Clonal Dynamics of IDH1 Mutations in Acute Myeloid Leukemia
Authors: Song Amy , Mahajan Jasmine , Srinivasan Nivetha , Sweet Kendra , Sallman David A. , Hussaini Mohammad 
Published: November 2021

Abstract
Introduction:
Isocitrate dehydrogenase 1 (IDH1) gene is mutated in 7-14% of acute myeloid leukemia (AML) patients. IDH1 encodes for an enzyme that catalyzes the conversion of isocitrate to α- ketoglutarate. IDH1 mutation leads to accumulation of the oncometabolite 2-hydroxyglutarate. Clonal evolutionary dynamics of IDH1 mutations in AML have not been clearly characterized. The introduction of targeted small-molecule therapy, Ivosidenib, in AML treatment underscores the significance of understanding the topography of clonal dynamics in IDH1-mutated AML to optimize precision medicine.
Methods:
We analyzed ~6000 patients with next-generation sequencing (NGS) data and identified 107 patients with IDH1 mutated AML. Disease status was determined for each NGS test date by manual chart review. IDH1 mutation status was characterized during course of AML at diagnosis, remission, relapse, and with persistent disease. Cytogenic risk category was determined using ELN 2017 guidelines. Kaplan Meier survival analysis and log-rank test were used to determine significant differences in overall survival among patient groups.
Results:
Of the 107 total patients, 39 patients (36%) had AML with myelodysplastic-related changes (AML-MRC) and 39 patients (36%) had AML-NOS. The most frequently co-mutated genes were SRSF2, DNMT3A, ASXL1, RUNX1, NRAS, BCOR, STAG2, NPM1, JAK2, and FLT-3 in order of frequency. Of the total patients, 74 patients (69%) had good cytogenetics, 17 patients (16%) had intermediate cytogenetics, and 16 patients (15%) had poor/very poor cytogenetics. Among the patients with IDH1-mutated AML, 85 patients (79%) were IDH1-positive at initial diagnosis, while 22 patients (21%) were IDH1- negative at diagnosis and acquired the mutation later in disease course. Of those 22 patients, 18 patients gained the mutation in the setting of persistent disease, 3 patients at remission, and 1 patient at relapse. In those with persistent AML (n=42), 30 patients (71%) remained IDH1-positive while 12 patients (29%) lost the mutation. In those achieving remission (n=66), 12 patients (18%) who were IDH1-positive remained IDH1-positive while 51 patients (77%) cleared the mutation. In those with relapsed disease (n= 21), 17 patients (81%) with IDH1-positive AML remained IDH1-positive while 4 patients (19%) lost the mutation at relapse.
There were no significant differences in median overall survival in patients who were positive or negative for IDH1 mutations at diagnosis, positive or negative with disease persistence, or among patients who remained IDH1-positive or lost the IDH1 mutation at disease relapse. Patients that were IDH1-positive at diagnosis were more likely to have poorer cytogenetics than patients who were IDH1-negative at diagnosis (p=0.0016).
Conclusion:
In summary, this study found that IDH1 mutations are unstable throughout the course of AML and periodic genetic testing of AML patients is necessary for optimizing precision medicine approaches. In disease remission, most patients (77%) cleared the IDH1 mutation. In the relapse setting, 81% of patients retained IDH1-positive status. Our study, the largest of its kind to our knowledge, shows that serial genomic profiling for the IDH1 mutation across disease course may be beneficial in helping to tailor targeted therapy for IDH1+ AML.

Disclosures
Sweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy.