Lymphoma is currently diagnosed using tissue biopsies and monitored during treatment with PET/CT scans. Although these methods are highly valuable, they may miss very small amounts of remaining disease or detect abnormalities that are not caused by cancer. In this thesis, we investigated whether a bloodplasma test could provide additional information about the presence and activity of lymphoma.

Tumor cells release small fragments of DNA into the bloodstream, known as circulating tumor DNA (ctDNA). By analysing ctDNA, lymphoma can be detected and monitored in a minimally invasive way. To improve the sensitivity of this approach, we developed a new analytical method called MNVista, which identifies highly specific DNA mutation patterns and is able to detect extremely small amounts of tumor DNA.

Using this technique, we studied several types of B-cell lymphoma. We demonstrated that ctDNA not only accurately reflects the genetic characteristics of the tumor but can also be more sensitive than current clinical methods for monitoring treatment response and detecting residual disease.

One of the most remarkable findings was that ctDNA could already be detected in blood samples collected years before lymphoma was diagnosed. In two-thirds of the patients studied, ctDNA was present before diagnosis, and in one case around 9 years earlier. Using our method, we showed that lymphoma can leave detectable molecular traces long before symptoms develop.

These findings contribute to the development of more accurate, less invasive, and more personalised approaches for the diagnosis and monitoring of lymphoma patients.

B-cell lymphomas represent a heterogeneous group of malignancies, with diffuse large B-cell lymphoma (DLBCL) being the most common and aggressive subtype. Aggressive B-cell lymphomas may arise de novo, through transformation from indolent lymphomas such as marginal zone lymphoma (MZL), or in specific clinical contexts such as post-transplant lymphoproliferative disorders (PTLD) and relapsed/refractory DLBCL (R/R DLBCL). This thesis investigates the biological mechanisms underlying lymphoma progression and transformation, and evaluates the utility of circulating tumor DNA (ctDNA) as a biomarker across various aggressive B-cell lymphoma subtypes.
Clinical and molecular analyses identified risk factors for MZL transformation and revealed that transformed MZL frequently acquires features of germinal center B cells. Multi-omics approaches showed only subtle genomic and transcriptomic changes during transformation. Across subtypes, ctDNA emerged as a promising non-invasive biomarker for diagnosis, prognosis, and disease monitoring. In PTLD, ctDNA profiling revealed recurrent genetic alterations and closely reflected tumor characteristics and guide treatment decisions.
In R/R DLBCL, a high ctDNA tumor fraction was associated with poor prognosis. Persistent ctDNA mutations or copy number alterations provided complementary diagnostic value when combined with PET-CT, supporting their integrated use in assessing disease progression and guiding treatment decisions.
Together, these findings underscore ctDNA as a clinically informative biomarker across aggressive B-cell lymphoma subtypes, with potential to improve risk stratification and therapeutic guidance.

Around 5000 people in the Netherlands are diagnosed with lymphoma each year. This thesis focused on two types of B-cell-derived lymphomas: marginal zone lymphoma and diffuse large B-cell lymphoma. We explored the clinical and biological factors underlying the development and transformation of lymphoma, as well as ways to improve its treatment.

We found that marginal zone lymphomas occurring in the salivary glands of patients with Sjögren’s syndrome are characterized by a small number of mutations. In addition, several factors associated with the development of transformed marginal zone lymphoma were identified: age above 60 years, prior systemic therapy before transformation, and the acquisition of germinal center B-cell features. These findings contribute to a better understanding of lymphoma transformation and may help to detect it earlier and treat it more effectively.

We also investigated the value of circulating tumor DNA (ctDNA) as a biomarker to evaluate treatment response in patients with diffuse large B-cell lymphoma. ctDNA showed to be a promising tool. However, further research is needed to improve its sensitivity, and its use should be standardized before it can be implemented in clinical practice.

Finally, we observed that adding the PD-L1 inhibitor atezolizumab to R-CHOP treatment improved survival outcomes in patients with diffuse large B-cell lymphoma.

Around 5000 people in the Netherlands are diagnosed with lymphoma each year. This thesis focused on two types of B-cell-derived lymphomas: marginal zone lymphoma and diffuse large B-cell lymphoma. We explored the clinical and biological factors underlying the development and transformation of lymphoma, as well as ways to improve its treatment.

We found that marginal zone lymphomas occurring in the salivary glands of patients with Sjögren’s syndrome are characterized by a small number of mutations. In addition, several factors associated with the development of transformed marginal zone lymphoma were identified: age above 60 years, prior systemic therapy before transformation, and the acquisition of germinal center B-cell features. These findings contribute to a better understanding of lymphoma transformation and may help to detect it earlier and treat it more effectively.

We also investigated the value of circulating tumor DNA (ctDNA) as a biomarker to evaluate treatment response in patients with diffuse large B-cell lymphoma. ctDNA showed to be a promising tool. However, further research is needed to improve its sensitivity, and its use should be standardized before it can be implemented in clinical practice.

Finally, we observed that adding the PD-L1 inhibitor atezolizumab to R-CHOP treatment improved survival outcomes in patients with diffuse large B-cell lymphoma.