Cancer Center Amsterdam

In a substantial proportion of patients with large B‑cell lymphoma (LBCL), an aggressive form of lymphoma, standard immunochemotherapy is insufficient. Approximately 4 in 10 patients experience disease relapse or die from their disease. Clinicians therefore need early, reliable tools to identify patients in whom first‑line therapy is unlikely to be effective, so that treatment can be adapted in time. Until now, such a molecular risk tool was lacking. Researchers at Cancer Center Amsterdam have now developed a promising assay that addresses this gap.

Cell‑free DNA as an early risk marker

In a new study involving 192 patients, Steven Wang, Parisa Mapar and their team worked closely across several preclinical laboratories and the clinic to analyse small fragments of tumour-derived cell-free DNA (cfDNA) in the blood using shallow whole-genome sequencing (sWGS).

This approach detects DNA alterations in the bloodstream that may indicate the presence of cancer. Traditionally, sWGS is less sensitive than deep whole-genome sequencing, which offers high sensitivity but is also costly and complex to implement in routine clinical practice. By applying AI-based analysis, the new test retains high sensitivity while becoming more affordable and easier to implement in clinical settings.

The samples came from patients participating in 2 national (HOVON) studies and were stored in the CCA’s Liquid Biopsy Center, a large biobank containing blood and other body fluids from cancer patients treated at our clinics. An AI‑based tool integrates three classes of cfDNA features—genomic aberrations, fragment length and composition, and terminal sequence motifs—into a single composite metric: the ACT score. 

ACT score: clear prognostic separation

Patients with a positive ACT score after 1 cycle of immunochemotherapy had markedly inferior outcomes compared with ACT‑negative patients. At two years, 71% of ACT‑positive patients had experienced disease progression or relapse, versus 17% in the ACT‑negative group. Overall survival followed the same pattern: 47% of ACT‑positive patients were alive at two years, compared with 93% of ACT‑negative patients

Substantial benefits for patients

For patients, the assay is minimally burdensome: it requires only a single blood draw after the first cycle of immunochemotherapy, without the need for additional tumour biopsies or baseline plasma sampling. The ACT score can support early treatment decisions, helping clinicians to identify patients who may benefit from treatment intensification or modification, and potentially sparing low‑risk patients from unnecessary escalation.

Ready for clinical implementation

Because the method uses open‑source software and shallow whole‑genome sequencing, it is technically and logistically suitable for integration into routine practice. The ACT score thus represents a promising new approach to early molecular risk stratification, enabling more individualized care for patients with aggressive B‑cell lymphomas.