The clinical impact of persistent IDH mutations at remission in acute myeloid leukemia

Persistent mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes have been detected in acute myeloid leukemia (AML) patients at the time of clinical remission. However, it is not known whether these mutations have any clinical impact. A group of investigators from the MD Anderson Cancer Center (MDACC) explored the use of mutant IDH1/2 as minimal residual disease (MRD) markers in predicting relapse in a large group of patients with AML. The results of the study were reported in Haematologica in August 2018.

Using the MDACC database, the researchers identified 80 patients (median age at diagnosis = 59 years, range: 31–90) with newly diagnosed IDH1 R132 or IDH2 R140/172 AML who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) between November 2012 and December 2017. Patients in this study received various frontline therapies including 7+3 (cytarabine and idarubicin), CIA (clofarabine, idarubicin, and cytarabine), FIA (fludarabine, idarubicin and cytarabine) or CLIA (cladribine, idarubicin, and cytarabine with or without sorafenib). However, no patient included in this study received IDH inhibitors as frontline therapy.

Only AML cases with > 10% mutant allelic frequency (MAF) of IDH1/2 were included in this study. To determine the impact of IDH mutations, bone marrow samples at the time of remission were analyzed using next-generation sequencing (NGS).

Key findings:

• Thirty-one patients (39%) had persistent IDH1/2 mutations in CR or CRi
  • IDH1 R132: 10 patients (38.5%)
  • IDH2 R140: 19 patients (41.3%)
  • IDH2 R172: 2 patients (25%)
• The MAFs of IDH1/2 mutations in all patients were lower in CR/CRi compared to pre-treatment samples: median MAF; 10.2% vs 43.8%
• The cumulative incidence of relapse (CIR) was significantly higher in patients (n = 39) with persistent IDH1/2 mutation at CR than patients (n = 49) with undetectable IDH1/2 at remission: P < 0.01
• After 1-year of follow-up, patients with a persistent IDH1/2 mutation at CR had an increased risk of relapse than patients with undetectable IDH1/2 at remission: 59% vs 24%, HR = 3.89 (95% CI, 1.98–7.62), P < 0.01
• High IDH1/2 mutational burden (≥ 10% MAF) did not correlate with relapse
• Other than IDH1/2, persistent mutations were observed in NPM1, FLT3, DNMT3A, and KRAS/NRAS
  • In the context of co-mutations, persistent mutations in IDH1/2 and FLT3 were significant for an increased risk of relapse

Flow cytometry was also used in this study to evaluate the potential of IDH1/2 as MRD marker in 79 patients with flow cytometric data. MRD by flow cytometry was positive in 19 (26%) patients and negative in 55 (76%) patients with five patients undetermined for MRD by flow cytometry. Similar to the data obtained from NGS, patients with positive MRD were at higher risk of relapse compared to patients with negative MRD.

In summary, this is the largest study investigating the impact of persistent IDH1/2 mutations in CR/CRi in patients with AML. The findings of the study show that persistent IDH1/2 mutation in remission is associated with an increased risk of relapse. However, the mutational burden of IDH1/2 does not harbor an “addictive predictive” value.

Key limitations of the study include the lack of uniformity in IDH1/2 analysis time point and the sample size was not relatively large to investigate the effect of co-mutations in remission. The researchers recommend larger studies to confirm the data obtained in this study. The investigators concluded by insisting that “monitoring IDH1/2 mutation in AML patients during remission using highly sensitive NGS-based assay may provide a useful indication for early intervention to facilitate longer remissions and better outcomes”.