The use of combination therapy as to improve treatment of Chronic Myeloid Leukaemia (CML)

Abstract

Chronic myeloid leukaemia (CML) is characterised by the uncontrolled proliferation of myeloid cells in the bone marrow typically after acquiring the Philadelphia chromosome. CML may be controlled using mono-therapeutic drugs such as all-trans retinoic acid (ATRA) and imatinib, however, after approximately 10 years of administration, patients develop resistance to both drugs. Combination therapy using imatinib and ATRA co-administered with other drugs, such as Venetoclax and Arsenic trioxide (ATO) respectively, has already shown promising results where the leukaemia was managed significantly better than if singular drugs were administered. This project aims to bring CML closer to a cure through the use of combination therapy with FDAapproved chromatin modifying agents (CMAs). CMAs were combined with imatinib and ATRA in vitro using K562 cells, both sensitive (K562-IS) and resistant (K562-IR) to the imatinib. Tests involved assays to monitor proliferation and differentiation of CML cells under different treatments. The promising combinations were stained and scored for differentiation under high power field analysis and then tested for cytotoxicity with healthy lymphocytes from donor blood. Results show that combination treatments not only increased susceptibility to imatinib, but also resensitized imatinib-resistant cells to the drug. The most effective combination proved to be suberanilohydroxamic acid (SAHA) (vorinostat) with imatinib. Furthermore, these combinations showed no toxicity to healthy blood cells thus proving to be potential treatments for CML patients. This research can serve as a preliminary experiment for future work with the aim of finding the optimal drug combination to treat each resistance mutation. This can be followed by studies in molecular mechanisms to ensure that the pathways causing differentiation and anti-proliferative effects are fully understood.