Blood cancer-related gene variants such as ASXL1 strongly predict treatment failure in patients with chronic myeloid leukaemia, even in those receiving potent frontline tyrosine kinase inhibitors, Australian-led research shows.
The team, led by haematologists and researchers from SA Pathology and the University of South Australia in Adelaide, had previously demonstrated additional genetic abnormalities at diagnosis negatively impacted failure-free survival and molecular response for 200 consecutive imatinib-treated patients.
Their latest study investigated whether potent TKIs could negate some of these effects. It found that while the therapies nullified the negative impact of Ph-associated rearrangements, this wasn’t the case for cancer-related gene variants, highlighting “the importance of diagnostic next generation sequencing in CML”.
The researchers performed targeted RNA-based next generation sequencing (NGS) on diagnostic samples of 315 patients in the chronic CML phase consecutively enrolled in four clinical trials of frontline potent TKIs.
Additional genetic abnormalities were present in just over a third of the cohort at diagnosis (34%), including 20% with blood cancer-related gene variants across 19 different genes and 18% with Ph-associated rearrangements (4% had both).
ASXL1 was the most frequently mutated gene, involving 7% of the 315 patients.
Findings showed treatment with frontline potent TKIs could overcome the negative impact of Ph-associated rearrangements observed with frontline imatinib, but patients with blood cancer-related gene variants still had inferior outcomes.
The researchers said this was largely attributable to patients with ASXL1 variants.
When comparing patients with ASXL1 variants to ASXL1 wildtype, the 12-month major molecular response was 55% versus 83%; the 2-year failure-free survival was 61% versus 91%; and notably, development of treatment emergent BCR::ABL1 kinase domain mutations at 2 years was 35% versus 1%.
In multivariable models, blood cancer-related gene variants and ASXL1 variants at diagnosis were independent predictors of each of these outcomes.
The researchers said the most notable finding was the high risk of TKI-resistant BCR::ABL1 KD mutations emerging in patients with ASXL1 variants at diagnosis.
The negative impact of ASXL1 remained irrespective of the frontline inhibitor used, with ASXL1-mutated patients having a 21% incidence of BCR::ABL1 KD mutations by 2 years if treated with 2G-TKI and 56% if treated with asciminib.
“Our findings indicate the potential clinical value of NGS at diagnosis of chronic-phase chronic myeloid leukemia (CP-CML) for personalisation of CML therapy although as yet, there is not a clear strategy of how to approach ASXL1-mutated CP-CML,” the researchers said.
“Even before we have better treatment strategies, recognising the high risk of BCR::ABL1 mutations in patients with ASXL1 variants may be helpful for clinicians, for instance, increasing vigilance when monitoring response.
“Strategies to overcome the negative impact associated with ASXL1 are being devised such as the current Australasian CML14 study, which is investigating combination therapy with asciminib and dasatinib for these select patients.
“While confirmatory work is pending, this data clearly highlights how genomic profiling at diagnosis can enhance outcome prediction and therapy optimisation in CP-CML patients.”
The findings were published in Blood [link here].