General AML,   DNMT3A,  IDH1/2,  TET2,  TP53,  RUNX1

ASH 2017 | Prevalence of AML-defining mutations in peripheral blood years prior to the development of leukemia 

Pinkal Desai, from the Weill Cornell Medical College, New York, NY, on behalf of colleagues  presented at the 59th Annual Meeting & Exposition of the American Society of Hematology (ASH), on Sunday 10th December, an abstract titled “Acute Myeloid Leukemia (AML) Patients Demonstrate Increased Prevalence of AML-Defining Mutations in Peripheral Blood Years Prior to the Development of Overt Leukemia: A Case-Control Study”.

Pinkal Desai began her talk by highlighting the importance of Clonal Hematopoiesis of Intermediate Potential (CHIP) which, has been reported to be associated with an increased risk of hematologic malignancies. However, the impact of specific CHIP mutations on AML risk and time to AML has not been elucidated yet. Moreover, the relevance of changes in Variant Allele Frequency (VAF) and clonal evolution leading to the development of AML has not been evaluated yet in any study.

The speaker then reported results from their study, which aimed to evaluate the likelihood of having a myeloid-specific mutation prior to the development of AML. The main objective of the study was to investigate whether specific mutations could be detected years prior to the onset of AML and also evaluate whether specific mutations would affect the risk and time-to-diagnosis of AML.  

Overall, 725 samples from 160,808 women (50–79 years of age at baseline) from the Women’s Health Initiative (WHI) were analysed. After a 10.8 years median follow-up, 212 women who eventually developed AML (average time to AML was 9.06 years) and 212 matched healthy, non-AML controls were identified from the cohort. Targeted deep sequencing of 67 genes were performed on peripheral blood samples at baseline and follow-up (year 1 and 3)

The key findings of the study were:
  • Participants who eventually developed AML had more mutations and had higher mutational complexity at WHI baseline evaluation than controls
    • Most frequently found mutations in AML cases and controls respectively were: DNMT3A (22.8% and 10%), TET2 (19.5% and 4.2%) and ASXL1/ASXL2 (8% and 6.8%)
    • Most common co-mutations in AML cases were:
      • DNMT3A + TET2
      • IDH2 + SRSF2
      • DNMT3A + TP53
    • Most common co-mutation in controls was:
      • DNMT3A + TET
    • TP53 (6.6%) and RUNX1 (2%) mutations were only observed in participants who eventually developed AML and were absent in controls
    • Increased prevalence of myeloid specific mutation were observed among AML cases compared to controls: OR = 2.87, P < 0.001
    • Myeloid specific mutation at baseline was associated with the development of AML; OR = 2.9, P < 0.001
    • There was a significantly higher odds of developing AML in participants with mutations in TP53 (OR = 2.89, P < 0.001), IDH (OR = 1.37, P < 0.004), spliceosome (OR = 1.5, P < 0.004), TET2 (OR = 2.5, P < 0.01) and DNMT3A (OR = P < 0.001) at baseline WHI evaluation
      • All participants with a RUNX1 or TP53 developed AML
      • 15/16 participants with IDH mutations eventually developed AML
      • ASXL1 was not significantly associated with development of AML
    • Median time to AML was significantly shorter in participants with mutations present at baseline WHI evaluation, P = 0.00045
    • Participants with DNMT3A (P < 0.0001) or TP53 (P = 0.0051) mutations at baseline were more likely to develop AML within five years
    • Time to AML is inversely correlated with the rate of increasing VAF in TP53, IDH2 and DNMT3A
      • Almost 90% of subclonal mutations found at baseline persisted in the same participant when samples were available at follow-up

Pinkal Desai stated that the presence of mutations was associated with significantly greater odds of developing AML when present at baseline WHI evaluation. Furthermore, mutations in IDH, TP53, spliceosome, TET2 and DNMT3A independently associated with greater odds of AML adjusting for age and confounding co-mutations. Additionally, time to AML is inversely correlated with increasing VAF in TP53, IDH2 and DNMT3A, which suggests that there might be a value in monitoring these mutations.  

Taken together, Pinkal Desai concluded that the findings of this study “suggests that subclonal stepwise acquisition of mutations may occur years prior to disease onset and that deep molecular monitoring using NGS may enable early intervention in selected patients.” In an interview with the AML Global Portal, Pinkal Desai highlighted that the findings of their study is “very important for developing a monitoring strategy” for a lot of patients and she further added by saying that “if we are almost sure that AML can occur in some of these participants, then we can maybe develop an interventional therapy for these group of people.

References
  1. Desai P. et al. Acute Myeloid Leukemia (AML) Patients Demonstrate Increased Prevalence of AML-Defining Mutations in Peripheral Blood Years Prior to the Development of Overt Leukemia: A Case-Control Study. Oral Abstract 408. ASH 59th Annual Meeting and Exposition, Atlanta, GA.
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