AML-170: High MYC Expression Predicts Poor Survival Outcomes in IDH1/2 Mutant AML Patients

Context: Clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. However, a substantial fraction of patients fail to respond to IDH1/2 inhibitors in AML. Recent preclinical studies have shown MYC prevents the normal myeloid differentiation and cell death by suppressing IDH1/2-TET2-5hmC signaling. Objective: Evaluate if high MYC expression is associated with poor survival outcomes in IDH1/2mut AML patients treated with ivosidenib or enasidenib. Design: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Pre-treatment MYC protein levels were assessed by immunohistochemistry (IHC) staining using BM biopsy specimens. Results: A total of 28 (IDH1mut, n=11; IDH2mut, n=18; IDH1/2mut, n=1) patients were included in the study. Median age at AML diagnosis was 66 years, and 60% of patients were male. Twelve (42%) patients had secondary AML and 9 (32%), 11 (39%), and 6 (21%) patients had favorable, intermediate, and adverse risk, respectively, at AML diagnosis. A total of 17 (60.7%) and 6 (21.4%) patients received intensive chemotherapy and hypomethylating agents as their first-line therapy. Among 28 patients, 22 (78.5%) and 6 (21.4%) patients had low and high MYC expression (≥5% by IHC staining), respectively, prior to IDH1/2 inhibitor treatment. Median number of treatments prior to IDH1/2 inhibitors was 3 (1–6) and the median duration of IDH1/2 inhibitor treatment was 3.2 (0.3–30) months (IDH1mut, 3.3 [0.3–30] months; IDH2mut, 2.5 [0.7–14.5] months). Treatment response was assessed in 27 patients, and 11 (40.7%) had CR/CRi (high vs low MYC, 20 vs 45.5%, p=0.6185). The median PFS was shorter in high MYC patients (1.6 vs 4.4 months, HR=2.348, p=0.0515). The median OS was also significantly shorter in high MYC patients (2.5 vs 8.5 months, HR=5.971, p Conclusions: High MYC expression was associated with significantly shorter PFS and OS in IDH1/2mut AML patients. Consistent with our recent studies that showed MYC represses IDH1/2 and TET2 expression in AML, this study suggests that MYC may play an important role in the resistance mechanism of IDH1/2 inhibitors. Additional studies with larger cohorts are warranted to further confirm and validate these findings.