Clinical Effects of IDH1/2-Mutant Inhibitors in IDH1/2-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients: Suggestions from Ex Vivo Experiments

Abstract

BackgroundIsocitrate dehydrogenase 1 and 2 mutations (IDH1/2MT) occur in up to 20% of MDS, MDS/MPN overlap and (secondary) AML, 80% of secondary glioma and 20% of cholangiocarcinoma patients. IDH1/2MT confer an improved prognosis in glioma and cholangiocarcinoma patients, but not AML patients, compared with IDH1/2 wild-type (IDH1/2WT)counterparts (Fig 1). IDH1/2MT enzymes produce D-2-hydroxyglutarate (D-2HG)at the expense of NADPH, an important cellular antioxidant. IDH1/2MT are ancestral in ~30% of AML/MDS cases, rendering them attractive therapeutic targets because all cancer cells carry IDH1/2MT and this limits the chance of therapy resistance. Inhibitors of IDH1/2MT were recently developed and are currently in clinical trials. IDH1MT inhibitors protect IDH1MT solid tumor cells against irradiation and cisplatin. Thus, IDH1/2MT inhibitors and cytotoxic drugs should not be used together in patients with IDH1/2MT solid tumors. It remains unknown whether IDH1/2MT inhibitors can be safely used as adjuvants to cytotoxic drugs in patients with myeloid malignancies.MethodsPrimary IDH1/2MT and IDH1/2WT AML and MDS cells (n=20) were cultured and treated with D-2HG, the IDH1/2MT inhibitors, the antioxidant N-acetyl cysteine (NAC) and/or irradiation, cisplatin, 5-azacytidine, cytarabine, daunorubicin or decitabine. We determined cell death, ROS levels and DNA double strand break numbers. In addition, maximal cellular IDH1/2 and glucose-6-phosphate dehydrogenase (G6PD) activity was determined.ResultsAfter treatment with irradiation, cisplatin, 5-azacytidine, cytarabine, daunorubicin or decitabine, we did not observe more reactive oxygen species (ROS), DNA double strand breaks or cell death in IDH1/2MT primary AML/MDS cells versus IDH1/2WT primary AML/MDS cells (Fig 2). Accordingly, IDH1/2MT inhibitors or the ROS scavenger NAC had no effect on these aforementioned outcomes in IDH1/2MT primary AML/MDS cells. These results contrast the situation in glioma and carcinoma cells, where increased ROS levels, DNA double strand breaks and cell death levels were observed in irradiated or cisplatin-treated IDH1/2MT cancer cells, and where IDH1/2MT inhibitors or NAC reverse these effects (Fig 1).IDH1/2MT were associated with a striking reduction in the IDH1/2-mediated NADPH production capacity in primary AML cells and solid tumor cells. However, IDH1/2 are not important NADPH providers in primary AML/MDS cells and the contribution of G6PD to the total NADPH production pool is ~4 times larger than IDH1/2 (Fig 3). In contrast, IDH1/2 provide 65% of all NADPH in glioma. Administration of D-2HG, the metabolite produced by IDH1/2MT enzymes, decreased IDH1/2-mediated NADPH production capacity in primary AML/MDS cells and solid tumor cells and is a likely cause of the decreased IDH1/2-mediated NADPH production in IDH1/2MT cells.DiscussionOur results offer an explanation for the relatively longer survival of patients with IDH1/2MT glioma and cholangiocarcinoma and the unchanged survival of patients with IDH1/2MT AML or MDS. A plausible mechanism is the strong production of the antioxidant NAPDH by IDH1/2 in solid tumor, but not AML/MDS cells. These data imply that concomitant use of IDH1/2MT inhibitors and cytotoxic therapy in patients with IDH1/2MT solid tumors may limit therapy efficacy. However, in patients with IDH1/2MT AML or MDS, IDH1/2MT inhibitors can probably be used safely as adjuvants to AML/MDS standard of care 5-azacytidine, cytarabine, daunorubicin and/or decitabine therapies, or whole-body irradiation in the context of bone marrow transplantations. These data are crucial for the rational design of clinical trials with IDH1/2MT inhibitors and complete understanding of their outcomes. [Display omitted] [Display omitted] [Display omitted] DisclosuresCarraway:Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees.