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Published on: September 18, 2013
Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group
E Manara1, G Basso2, M Zampini1
1Istituto di Ricerca Pediatrica - Città della Speranza, Padova, Italy.
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.
Insights
High FLT3-internal-tandem duplication allelic ratio (ITD-AR) and persistent minimal residual disease (MRD) in childhood acute myeloid leukemia (AML) correlate with worse outcomes. These molecular markers impact event-free survival and suggest novel therapeutic strategies.
Area of Science:
- Pediatric Hematology/Oncology
- Molecular Diagnostics
- Cancer Genomics
Background:
- Recurrent molecular markers are standard for acute myeloid leukemia (AML) risk assessment at diagnosis.
- The role of post-induction monitoring of these markers, particularly FLT3-internal-tandem duplication (ITD) allelic ratio (AR) and minimal residual disease (MRD), remains debated in childhood AML.
- FLT3-ITD mutations are common in AML and associated with distinct clinical behaviors.
Purpose of the Study:
- To evaluate the prognostic significance of FLT3-ITD allelic ratio (AR) and minimal residual disease (MRD) in pediatric acute myeloid leukemia (AML).
- To investigate the biological impact of high ITD-AR and persistent MRD on gene expression profiles.
- To explore the potential of these markers for guiding clinical management and identifying therapeutic targets.
Main Methods:
- Retrospective analysis of 494 children with de novo acute myeloid leukemia (AML).
- Screening for FLT3-ITD mutations and assessment of allelic ratio (AR) at diagnosis.
- Measurement of minimal residual disease (MRD) using patient-specific real-time PCR after the first induction course.
- Correlation of molecular markers with gene expression profiles, including CyclinA1.
Main Results:
- FLT3-ITD mutations were identified in 54 children; 51% had high ITD-AR, associated with significantly worse event-free survival (EFS).
- High levels of MRD post-induction were detected in 41% of patients, also correlating with inferior EFS.
- High ITD-AR and persistent MRD were linked to distinct gene expression profiles involving methylation and acetylation pathways.
- Elevated CyclinA1 expression was independently associated with unfavorable EFS.
Conclusions:
- FLT3-ITD allelic ratio (AR) at diagnosis and molecular minimal residual disease (MRD) after induction are crucial prognostic factors in childhood AML.
- Distinct transcriptional profiles in patients with high ITD-AR or persistent MRD highlight the role of epigenetic and oncogenic dysregulation.
- These findings support incorporating ITD-AR and MRD monitoring into clinical management strategies for FLT3-ITD positive AML, suggesting a need for novel therapeutic approaches.
