A new study identifying 11 distinct genomic subtypes of acute myeloid leukaemia, and linking them to prognosis, has provided an unprecedented understanding of the pathways leading to the disease.
An editorial comment on the study, published in the New England Journal of Medicine, said it provided practice-changing insights that redefined the molecular classification of AML, and a deeper understanding of the events that drove its development.
The study provided an unprecedented understanding of AML with important biological and clinical implications, it claimed.
A multinational team searched for driver mutations in 111 cancer genes, combining the findings with cytogenetic and clinical data, in 1,540 patients enrolled in three treatment studies conducted by the German-Austrian AML Study Group.
They identified a total of 5,234 driver mutations in 76 genes or genomic regions. At least one mutation was found in 96% of patients, and two or more mutations were found in 86%.
“Patterns of co-mutation compartmentalised the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes,” the researchers said.
“In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2R172 mutations (in 1%).”
Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with different class-defining mutations contributing independently and additively to the outcome. Other co-occurring driver mutations also had a substantial effect on overall survival.
“The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations,” they said.
“Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favourable or adverse prognosis.”
The researchers acknowledged that systematic studies of the genomic landscape of AML, including analyses of data from the Cancer Genome Atlas, had generated an increasingly comprehensive catalogue of leukaemia genes.
“It is an opportune time to revisit the possibility of an AML classification scheme that is fully genomic, they said.
“With whole-genome sequencing, AML emerges as a complex, dynamic disease…these discoveries are revealing the biologic intricacies of AML, but how they inform clinical practice is unclear.”
The editorial noted that findings from the study would allow better identification of patients with very poor clinical outcomes after standard-of-care AML therapy, and facilitate their enrolment in trials of investigational agents early in their disease course.
It would also allow identification of patients who were candidates for mechanism-based clinical trials of agents targeting specific mutations or combinations of mutations.