King's College London

Acquired aplastic anaemia is a rare and serious blood disorder in which the bone marrow fails to produce enough blood cells. As a result, patients develop very low levels of red blood cells, white blood cells and platelets. Current treatment options include stem cell transplantation or immunosuppressive therapy, sometimes combined with the drug eltrombopag, which helps stimulate blood cell production.

Although many patients respond well to treatment, a small but significant proportion later develop serious blood cancers such as myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Researchers still do not fully understand why this happens or whether eltrombopag influences this long-term risk.

The new study focused on a process known as clonal haematopoiesis (CH), in which blood stem cells acquire genetic mutations and give rise to groups, or “clones”, of cells carrying the same mutation. Some of these clones may survive better in the damaged bone marrow environment, while others may potentially contribute to cancer development over time.

To better understand this process, the research team analysed blood and bone marrow samples from 197 patients with severe aplastic anaemia enrolled in the European RACE clinical trial. The original RACE study in which King's researchers were one of the lead investigators, had previously shown that adding eltrombopag to standard immunosuppressive treatment improved the speed and durability of blood count recovery without increasing the short-term risk of blood cancer (.

In this follow-up study, researchers examined samples collected at diagnosis, six months after treatment and again after 24 months. Using advanced genetic sequencing techniques, they tracked mutations across hundreds of genes linked to blood cancers to understand how these altered cell populations evolved over time and whether they were associated with age, disease severity, treatment response or later cancer development.

The researchers found that around one-third of patients already had detectable genetic mutations at diagnosis. Over time, the number of patients with mutations increased, with more than 70 per cent showing detectable mutations in their blood or bone marrow cells two years after treatment.

However, very few patients went on to develop blood cancer. Only three patients in the study developed myeloid malignancies such as leukaemia, suggesting that many of the mutations identified are likely to be harmless or low risk rather than a sign of future cancer development.

The study also showed that older patients were more likely to have mutations, while patients with less severe disease unexpectedly had more detectable mutations at diagnosis. Researchers also observed that some mutations disappeared over time, possibly because healthy blood production recovered following treatment.

The team identified several mutations in genes commonly associated with normal ageing, including DNMT3A and TET2, which are known to grow slowly and are not strongly linked to cancer progression. In contrast, mutations commonly associated with aggressive blood cancers were relatively uncommon.

Importantly, the findings indicate that the drug eltrombopag did not appear to increase harmful genetic changes linked to cancer risk. Instead, the researchers believe the mutations largely reflect the stressed and damaged bone marrow environment seen in aplastic anaemia itself.

Read the full paper published in NEJM Evidence with an accompanying editorial and a paper from NIH Bethesda showing similar results to Deniz Ece Kaya and the other researchers involved.