General AML

Somatic mutation clearance at CR may predict survival and relapse in AML patients

Clearance of somatic mutations at complete remission (CR), particularly in non-preleukemic genes, associated with a better survival and a reduced risk of relapse in patients with acute myeloid leukemia (AML), according to a study published in the Journal of Clinical Oncology by Kiyomi Morita and colleagues from The University Texas MD Anderson Cancer Center, Houston, US.

Predicting the risk of relapse is a significant challenge in AML. The researchers at the MDACC aimed to investigate whether the degree of mutation clearance (MC) at remission can predict relapse in AML patients.

The authors retrospectively performed DNA sequencing on pre-treatment and CR samples, collected from a total of 131 patients (median age = 51 years, IQR: 39–55) with AML who were treated with frontline intensive induction chemotherapy (frontline idarubicin plus cytarabine-based) and attained morphologic CR at Day 30. Three levels of MC were defined based on the variant allele frequency (VAF) of residual mutations at CR including MC2.5 (if at least one mutation persisted with a VAF of 2.5%), MC1.0 (if at least one mutation persisted with a VAF of 1%) and complete mutation clearance (CMC, if there were no persistent mutations).

Key findings:
  • Patients who achieved MC1.0 or CMC had significantly better overall survival (OS), and lower cumulative incidence of relapse (CIR) than those who did not attain these MC levels
    • 2-year OS in MC1.0 and non-MC1.0: 75% vs 61% respectively, P = 0.0465
    • 2-year OS in CMC and non-CMC: 77% vs 60% respectively, P = 0.0303
    • 2-year CIR in MC1.0 and non-MC1.0: 26% vs 46% respectively, P = 0.0349
    • 2-year CIR in CMC and non-CMC: 24% vs 46% respectively, P = 0.03
  • There were no significant differences observed for OS or CIR when assessed for MC2.5
  • Compared to Non-CMC, CMC significantly associated with an improved EFS (HR = 0.43, P = 0.0083) and OS (HR = 0.47, P = 0.04), and lower risk of relapse (HR = 0.27, P = 0.001)
    • Exclusion of preleukemic mutations, such as DNMT3A, TET2, and ASXL1, led to a more prognostic significance for CMC

The authors noted that their study supports “a proof of concept that somatic mutations, particularly non-preleukemic mutations, can serve as molecular minimal residual disease (MRD) markers in AML”. They further added that “MC may be a promising tool with which to identify patients with AML who are at high risk of relapse, and should be explored, along with a flow MRD, as an MRD marker in AML.

References
  1. Morita K, Kantarjian HM, Wang F. et al. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. J Clin Oncol. 2018 Apr 27. DOI: 10.1200/JCO.2017.77.6757. [Epub ahead of print].
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