Benchmarking standard-of-care and emerging genomic approaches to enhance diagnosis in pediatric acute lymphoblastic
José Vicente Gil1, Gayane Avetisyan2, Alberto Miralles2
1Accredited Research Group on Hematology. Instituto de Investigación Sanitaria la Fe, Valencia, Spain. jose_gil@iislafe.es.
Background:
The molecular characterisation of pediatric acute lymphoblastic leukemia (pALL) is essential for accurate diagnosis and risk stratification. However, standard-of-care (SoC) methods have limited sensitivity and resolution.
Methods:
This study evaluates the clinical utility of emerging genomic technologies-including optical genome mapping (OGM), digital multiplex ligation-dependent probe amplification (dMLPA), RNA sequencing (RNA-seq), and targeted next-generation sequencing (t-NGS)-in the largest cohort of pALL patients analysed to date, with 60 cases using OGM.
Results:
Considering clinically relevant alterations identified with at least two different methods, OGM as a standalone test demonstrated superior resolution, detecting chromosomal gains and losses (51.7% vs. 35%, p = 0.0973) and gene fusions (56.7% vs. 30%, p = 0.0057), while resolving 15% of non-informative cases. Combining dMLPA and RNA-seq was the most effective approach, achieving precise classification of complex subtypes and uniquely identifying IGH rearrangements undetected by other techniques. OGM identified clinically relevant alterations in 90% of cases, and the dMLPA-RNAseq combination reached 95%, compared to 46.7% with SoC techniques.
Conclusions:
Integrating these technologies into diagnostic workflows overcomes SoC limitations. OGM and the dMLPA-RNAseq combination emerge as front-line strategies, addressing pALL heterogeneity, streamlining molecular testing, and informing treatment decisions to improve outcomes.
