ABSTRACT

The present PhD dissertation was carried out at the Department of Haematology, University of Aarhus, Aarhus, Denmark, and is based on three publications and an overview.

In Denmark about 200 new cases of acute myeloid leukaemia (AML) are diagnosed annually. AML is usually treated by combination chemotherapy, and in some groups of patients with stem cell transplantation. Currently, long-term cure rates can be achieved in up to 40-50% of patients below 65 years of age. However, much lower cure rates are obtained in elderly patients. Today, a number of clinical and molecular factors are known or suspected to influence the prognosis in individual patients.

The aim of the present study was to investigate and to evaluate the role of a variety of lesions in AML and to create a molecular phenotype, which will enable upfront prognostication in the patients.

While, in the first two papers I validated molecular analysis in a laboratory manner, I have in the last paper made a retrospective study where I analyzed 250 AML patients, 72% of whom were treated with curative intent, at our department during an eighteen year period from 1985 to 2002. In univariate Cox regression analysis I could reproduce that age, white blood cell counts at presentation, and cytogenetic aberrations were of prognostic value. Furthermore, I extended our knowledge of this disease by showing that balanced translocations or chromosomal aberrations demonstrated by multiplex PCR could predict overall survival. In addition, promotor methylation of the E-cadherin gene was associated with a favourable prognosis (p<0.01), while the presence of FLT3 ITD, the increased expression of MDR1, and a high BCL2/BAX ratio all showed trends towards being adverse prognostic signs (0.05<p<0.12). In multivariate Cox regression analyses, I still found that chromosomal aberrations were a significant prognostic factor, even when adjusted for age and leukocyte counts at presentation. Moreover, FLT3 ITD was revealed to be associated with an adverse prognosis (p<0.05), when data were adjusted for age, leukocyte counts and cytogenetic analysis. On the other hand, the significance of E-cadherin promotor methylation and of MDR1- and BCL2/BAX expression was lost when data were adjusted for age, leukocyte counts and cytogenetic analysis.

I conclude that when a battery of molecular changes is applied to AML patients from a larger single study, recurrent translocations remain the prime target for stratification. These data underline the importance of a broad application of molecular assays in AML and suggest that even larger studies should be performed focusing on the characterization of patients with no translocations as prime candidates for discovery of new pathways of leukemogenesis and AML.