IDHENTIFY trial: Impact of mutational burden and pattern on outcomes in patients with R/R IDH2-mutated AML

Patients with relapsed/refractory (R/R) IDH2-mutated acute myeloid leukemia (AML) have very limited treatment options and poor survival outcomes, especially for those who are ineligible for intensive chemotherapy.¹ Enasidenib, an inhibitor of the mutant IDH2 enzyme, has shown meaningful response rates in the phase III IDHENTIFY trial (NCT02577406) for patients with R/R IDH2-mutated AML as well as a phase I/II trial (NCT01915498) in patients with newly diagnosed AML.¹

Recently, Risueno et al.¹ published a post hoc analysis of the IDHENTIFY trial in Leukemia Research, evaluating the molecular characteristics and prognostic impact of co-occurring mutations in patients with R/R IDH2-mutated AML. We summarize the key findings below.

Methods¹

• The study design of the IDHENTIFY trial has been previously reported on the AML Hub.
• Mutation and variant analyses were based on the 37-gene AML panel.
• Next-generation sequencing was used to identify co-occurring mutations at a ≥1% variant allele frequency positivity threshold.
• IDH2 variant allele frequency was quantified in DNA from bone marrow mononuclear cells by digital polymerase chain reaction.

Key findings¹

• A total of 249 samples were analyzed
  • 181 had the IDH2^R140 variant
  • 68 had the IDH2^R172 variant
• Patients with IDH2^R140 had significantly greater numbers of mutations at baseline compared with patients with IDH2^R172 (p < 0.0001).
• Patients with ≥5 mutations at baseline had a shorter median overall survival (OS) compared with patients with ≤4 mutations at baseline.
• The most common co-occurring mutations in patients with IDH2^R140 were SRSF2 and RUNX1 (59%).
• The most common co-occurring mutation in patients with IDH2^R172 was DNMT3A (57%).
• There were statistically significant differences between the two IDH2 variants in co-occurring mutation patterns for SRSF2, FLT3-ITD, FLT3-TKD, NPM1, DNMT3A, RUNX1, and JAK2.
• Patients with IDH2^R140 showed a trend toward beiing predominantly enriched with poor-risk mutations compared with those with IDH2^R172.
• Mutant DNMT3A was associated with longer event-free survival during enasidenib monotherapy (p = 0.021).

Multivariable analysis

• Patients with mutations in the RAS and receptor tyrosine kinases signaling pathways had shorter OS when adjusted for treatment type, IDH2 variant (p = 0.3864) and number of mutated genes (p = 0.3086).
• Patients with IDH2^R172 showed improved OS vs patients with IDH2^R140 (p = 0.0240).
• A greater number of mutated genes was associated with reduced OS in patients treated with conventional care regimens vs enasidenib (p = 0.0227).

Key learnings

This post hoc analysis of the IDHENTIFY trial suggests potential novel associations between molecular profile and clinical outcomes following enasidenib monotherapy. Patients with IDH2R172 were preferentially comutated with DNMT3A and were associated with improved OS compared vs patients with IDH2R140. Further investigation is needed on the impact of comutational profiles and their relation to disease etiology, clonal evolution patterns, therapy resistance, and disease progression.