Micrograph showing MDS
Research published in Cell Reports helps explain why some patients with myelodysplastic syndrome (MDS) do not respond to treatment with azacitidine.
The study showed that patients who were resistant to the drug had relatively quiescent hematopoietic progenitor cells (HPCs).
A smaller proportion of their HPCs were undergoing active cell-cycle progression when compared to the HPCs of patients who responded to azacitidine.
This discovery could provide the first method to identify non-responders to azacitidine early, according to study author Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.
“These are early days, but this could avoid what has really been a ‘wait and see’ approach with patients that sometimes results in them receiving futile treatment for 6 months,” Dr Unnikrishnan said.
“By that stage, the patient’s disease has progressed, and there’s no alternative for them.”
Dr Unnikrishnan and his colleagues also found the HPC quiescence in non-responders was mediated by integrin α5 (ITGA5) signaling, and the cells’ hematopoietic potential improved when the team combined azacitidine treatment with an ITGA5 inhibitor.
This suggests a potential avenue for future combination therapies that would improve azacitidine responsiveness.
Lastly, the researchers made discoveries that could explain why some patients who initially respond to azacitidine eventually relapse.
“All of the pernicious mutations that we associate with MDS never disappear in these patients, even after years of treatment,” Dr Unnikrishnan said. “From a clinical perspective, blood cell production is restored in patients, but they are a ticking time bomb, waiting to relapse.”
“[Azacitidine] is not a cure, and we are starting to understand why it does what it does. We need to find better treatments than azacitidine if we want a more durable therapy for MDS, and that’s the basis for our future work.”
