Molecular MRD Monitoring Is Feasible in the Majority of Children with AML and Is Highly Predictive of Outcome: Results from the International MyeChild01 Study

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.1393-1393
• Main Authors: Jovanovic, Jelena, Potter, Nicola, Kanda, Anju, Schwab, Claire, Jackson, Aimee E, Dillon, Richard, Lawson, Anna, Runglall, Manohursingh, Vyas, Paresh, Virgo, Paul, Shenton, Geoff, Heaney, Nicholas, James, Beki, Patrick, Katharine, Amrolia, Persis J, Dalle, Jean-Hugues, Michel, Gerard, Moore, Andrew S., Lapillonne, Hélène, Preudhomme, Claude, Leverger, Guy, Smith, Owen P, Baruchel, Andre, Bertrand, Yves, Petit, Arnaud, Wheatley, Keith, Kearns, Pamela R., Harrison, Christine J., Gibson, Brenda
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-125257

Introduction Most children with acute myeloid leukaemia (AML) harbour fusion genes which are ideal targets for molecular minimal residual disease (MRD) monitoring. However, evidence of prognostic significance is currently lacking and consequently most current paediatric AML treatment protocols rely on flow cytometric (FCM) evaluation to allocate treatment. Molecular MRD techniques provide significantly greater sensitivity and specificity and could allow more accurate outcome prediction, and consequently more personalised therapy, which is highly relevant in a disease where treatment related mortality, morbidity and relapse remain significant. Methods Between June 2016 and February 2019, MyeChild01 enrolled 170 children aged 0-18y with newly diagnosed AML who were randomly assigned to induction therapy with liposomal daunorubicin or mitoxantrone with cytarabine with or without gemtuzumab ozogamicin. Consolidation treatment was determined by karyotype, mutational profile and MRD status. Comprehensive centralised diagnostic assessment consisted of: •Karyotype and fluorescence in-situ hybridisation (FISH) using a custom panel of probes to detect paediatric AML-associated gene fusions.•PCR based screening for mutations in FLT3, NPM1 and CEPBA.•Targeted capture of known fusion loci and paired end sequencing.•RNA-seq using the Illumina TruSight fusion panel. Where a fusion gene was identified, RT-qPCR assays were designed and optimised for each patient. NPM1 mutation was also used as an MRD target if present. Paired PB and BM samples were requested after each cycle of treatment. Patients could have sequential monitoring after completion of therapy although this was not mandated. For this analysis, patients with core-binding factor (CBF) leukaemias i.e. inv(16)(p13q22) or t(8;21)(q22q22) with transcript levels above previously defined thresholds (Yin et al, 2012) were considered MRD positive. For all other targets, amplification in at least 2/3 replicates at