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Medical researchers have identified key stem cell changes that could explain why some patients with blood cancer respond well to a key treatment, while others do not.

People with myelodysplastic syndromes (MDS), a group of blood cancers where bone marrow produces abnormal blood cells, have about a one in two chance of responding to the commonly used chemotherapy drug azacitidine.

The drug, which helps bone marrow make healthy blood cells and kills abnormal blood cells, is used for those with high risk MDS who cannot have a stem cell transplant – the only known curative treatment for the disease.��

About 500 Australians start on the drug each year in hope that it will help improve their quality of life, lower the chance of their MDS progressing to , and even help them live longer.

However, they must spend up to six months on the drug, pushing through side effects like nausea and vomiting, diarrhoea or constipation and loss of appetite, to learn if it will help. Now, new findings from a �°IJʹ���-led clinical trial, published in , could change that.��

Researchers discovered a molecular signature in the blood stems cells of people who responded to the treatment, during a phase 2 clinical trial comparing the effectiveness of the standard injectable azacitidine and a tablet version in 40 patients recruited from 13 hospitals across NSW. The trial was coordinated by Professor Mark Polizzotto, now at ANU, and a team at the .��

They found distinct, early changes in the DNA methylation patterns —chemical modifications that regulate gene activity — in hematopoietic stem and progenitor cells (HSPCs) in the bone marrow.

“Patients who respond to treatment have distinct molecular signatures in their blood stem cells, even before treatment begins,” said senior author Professor John Pimanda, from �°IJʹ���’s School of Biomedical Sciences.

“It uncovers why some patients respond and others don’t, that’s always been a puzzle and something we’ve been investigating for a very long time.”

Prof. Pimanda said the discovery lays the foundation for a test that predicts who will benefit from the drug, bypassing the four to six months it currently takes to learn if a patient will respond. It also brings researchers a step closer to improving patient outcomes.�� 

“This study not only gives us clues about who will respond and who won’t, but also what needs to change in the cells for the drug to work,” Prof. Pimanda said.��

“If we know we need to change X, Y and Z in a stem cell for a patient to respond, the next step is figuring out how to make that happen for patients who currently don’t benefit from the drug.” 

First author Dr Julie Thoms, a Senior Research Fellow in the School of Biomedical Sciences, said a predictive test would help patients to make more informed decisions about their care, and avoid giving them false hope.�� 

“Some might question why patients would want that news if there is nothing else to be done at this stage,” Dr Thoms said.�� “But knowing whether you’re likely to respond can help people make better choices about their treatment, especially older patients, and whether they want to go ahead with a demanding treatment which probably won’t work for them, or opt for a different approach, such as blood transfusions.” 

As for the initial aim of the study, the researchers found that the tablet they were testing – as a more convenient way of delivering the drug – was just as effective as the injection. That tablet has since been registered in Australia as a treatment for leukaemia but not yet for MDS, however another, newer oral drug known as Inqovi is now available to MDS patients in Australia on the pharmaceuticals benefit scheme.��

All three options act on DNA, meaning that the molecular signature identified by the researchers, could help predict whether a patient would respond, regardless of which option was utilised.

The researchers are now working to develop a predictive test to help guide treatment decisions, with funding support from the Cancer Council NSW. Longer term, they hope the finding can help them investigate ways to make the drug more effective for a wider group of patients.��

“Our long-term aim is to improve treatment options for patients,” Dr Thoms said. “Now that we better understand why some people don’t respond to current therapies, we can start exploring new combinations or strategies to change that. It’s a continuous cycle — we learn from patients, test ideas in the lab, and bring the most promising ones back into clinical trials. It’s about building toward smarter, more effective treatments over time.”