Research Article Open Access
Volume 4 | Issue 1 | DOI: https://doi.org/10.33696/haematology.4.054

Molecular Features Associated with Response to Enasidenib Plus Azacitidine in Newly Diagnosed IDH2-Mutated Acute Myeloid Leukemia

  • 1Bristol Myers Squibb, Princeton, NJ, United States
  • 2Bristol Myers Squibb, Summit, NJ, United States
  • 3The University of Texas MD Anderson Cancer Center, Houston, TX, United States
  • 4Ulm University Hospital, Ulm, Germany
  • 5Memorial Sloan Kettering Cancer Center, New York, NY, United States
  • 6Massachusetts General Hospital, Boston, MA, United States
  • 7MRC Molecular Haematology Unit and Oxford Biomedical Research Centre, University of Oxford and Oxford University Hospitals, Oxford, United Kingdom
  • 8King’s College Hospital NHS Foundation Trust, London, United Kingdom
+ Affiliations - Affiliations

Corresponding Author

Maroof Hasan, Maroof.Hasan@bms.com

Received Date: July 10, 2023

Accepted Date: August 24, 2023


IDH2 gene mutations, typically at residues R140 and R172, occur in 8–19% of patients with acute myeloid leukemia (AML). These mutations induce production of 2-hydroxyglutarate (2-HG), an oncometabolite that causes DNA and histone hypermethylation, and subsequent blockade of hematopoietic cell differentiation. In a phase 1b/2 trial (NCT02677922), combination therapy with azacitidine + enasidenib significantly improved overall response rate compared with azacitidine only therapy (74% vs 36%; P<0.001) in patients with newly diagnosed IDH2-mutated AML not eligible for intensive chemotherapy. We investigated the association between molecular features and clinical outcomes from that trial. In all, 101 patients were randomized to enasidenib + azacitidine (n=68) or azacitidine only (n=33); 74% of patients had IDH2-R140. Baseline 2-HG levels and IDH2 variant allele frequency (VAF) were similar between treatment arms and IDH2 variants, and were not significantly different between clinical response categories. Significant 2-HG and IDH2 VAF reductions from baseline were observed with combination therapy compared with azacitidine only. Molecular profiling revealed SRSF2 preferentially co-mutated with IDH2-R140, and DNMT3A co-mutated with IDH2-R172. IDH2 VAF was reduced to <1% in 50% of patients who achieved CR with combination therapy (18/36) and azacitidine only (2/4). VAFs of genes in the DNA methylation, receptor-tyrosine-kinase, and RAS canonical pathways were reduced in patients achieving CR. Of note, combination therapy improved event-free survival in patients with RAS-pathway mutations, which have been associated with resistance to enasidenib monotherapy.


Acute myeloid leukemia, Newly diagnosed, IDH2-mutated, 2-hydroxyglutarate, Enasidenib, Azacitidine, Variant allele frequency, Molecular characterization

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