PARP inhibitors in acute myeloid leukaemia therapy: How a synthetic lethality approach can be a valid therapeutic alternative.

ABSTRACT

Acute myeloid leukaemia (AML) is a malignancy in need of new therapeutic options. The current standard of care chemotherapy, leads to complete remission (CR) in the vast majority of adult patients under the age of 60. In contrast, CR rates in patients over the age of 60 reaches only 40-60%. While achievement of a CR is an important stepping stone in the treatment of AML, the majority of these patients experience relapse and die of their disease without adequate consolidation chemotherapy. Blood and marrow transplantation (BMT) can improve outcome in a select patient with AML but unfortunately, it is not a valid treatment option for the majority of older patients. Thus, the development of novel chemotherapy regimens that capitalizes on AML biology to eliminate the malignant clone with little to no side effects on the normal haematopoiesis is paramount in the treatment of elderly patients. In the current paper, we propose to take advantage of the dysfunctional DNA repair mechanisms present in AML cells and induce synthetic lethality using a combination of PARP inhibitors with low dose anthracycline and DNMT inhibitors. Such a combination, while effectively eliminating leukaemia should be well tolerated and thus, suitable for the treatment of frail patients.