CLINICAL NEWS

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 .

— KOICHI TAKAHASHI , MD

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 .

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 ]

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

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