应用全基因组测序（WGS）对急性髓系白血病（AML）进行快速临床诊断分类和风险分层

Waiting for test results is a primary cause of delay in the diagnostic classification and risk stratification of patients with AML. With conventional cytogenetic, FISH, and targeted NGS approaches taking a median turnaround time (TAT) of 7-15 days, there is a significant unmet need to deliver these results faster using a more comprehensive testing platform. We have very recently developed, and demonstrated Analytical Validity (AV), Clinical Validity (CV) and Clinical Utility (CU) in accordance with MolDX L38047, for a rapid Whole Genome Sequencing (WGS) approach for AML (DEX Z-Code Z04C0). Importantly, this test (termed ALTseq) was specifically designed to deliver clinically actionable genomic results that encompass those from cytogenetics, FISH, and targeted NGS in under 48 hours (TAT mean = 33 hours). This accelerated turnaround time was enabled by streamlining laboratory workflows, enhancing bioinformatic pipelines, and expediting variant approval for reporting. The assay captures single nucleotide variants, indels (including FLT3-ITDs and KMT2A-PTDs), and 155 distinct structural variants including KMT2A rearrangements, and genome-wide copy number alterations. Additionally, we have recently developed a method to measure monosomal and complex karyotypes from WGS sequencing data. By deploying WGS we are able to gain insight in all genes in the human exome, with the curated clinical reporting covering all current key AML-related aberrations. These include mutations in NPM1, TP53, RUNX1, IDH1/2, FLT3, MEN1, rearrangements involving KMT2A, MECOM, NUP98, and canonical translocations such as PML::RARA, RUNX1::RUNX1T1, and BCR::ABL1. ALTseq has a limit of detection of 9%, 8%, 10%, and 7% for SNVs, indels, CNAs, and SVs, respectively, with sensitivities of 96%, 96.4%, 95.7%, and 100%, respectively. The positive predictive value for all variant types is ≥99.5%. Since implementation, ALTseq has been used in 66 AML cases, achieving a mean TAT of 33 hours from sample receipt to report delivery. Recent evidence of clinical utility includes the incorporation of Mylotarg in induction therapy based on the identification of CBFB::MYH11 fusion gene, and the inclusion of Revumenib for a KMT2A rearrangement that could not be identified with standard breakaway FISH probes. In summary, we will describe the clinical deployment of a high-throughput, fast-turnaround WGS platform for AML, capable of delivering comprehensive genomic profiling in <48 hours from sample receipt to clinical reporting enabling earlier, more informed treatment decisions.