Preclinical Research Shows Activity of Fidaxomicin Combination Therapy in MLL-AML

Get Permission

A specific type of acute myeloid leukemia (AML) that contains a rearrangement in the MLL gene (also known as KMT2A) might be made more sensitive to chemotherapy using an antibiotic currently available to treat diarrhea, according to new research published by Zeisig et al in Science Translational Medicine.

This type of leukemia, often referred to as MLL-AML, has a particularly poor prognosis, as it may quickly become resistant to the standard chemotherapies used to treat it. Tackling this resistance is a major challenge to successfully treating the disease.

MLL-AML Origins

A challenge for researchers has been understanding why some AMLs respond to treatment while others become resistant. Led by Eric So, PhD, of King’s College London, researchers studied how MLL-AML develops in humans for the first time by establishing a new way of modelling how the stem cells that form our blood could turn into AML when affected by the MLL genetic alteration.

“Having worked on the research that shed light on the origins of MLL leukemia in mice 18 years ago, this development is an important step forward for AML research and provides a new avenue to screen for and identify new targets to treat it,” said Dr. So.

Using the new approach, Dr. So and his team found that the disease could originate from two different types of cell, with one leading to more resistant disease than the other. Studying the more resistant type in detail showed that it produced much more of a particular protein, ABCC3, than the other, which could be responsible for making it more resistant to chemotherapy.

They confirmed this theory in human cells—when the team removed a cell’s ability to produce ABCC3, it was far more sensitive to chemotherapy.

Treatment With Fidaxomicin

The next step for the team was to find a drug that could either stop ABCC3 from being made or prevent it from working. By looking into existing research, they found a recent paper showing that fidaxomicin—an antibiotic currently prescribed to treat diarrhea caused by the bacteria Clostridium difficile—was effective at inhibiting ABCC3.

“It was both unexpected and, frankly, good fortune that there happened to be a recent study showing an already approved antibiotic could work for this research. It was the perfect candidate to test out,” said Dr. So.

Testing the drug on treatment-resistant MLL-AML, the team found that it successfully sensitized the cancer to chemotherapy in both cells grown in the lab and in mice. The researchers now want to test the effectiveness of fidaxomicin at helping to treat MLL-AML in a clinical trial. As fidaxomicin is already used to treat diarrhea and has been shown to be safe, they hope that a trial could be set up relatively quickly.

The study authors concluded, “This study not only functionally established two distinctive origins of human leukemia stem cells for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell–associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic.”

Disclosure: For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.