Acute Myeloid Leukaemia (AML) is the most common and aggressive blood cancer in adults and is incurable in most patients. About 12-15% of AML patients have a mutation in the IDH2 gene that stops bone marrow cells from differentiating, or maturing, into blood cells that are required for life. Instead, these immature cells accumulate in the bone marrow and blood, which is a hallmark of AML.
Previous research from the same team showed that enasidenib prompts blood cell differentiation and restores normal blood cell production. A phase I/II clinical trial showed that the drug was effective in 40% of AML patients with an IDH2 mutation who had failed previous treatments, leading to the US Food and Drug Administration (FDA) giving approval for enasidenib in 2017. However, after an average of nearly nine months, the cancer returned in these patients. The Oxford team, led by Prof Paresh Vyas, Professor of Haematology at MRC Molecular Haematology Unit (MRC MHU) at the MRC Weatherall Institute of Molecular Medicine, joined forces with colleagues in France and the USA to understand why cancer cells became resistant to this therapy.
Using samples from 37 patients in the trial who had responded to enasidenib, the team looked at markers on the surface of the bone marrow cells to identify the different populations of bone marrow cells, from the immature, undifferentiated cells, called progenitor cells, through to mature, differentiated cells.
“You can imagine the bone marrow as an assembly line that constantly needs to produce mature blood cells,” said co-author, Dr Lynn Quek, MRC clinician scientist and consultant haematologist at the MRC WIMM. “In a patient before treatment, this assembly line becomes blocked. Using specialist techniques, we studied bone marrow cells from patients to find out how the bone marrow assembly line becomes blocked and how enasidenib helps to promote differentiation to unblock the assembly line.”
As AML is caused by errors in DNA sequence, or mutations, in blood cells, the team studied the genetic make-up of AML cells. They found that AML cells from the same patient can be grouped into families which share genetic mutations, called clones. Cells belonging to the same clone or family, come from the same ancestor cell. Understanding how clones relate to each other is important as they provide information as to how the AML started in the first place.
“When an AML patient has a bone marrow test, we are taking a snapshot of the family tree of leukaemia cells,” said Dr Quek. “As we treat the AML, there are shifts in the family dynamics as some clones will die and others will grow. In every cancer there are several families or clones of cancer cells. In AML we were able to see how these responded to enasidenib. We used techniques to study genetic mutations on a cell-by-cell basis, and re-constructed the family tree of a patient’s AML. We then tracked changes in the family of AML cells as they responded to enasidenib and as patients lost response to the drug. This is the first time that anyone has done such a detailed study at a single cell level, and we are very fortunate to have access to excellent facilities at MRC WIMM that allow us to perform such single cell studies. As enasidenib is a new anti-leukaemic drug, it was vital to understand the effects of the drug on leukaemic cells.”
The cancer returned in almost all the patients in the clinical trial, and the team was able to show for the first time that the leukaemic cells stop responding to enasidenib when some of the clones develop additional mutations. These new sub-clones are resistant to enasidenib, providing clues about the mechanism of drug resistance. This may help in designing future therapy trials to overcome therapy resistance. It may also mean that enasidenib needs to be combined with other anti-cancer drugs to prevent relapse, and clinical trials have already started investigating whether patients respond to these combinations, for how long and whether they are likely to relapse.
Professor Paresh Vyas pointed out: “The approach we have implemented can be applied to any cancer and to any therapy to understand how any drug attacks each clone in a cancer and how different clones respond to therapy. This makes it a very powerful approach to improve our understanding of how to achieve better outcomes from cancer therapy.”
The study, published in Nature Medicine today, is an international collaboration between researchers from the Gustave Roussy Cancer Campus and Inserm in Paris (France), the MRC MHU and the MRC WIMM at the University of Oxford (UK), Memorial Sloan Kettering Cancer Center (USA) and Celgene (USA).
The MRC WIMM team was funded by the Medical Research Council, NIHR Oxford Biomedical Research Centre and an Oxford-Celgene Fellowship.