PhD defence C.M. (Christian) Vonk

Below is a brief summary of the dissertation:

Acute myeloid leukemia (AML) is a type of malignancy of the hematopoietic system arising in the bone marrow by an uncontrolled proliferation of undifferentiated blood cells. Initial induction chemotherapy leads in the majority of AML patients to a morphologic complete remission in the majority of patients, but most of them will experience AML relapse relatively fast, caused by re-proliferation of a small amount of leukemic cells still present in the blood. This is called measurable residual disease (MRD), and is currently undetectable by conventional screening methods in most cases. However, The presence of MRD can predict in an early stage which patients will develop a relapse, but this predictive value can differ between patients based on their molecular profile. Currently, detection of MRD is mostly based on immunophenotypic cell-surface markers, but the development of Next-Generation Sequencing (NGS) techniques in recent years has made it possible to perform MRD measurements for DNA-mutations. However, AML is characterized by a great molecular heterogeneity, making it difficult to perform adequate analyses into the predictive value of persisting individual gene mutations. The research presented in this thesis shows that these analyses are now possible for frequently mutated genes in AML, partly due to addition of data from the HOVON-132 clinical trial. We show that NGS is a reliable method to detect the frequently occurring FLT3-ITD mutation and mutations in the NPM1, CEBPA and IDH1/2 genes. In particular, persistence in CR of mutations in FLT3 and NPM1 are strong independent predictors of impending relapse in AML.