Real world molecular characterisation and clonal evolution of acute myeloid leukaemia reveals therapeutic opportunities and challenges

Abstract

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with poor prognosis. Increasing understanding of the molecular mechanisms driving clonal proliferation has resulted in advancements in classification and available therapeutic targets. Fms-related tyrosine kinase 3 (FLT3) mutations are prognostically important and offer options for targeted inhibition, however they are not stable and can emerge or disappear at relapse. Our aim was to review diagnostic testing of consecutive cases of newly diagnosed and relapsed AML reported across Queensland in comparison to available literature. We conducted a retrospective review of 1531 samples from 1231 patients to identify patterns of molecular testing and AML subtypes in our cohort. Outcomes included World Health Organization (WHO) classification, European LeukaemiaNet (ELN) risk category and rates of missed FLT3 mutation testing. Patients aged <60 years had significantly more favourable risk AML (48% vs 25%, p<0.01), with favourable risk chromosomal translocations [t(8;21) and inv(16)] being more common. Thirteen patients (1%) did not have FLT3 mutation testing at diagnosis, with 103 relapse samples (39%) not being tested. Eighteen patients (10%) had FLT3 mutations lost at relapse, with five patients (3%) developing new FLT3 mutations at relapse. This study identifies the subtypes and risk stratification of a large cohort of AML patients over an extended period. The relatively high rate of absent FLT3 mutation testing at relapse as well as FLT3 loss or gain highlights the potential missed opportunities for salvage treatment strategies.

Keywords: FLT3; Myeloid; genetics; leukaemia; molecular.