Liquid biopsy‐based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results

Aims Liquid biopsy (LBx)‐based next‐generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue‐based NGS is infeasible. Methods and Results We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non‐Hodgkin lymphoma (NHL), 43 plasma‐cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B‐cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) ( P = 0.001). LBx detected characteristic alterations across HNs, including in TP53 , KRAS , MYD88 , and BTK in NHLs; TP53 , KRAS , NRAS , and BRAF in PCNs; IGH in DLBCL; TP53 , ATM , and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53 , SF3B1 , DNMT3A , TET2 , and ASXL1 in MDS; JAK2 in MPNs; and FLT3 , IDH2 , and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. Conclusion These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy‐resistant clones that may be undetectable in site‐specific tissue biopsies.