Complete Mutation Clearance Predicts Longer Survival and Lower Relapse Risk in AML

Somatic mutation clearance (MC) at complete remission (CR) of acute myeloid leukemia (AML) was associated with improved survival and reduced risk of relapse, according to results of a study published in the Journal of Clinical Oncology. Specifically, somatic MC in the nonpreleukemic genes was associated with reduced relapse risk and longer survival.

These data suggest that, as a whole, the persistence of these mutations “may function as a molecular minimal residual disease (MRD) marker in AML,” Koichi Takahashi, MD, from The University of Texas MD Anderson Cancer Center in Houston, and coauthors noted.

To test this hypothesis, researchers performed DNA sequencing on samples collected from 131 patients with untreated AML who were studied in three phase II trials. Patients had received frontline intensive induction chemotherapy consisting of idarubicin plus cytarabine and achieved morphologic CR at 30 days following therapy.

Investigators characterized three levels of MC (based on variant allele frequency [VAF] of residual mutations at CR):

  • MC2.5, meaning at least one mutation persisted with a VAF <2.5%
  • MC1.0, meaning at least one mutation persisted with a VAF <1%
  • complete MC (CMC), meaning no persistent mutations

The authors also assessed event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) from the data of CR.

The median VAF of pre-treatment mutations was 0.30 (range = 0.17-0.42), and the most frequently mutated genes in the cohort included:

  • NPM1 (28%; n=37)
  • DNMT3A (24%; n=32)
  • FLT3 (22%; n=29), 62% as internal tandem duplication and 38% as non-internal tandem duplication
  • CEBPA (15%; n=20)

MC2.5, MC1.0, and CMC was achieved in 75 (57%), 64 (49%), and 59 patients (45%), respectively. “Rates of MC varied by the mutated genes,” the authors reported. “We observed frequent persistence of somatic mutations at CR in genes that are often preleukemic (e.g., DNMT3A, TET2, SRSF2, ASXL1, and TP53), whereas mutations in NPM1, hematopoietic transcription factors, or the receptor tyrosine kinase pathway were often cleared” (see TABLE).

The rates also differed by molecular pathway: Mutations in hematopoietic transcription factors or receptor tyrosine kinase genes had higher MC rates; mutations associated with clonal hematopoiesis of indeterminate potential, DNA methylation, and RNA splicing had lower MC rates.

Rate of Mutation Clearance on the Basis of Genes and Molecular Pathways

Patients who achieved CMC had lower median pre-treatment VAF than those who did not (0.41 [range = 0.31-0.47] vs. 0.25 [range = 0.14-0.36]; p<0.001).

During a median follow-up of 35.2 months (range = 28.3-39.7 months), approximately 39 percent of patients (n=51) experienced relapse and 37 percent (n=49) died. Participants who achieved MC1.0 and CMC had significantly improved two-year OS and significantly lower CIR:

  • 2-year OS: 75% vs. 61% (MC1.0 vs. non- MC1.0; p=0.05) and 77% vs. 60% (CMC vs. non-CMC; p=0.03)
  • 2-year CIR: 26% vs. 46% (MC1.0 vs. non- MC1.0; p=0.03) and 24% vs. 46% (CMC vs. non-CMC; p=0.03)

However, in participants achieving MC2.5 versus not achieving MC2.5 or better, no significant differences were found for any of the study outcomes.

These associations remained constant in multivariable analyses that adjusted for age, cytogenetic risk, allogeneic hematopoietic cell transplantation (alloHCT), and flow cytometry– based MRD status: Patients who achieved CMC at remission had greater EFS (hazard ratio [HR] = 0.43; p<0.01), OS (HR=0.47; p=0.04), and CIR (HR=0.27; p<0.001) than those who did not achieve CMC.

“The real impact of MRD assessment will be observed when it affects clinical decision making,” the researchers explained.

The relatively small sample size limited the investigators’ ability to characterize the MC rate of individual mutations. In addition, considering that most patients in the analysis were younger than 60 years, these findings may not be generalizable to older patients, nor to other centers where assessments of mutation status differ.

“MC may be a promising tool with which to identify patients with AML who are at high risk of relapse,” the authors concluded, “and should be explored, along with [flow cytometry–detected] MRD, as an MRD marker in AML.”

The corresponding authors report no financial conflicts.

Reference

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. [Epub ahead of print]

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