The Hodson Group and collaborators have developed a customised blood test that can predict, more accurately than standard scans, whether treatment has successfully eradicated diffuse large B-cell lymphoma (DLBCL).
DLBCL is the most common form of aggressive non-Hodgkin lymphoma, and is typically treated with a combination of chemotherapy and the antibody treatment rituximab over several cycles. While many patients are cured, around 30–40% either fail to respond at all, or suffer a relapse.
A major challenge is distinguishing, at the end of treatment, those patients who are truly cured from those who still have tiny amounts of lymphoma left behind and are at risk of relapse. Doctors usually rely on PET-CT scans to assess response to treatment. However, residual lymphoma is often present at such low levels that it cannot be detected by these scans. In addition, some scans can also be difficult to interpret because inflammation or healing tissue can mimic the appearance of active lymphoma. This uncertainty often leads to anxious ‘watch and wait’, repeat imaging, and sometimes invasive biopsies to confirm whether lymphoma is still present.
Researchers led by Dr Dan Hodson and Dr Joanna Krupka at the Cambridge Stem Cell Institute developed a special blood test, or ‘liquid biopsy,’ that looks for evidence of residual lymphoma. The test detects circulating tumour DNA (ctDNA) – small fragments of DNA shed by lymphoma cells into the bloodstream. If ctDNA is still detectable at the end of treatment, it can indicate residual lymphoma.
The challenge was to be able to confidently identify ctDNA at extremely low levels, perhaps only one in every million molecules tested.
While standard ctDNA tests look for individual genetic mutations associated with the lymphoma to identify ctDNA, this can be challenging at very low levels because rare mutations can be indistinguishable from background ‘sequencing noise.’ To overcome this, the new test identifies and tracks pairs (or clusters) of lymphoma-specific genetic changes that occur together on the same DNA fragment. This pattern of mutations is extremely unlikely to occur by chance, allowing high confidence detection of very low-level disease.
The new test was assessed in the DIRECT study, which enrolled 184 patients from Addenbrooke’s Hospital and five other NHS hospitals. Blood samples were collected before, during and after treatment, and patients were followed over time. After two years, the difference in patient outcomes was striking: almost all of the patients with undetectable ctDNA were cured of their lymphoma, whereas those with detectable ctDNA had a 58% chance of their lymphoma returning.
Importantly, the blood test gave a more accurate prediction of relapse risk than a PET-CT scan alone. The researchers suggest this could help clinicians identify patients who are effectively cured, potentially reducing the need for additional scans or invasive biopsies, while also flagging those at high risk of relapse who may benefit from closer monitoring or future clinical trials of potential new treatments.
Dr Hodson said, “This technology offers huge benefits to patients by allowing us to accurately measure their response to treatment. Ultimately this may allow us to personalise the intensity and duration of chemotherapy to the needs of an individual patient."
The new blood test will be tested further in a UK-wide trial later this year. In the RADICAL (UK Risk Adapted Immunochemotherapy to Cure Aggressive Lymphoma) trial higher-risk patients will be prioritised for experimental immunotherapy in addition to their standard of care treatment.