Diagnostic Genomic Analysis is Prognostic in AYA ALL Patients Treated on a MRD-Stratified Pediatric Protocol

• This is one of the first AYA ALL cohorts (aged 15-39) treated on uniform intensive chemotherapy, to report a detailed genomic description.

• Adverse genomic risk lesions correlated with high MRD at end of induction; combining these risk factors identified a group with very high risk of relapse.

Over the last decade, next generation sequencing has enabled classification of multiple new recurrent genomic drivers of acute lymphoblastic leukemia (ALL). The aim of this study was to describe the genomic drivers of ALL in an adolescent and young adult (AYA) cohort (ALL06 target age 15-39 years, recruited age 16.6-39 years), treated uniformly on a pediatric inspired protocol (the Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study). ALL06 assessed the safety and efficacy of adapting a pediatric chemotherapy protocol in older patients. Genomic risk classification of B- and T-ALL patients enrolled to the study was based on the use of multiple assays: mRNA-Sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), immunophenotyping and cytogenetics. Using this approach, 36/40 (90%) B- and 13/17 (76.5%) T-ALL patients were classified according to genomic risk. A strong correlation existed between adverse genomic risk and minimal residual disease (MRD) at the end of consolidation, translating to inferior overall and relapse free survival. Patients with adverse risk genomics who achieved negative MRD status had improved responses compared to those with persistent MRD. Patients with standard risk genomics had excellent responses regardless of MRD status. This is the first report of the impact of genomics in an individual cohort of AYA patients treated on a single protocol. These data argue strongly for incorporation of a genomic risk classification into future ALL treatment paradigms at the time of diagnosis, and also for the rigorous assessment of risk assignments in a group of patients who are not children and not older adults. ACTRN12611000814976 https://anzctr.org.au/