AML Family Trees Shed Light on Responsiveness to Enasidenib

A team of international researchers have joined forces to map the family trees of cancer cells in the most aggressive rare blood cancers found in adults—acute myeloid leukemia (AML)—in an effort to understand how responsive the cancer would be to a new drug, enasidenib.

The collaboration consisted of researchers from the Gustave Roussy Cancer Campus and Inserm in Paris, France, the MRC Molecular Haematology Unit and the MRC Weatherall Institute of Molecular Medicine at the University of Oxford, United Kingdom, Memorial Sloan Kettering Cancer Center, and Celgene. Through their research, they were able to shed light on what happens when patients stop responding to treatment, how to produce longer-lasting remissions, and how to prevent relapse.

Although enasidenib, an anti-cancer ("antineoplastic") chemotherapy drug, was approved by the US Food and Drug Administration (FDA) in 2017 due to its effectiveness in patients with an IDH2 mutation for whom previous treatments did not work, investigators found that disease recurrence occurred in these patients within 9 months.

In an effort to better understand how AML cells responded to the treatment, researchers decided to take a closer look at the genetic make-up of AML cells.

For their analysis, the team looked at samples collected from 37 patients that had been enrolled in the phase 1/2 clinical trial that led to the drug’s approval. By looking at the markers on the surface of the bone marrow cells, they were able to identify the different populations of bone marrow cells, ranging from the immature, undifferentiated cells to the mature, differentiated cells.

Lead author of the study, Dr Lynn Quek, MRC clinician scientist and consultant hematologist at the MRC Weatherall Institute of Molecular Medicine stressed that bone marrow serves as an “assembly line” responsible for creating mature blood cells. Previous to treatment, patients experience a blockage in their assembly line. By looking at bone marrow cells, the investigators were able to better understand what causes the blockage and how enasidenib works to unblock the line.

The research team found shared genetic mutations among AML cells from the same patient that could be grouped into families, referred to as clones, which are thought to originate from the same ancestor cell.

“When an AML patient has a bone marrow test, we are taking a snapshot of the family tree of leukemia cells," Dr Quek explained in a recent statement. "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.”

Using techniques to study genetic mutations on a cell-by-cell basis and reconstruct the family tree of a patient's AML cancer cells allowed the team to track changes in the family of AML cells as they responded to enasidenib and as they became unresponsive to the drug.

The study provided genetic insight that proved enasidenib was able to differentiate cancer cells and restore some of their normal functions, despite their still containing the IDH2 mutation.

“This is important because unless we can track these clones, we don't know whether the mature cells in a patient are coming from normal cells after all the cancer cells have been killed or from leukaemic cells that are now able to mature,” study co-author Dr Virginie Penard-Lacronique, research director and team leader at the Inserm unit at Gustave Roussy, added. “In this paper we show that in four out of five cases, the mature cells are coming from leukaemic bone marrow cells that can be induced to differentiate by this new drug."

Since the cancer recurred in almost all the patients involved in the clinical trial, researchers were able to prove, for the first time, that leukemic cells stop responding to enasidenib when some of the clones develop additional mutations. The new sub-clones proved to be resistant to enasidenib, shedding light on the mechanism of drug resistance in AML. This knowledge can be used to inform the development of future therapy trials that can evaluate what is needed to overcome treatment resistance.

Furthermore, based off their research, the investigators postulate that combining enasidenib with other anti-cancer drugs may be needed to prevent relapse, a notion currently being investigated in clinical trials which strive to answer whether or not patients will respond to these combinations, for how long, and the likelihood of a relapse.

"Enasidenib a very good example of a modern cancer therapy that specifically targets principally cancer cells, sparing normal cells, and in this regard is very safe and has limited side effects,” concluded Dr Stéphane de Botton, physician in the haematology department at Gustave Roussy.

“Now that we have shown that it needs to be combined with other drugs to stop the cancer returning, we think that it's important that the combination therapy should be given to AML patients early on in their disease. International trials are now taking place comparing combinations of enasidenib and other drugs with the normal standard of care," she added.