leukemia burden and extended survival in OCI-AML3/Luc/GFP model and in FLT3-ITD+ AML PDX model. In the latter, IACS-010759 led to the reduction of leukemia burden and delayed leukemia recurrence when administered post completion of DA. At the single-cell level, CyTOF analysis demonstrated that this combination reduced frequency of CD34+CD38lowCD123+AML LSCs and facilitated differentiation of immature subpopulations (Fig.1A). Furthermore, addition of OXPHOS-i to DA extended survival of mice inoculated with chemoresistant PDX AML models. Finally, OXPHOS-i administered during consolidation phase significantly extended mice survival compared to standard of care arm, supporting clinical utility of OXPHOS inhibitors in AML (Fig.1B).

In conclusion, our findings indicate that chemotherapy fosters mitochondrial respiration in AML, which could be abrogated by OXPHOS inhibitor at the LSCs and MRD level, in vitro and in vivo. While IACS-010759 (Yap et al. Nat Med 2023) showed toxicities impeding its clinical utility, our data advocate for combining mitochondrial targeting strategies with chemotherapy as a part of induction and consolidation treatment for improved control of MRD, eradication of AMLSC and extended response duration. Thus, further studies to identify compounds with improved safety profile are warranted.

Disclosures: Battula: Daiichi Sankyo: Research Funding; Y-mAbs Therapeutics: Research Funding; CytoMed Therapuetics: Research Funding; Fate Therapeutics: Research Funding; Inspirna, Inc.: Research Funding; Tolero Pharmaceuticals: Research Funding; Nektar Therapeutics: Research Funding. Daver: Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Trovagene: Research Funding; Agios: Consultancy; Novimmune: Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Servier: Consultancy, Research Funding; Glycomimetics: Research Funding; AROG: Consultancy; Jazz: Consultancy; Shattuck Labs: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; FATE: Research Funding; Novartis: Consultancy; Syndax: Consultancy; Kite, a Gilead company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kronos Bio: Research Funding. Andreeff: PMV: Research Funding; Kintor Pharmaceutical: Research Funding. Konopleva: AbbVie, Ablynx, Allogene, AstraZeneca, Cellectis, Daiichi, FortySeven, Genentech, Gilead, Immunogen, MEI Pharma, Precision Biosciences, Rafael Pharmaceutical, Sanofi Aventis, Stemline-Menarini: Research Funding; Reata Pharmaceuticals.: Current holder of stock options in a privately-held company, Patents & Royalties; AbbVie, AstraZeneca, Genentech, Gilead, Janssen, MEI Pharma, Sanofi Aventis, Stemline-Menarini, Vincerx: Consultancy.

*signifies non-member of ASH