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

Background

In AML, IDH1/2 somatic mutations can be frequent in patients at about 20%. Physiologically, IDH1/2 catalyze isocitrate conversion to alpha-ketoglutarate (α-KG). α-KG is an activating co-factor for ten-eleven translocation 2 (TET2), an important epigenetic regulator which converts 5mC to 5hmC in the genomic DNA ultimately turning on the myeloid differentiation. In contrast, mutant IDH1/2 proteins promote α-KG conversion to 2-hydroxyglutarate (2-HG), an onco-metabolite. In pre-clinical studies, 2-HG inhibits TET2 activity by suppressing 5mC-to-5hmC conversion and thus allowing AML development and maintenance. Clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2 ^mut AML patients. However, a substantial fraction of patients fail to respond to IDH1/2 inhibitors in AML. Our recent preclinical studies have shown MYC prevents the normal myeloid differentiation and cell death by suppressing IDH1/2-TET2 signaling. We evaluated if high MYC expression is associated with poor survival outcomes in IDH1/2 ^mut AML patients treated with Ivosidenib or Enasidenib

Patients and Methods

Patients diagnosed with AML at Moffitt Cancer Center between 2013-2020 were evaluated. IDH1/2 mutation status was assessed via next generation sequencing and those with documented IDH1/2 ^mut were included for the analysis. Clinical and demographic data were retrospectively extracted from the medical records. Pre-treatment MYC protein levels were assessed by immunohistochemistry staining using BM biopsy specimens. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Multivariate survival analysis was performed by means of Cox proportional hazards regression

Results

A total of 28 (IDH1 ^mut, n=11; IDH2 ^mut, n=18; IDH1/2 ^mut, 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 1 ^st-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 (IDH1 ^mut, 3.3 [0.3-30] months; IDH2 ^mut, 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=.6185). The median PFS was shorter in high MYC patients (1.6 vs. 4.4 months, HR=2.348, p=.0515). The median OS was also significantly shorter in high MYC patients (2.5 vs. 8.5 months, HR=5.971, p<.0001).

Conclusion

In our study, we demonstrated that high MYC expression was associated with significantly shorter PFS and OS in IDH1/2 ^mut AML patients. In 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.