Myelodysplastic syndromes (MDS) constitute a heterogenous group of malignant disorders of the blood and bone marrow, which are characterized by ineffective haematopoiesis leading to peripheral blood cytopaenias and a variable risk of leukaemic progression. Besides allogeneic haematopoietic stem cell transplantation, which is potentially curative, the treatment of patients with higher-risk MDS consists mainly of DNA demethylating therapy. This therapy can improve haematopoiesis, delay leukaemic progression, and prolong overall survival. However, only a subset of the patients respond to the therapy and their benefit remains modest and temporary. Moreover, the mechanisms by which these drugs exert their effects in the patients are yet to be fully elucidated. This PhD study was based on four studies. The review served as an extended clinical background on DNA demethylating therapy. The three investigational studies all involved the immunomodulatory mechanisms of DNA demethylating therapy and the rationale for potential combination of this therapy with immunotherapy in higher-risk MDS. Collectively, the studies provide new insights on how DNA demethylating therapy may modulate the immune system in MDS. Furthermore, the studies contribute to the scientific basis of the potentially advantageous effect of combining DNA demethylating therapy and immune checkpoint therapy in MDS and in cancers in general.

Professor Kirsten Grønbæk, MD, DMSc, Dept. of Haematology, Rigshospitalet, and BRIC, University of Copenhagen (primary supervisor).

Professor Sine Reker Hadrup, MSc, PhD, Technical University of Denmark.

Professor Shohreh Issazadeh-Navikas, MD, DMSc, PhD, BRIC, University of Copenhagen.