Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group

Abstract

Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, <0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P<0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P<0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.

Pattern and prognostic value of FLT3‐ITD mutations in Chinese de novo adult acute myeloid leukemia

“…4 Subsequent retrospective studies of pediatric de novo AML patients showed worse prognosis with mutant/wt ratio higher than .4 or .51. 12,13,28 In this paper, we confirmed that patients with mutant/wt ratio of higher than .5…”

“…However, when ITD contains part of the intron, the partial intron would remain during DNA transcription (). Although some of study groups also used cDNA as a detection template, they did not claim to attain different results compared with genomic DNA template. For the first time, we observed this intron transcription rule during ITD duplication events.…”

Prognostic significance of flow‐cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP‐AML 2002/01 study protocol

“…Samples were analysed for the presence of t(8;21), inv(16), t(16;16), t(15;17), and t(11q23)/ KMT2A (previously termed MLL ) and the associated molecular transcripts, namely core‐binding factor (CBF)‐β ( CBFB ) abnormalities, PML ‐ RARA , and KMT2A rearrangements (Vardiman et al , ; Campo et al , ; Pigazzi et al , ). FLT3 ‐ITD was investigated in all patients but one (Manara et al , ).…”

“…Despite these observations, it has recently been shown that assessment of FLT3‐ ITD transcript levels after the first induction course is feasible and correlated with EFS in childhood AML (Manara et al , ).…”

Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia

“…Recent studies have reported similar incidence of ITD and activating TKD mutations in childhood AML ( 15 , 22 – 25 ). Numerous clinical trials have demonstrated inferior clinical outcomes in patients with FLT3–ITD AML ( 14 – 16 , 26 , 27 ).…”