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Acute myeloid leukaemia (AML) is an aggressive blood cancer, for which most patients are not eligible for intensive chemotherapy or stem cell transplantation. Therefore, less toxic and more efficient targeted therapies are urgently needed.
A recent clinical trial for AML patients with IDH1 mutations tested the effectiveness of a drug combination of ivosidenib and venetoclax (with or without azacitidine). Although most patients responded well, several developed resistance to treatment and relapsed. To understand why, the Vyas Group in Oxford worked with collaborators at the MD Anderson Cancer Center in Houston to study bone marrow samples from patients before, during, and after treatment.
The researchers used a powerful single cell technique, called TARGET-seq+, to track cancer clones in patient samples. They discovered that drug-resistant cancer cells were selected very quickly – within one to three treatment cycles – even while patients were still in remission. This occurred in all analysed patients who relapsed, whether relapse occurred within months or even years of treatment.
These resistant clones came from small populations of immature cells known to have “stem cell–like” properties. Meanwhile, most of the cells in the bone marrow remained clear of relapse-associated mutations and blood production was sustained by normal cells, masking the hidden resistant clones. In contrast, patients who stayed in long-term remission showed complete or near-complete removal of all leukaemic cells.
Despite having different genetic mutations, resistant cells shared common patterns of gene activity. This included the activation of genes stimulating stem cell properties and, most importantly, genes controlled by the menin–MLL complex – a well-known driver of leukaemia. This finding suggests that menin inhibitors, a new class of drugs currently showing promise in clinical trials, could help prevent or treat relapse after ivosidenib and venetoclax therapy.
Felix Radtke, a lead author on the study, said:
Our study has shown that early genetic screening of specific immature bone marrow cell populations, while patients are still in remission, could identify those most likely to relapse. Our finding that genes regulated by menin-MLL were upregulated in resistant cells months before relapse was striking – if confirmed in larger cohorts this may show resistant disease to be vulnerable to menin inhibition.
Senior author Professor Paresh Vyas said:
Our study may have important implications for clinical practice in resistant disease specifically and, more generally, in how we treat all patients with the most aggressive adult leukaemia, acute myeloid leukaemia. Specifically, our work may make the use of treatments called menin inhibitors important for a greater patient population and may usher in a new era of precision targeted therapy for patients. We will be testing if this is the case in future studies.
Read the full paper, published in Blood: Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy