AS545 - Prospective identification of pre-leukemic clones in the peripheral blood of women with acute myeloid leukemia prior to the onset of overt disease

Investigator Names and Contact Information

Pinkal Desai MD MPH [pid9006@med.cornell.edu]

Introduction/Intent

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults, with an annual incidence of approximately 13,000 cases. The median age at presentation is 66 years and the prognosis is generally poor, with 40-50% five-year survival for patients <60 years and less than 10% survival for patients ≥ 60 years. Historically, age and cytogenetics have been the most important determinants of prognosis. Over the last few years, next generation sequencing technologies have revealed that AML is a molecularly heterogeneous disease characterized by the accumulation of somatic mutations that occur early in leukemogenesis. In some patients, pre-leukemic mutations may be present and potentially detectable in the peripheral blood before the onset of overt disease. The objectives of this proposal are: 1. To compare the frequency of clonal, preleukemic mutations in the peripheral blood of patients with AML taken prior to the development of overt disease with age matched controls; 2. To investigate the frequency, repertoire and evolution of somatic mutations as well as baseline hematologic parameters in peripheral blood specimens taken from patients with pathologically confirmed AML prior to the development of overt leukemia; and 3. To assess possible correlations between the nature, timing and pattern of specific pre-leukemic mutations and development of AML. Targeted sequencing using DNA (1 µg) from peripheral blood samples obtained prior to the development of AML will be performed on 229 pathologically confirmed cases and 200 age matched controls from both CT and OS participants using a 200 gene panel on an Illumina platform. In some cases, several blood specimens are available for sequencing for participants prior to disease development. It is expected that this work will result in unprecedented insights into the ontogeny and pathogenesis of AML. The data may pave the way for novel strategies in early treatment and prevention of AML.

Specific Aims

1. To compare the mutations identified using a 200 gene panel on DNA from banked peripheral blood specimens from women taken prior to their diagnosis of acute myeloid leukemia (AML) with those identified in age-matched controls.
2. To compare the time to development of overt disease in AML patients with precursor mutations identified by a 200 gene panel, with those patients who did not have pre-disease clonal hematopoiesis.
3. To study the evolution of clonal changes in the banked peripheral blood of women who underwent serial monitoring and had multiple specimens prior to their subsequent diagnosis of AML (if available).
4. To assess possible correlations between the baseline hematological parameters as well as nature, timing and pattern of specific pre-leukemic mutations and the development of AML.
5. To compare the metabolic (2 hydroxyglutarate, vitamin C, glucose) and inflammatory risk factors (inflammatory chemokine panel and bacterial translocation) in plasma that modify the relationship of mutations in IDH, TP53, DNMT3A and TET2 as identified in the proposal and risk of AML. ( requesting plasma samples)
6. To compare the DNA methylation pattern and telomere length between cases and controls using left over DNA samples to understand the functional genomic state associated with the preleukemic mutations. ( left over samples)
7. To characterize the differences in clonal hematopoiesis patterns in participants with therapy related AML by sequencing additional therapy related AML cases (n=13 appx.)