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).