General AML,   RUNX1

International study of the genomic landscape of acute myeloid leukemia with t(8;21)

Acute myeloid leukemia (AML) can be divided into subgroups based on cytogenetics. AML with t(8,21)(q22;q22) is considered a unique entity by the WHO within the category of “AML with recurrent genetic abnormalities.” Patients with this subtype are considered to be a favorable risk group due to the high remission and survival rates. In t(8;21)(q22;q22) patients, following the RUNX1-RUNX1T1 fusion, an additional genetic aberration is required to cause leukemia. Recent parallel sequencing studies have identified a long list of somatic gene mutations underlying the leukemogenesis of t(8;21) AML including RAS (K/NRAS) and tyrosine kinase (RTK) signaling pathways.

Whilst previous studies have been limited by small sample numbers, this study led by Friederike Christen from the Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany, and colleagues, used a 66-gene targeted sequencing panel approach in a cohort of 331 adult patients with t(8;21) AML (median age: 41.7 years; range, 15–84), to comprehensively analyze commonly mutated genes which could be relevant to the choice of therapy used. Whole exome sequencing (WES) was also conducted on 19 pairs of diagnosis, complete remission (CR) and relapse trios, with the different genetic clones tracked during disease evolution.

Key Findings

Mutation and variant allele spectrum in t(8;21) AML

  • A total of 729 mutations were found
  • Mutations were observed in 49 genes, of these genes 42 were recurrently mutated
  • At least one mutation was identified in 95% of patients with a mean of 2.2 ± 1.4 driver mutations per patient
  • Recurrent mutations found in the following genes:
    • RAS/RTK signaling pathway: 63.4%
    • Epigenetic regulator genes (chromatin remodeling and DNA methylation): 45%
    • Cohesin complex: 13.6%
    • MYC signaling: 10.3%
    • Spliceosome: 7.9%
  • Mutations in GIGY2F, DHX15, G2E3 were reported for the first time
  • Variant allele frequency (VAF): 0.28
  • Highest median VAF was observed in the following genes: DNMT3A (0.43), TET2 (0.40), and IDH2 (0.39)
  • In 34% of RAS/RTK mutated patients, there were multiple mutations in the same pathway
  • Seventy-one patients harbored ≥ 2 signaling mutations, of these, 35 cases harbored mutations in different RAS/RTK genes

Clinico-biological associations and prognostic impact of gene mutations in t(8;21) AML

  • Deep sequencing of 126 mutations in 62 complete response (CR) samples from 56 patients found 16 persisting mutations in 12 patients (all lacked RUNX-1-RUNX1T)
  • KIThigh mutations (mutant level ≥ 25%) were significantly associated with poor relapse-free survival (RFS): HR = 1.96 (95% CI, 1.22–3.15), P = 0.005
  • During multivariate analysis, JAK2, FLT3-internal tandem duplication (ITD)high and KIThigh mutations were found to be prognostic factors for overall survival (OS)

Profiling of somatic mutations in AML with t(8;21) at diagnosis, CR, and relapse

  • WES on 19 paired diagnosis:remission:relapse trios was conducted showing an average of 16 mutations with signs of substantial clonal evolution
  • In total, 131 mutations (31%) present at diagnosis were lost at relapse and 110 mutations (26%) were selected/acquired during disease progression, while 184 mutations (43%) were found in both diagnosis and relapse samples of patients
  • Patients harboring unstable mutations (n = 6) had a dynamic tumor development with relapse samples showing little or no resemblance to the cancer found at diagnosis
  • Signaling mutations are late events and have an impact on patient outcomes:
    • JAK2 and FLT3-ITDhigh are associated with reduced CR rates
    • KIThigh is associated with shorter RFS
    • JAK2, FLT3-ITDhigh and KIThigh with shorter OS

This comprehensive overview of the mutational landscape of AML t(8;21) has provided a foundation for future guided and risk-adapted treatment strategies. In this analysis, high levels of KIT and FLT3-ITD mutations were associated with poor prognosis. It was also observed that epigenetic regulator mutations more likely occurred before signaling mutations. As such, treatment with midostaurin, a multi-targeted kinase inhibitor for FLT3mutated AML, the multi-kinase inhibitor dasatinib or other RTK inhibitors, appear to be promising approaches to improving patient outcome.

References
  1. Christen F. et al. Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients. Blood. 2019 Jan 4. DOI:  https://doi.org/10.1182/blood-2018-05-852822. [Epub ahead of print]
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