Circulating Tumor DNA as Measurable Residual Disease in Aggressive B-Cell Lymphoma

Importance Achieving remission is the first step toward a cure in treating aggressive B-cell lymphomas. Radiographic imaging, such as fluorodeoxyglucose–positron emission tomography/computed tomography scans are the current standard to define remission at the end of therapy but lack specificity for lymphoma and cannot detect disease at the molecular level. Identifying measurable residual disease with ultrasensitive detection of circulating tumor DNA potentially offers the possibility of improving clinical outcomes. Observations Early studies of circulating tumor DNA in aggressive B-cell lymphomas showed a strong association with overall tumor burden, and baseline quantitative levels are associated with clinical outcomes after frontline chemotherapy. Next-generation sequencing methods that detect lymphoma-relevant genetic aberrations in circulating tumor DNA can also be used for noninvasive genotyping that strongly mirror tissue biopsies. Rapid changes in circulating tumor DNA dynamics after 1 or 2 cycles of frontline chemotherapy or within weeks of treatment with chimeric antigen receptor T-cell salvage therapy are also highly prognostic. Although serial monitoring of circulating tumor DNA can detect molecular relapse 3 to 6 months before clinical relapse, improved analytical thresholds are required to detect measurable residual disease at a singular point at the end of therapy. Modern advances in circulating tumor DNA methods now allow for the reliable detection of measurable residual disease, with an analytical detection threshold of 1 in 1 million cell-free DNA molecules. Conclusions and Relevance The results of this review suggest that modern ultrasensitive methods of detecting circulating tumor DNA may improve the current definition of remission in aggressive B-cell lymphomas. Incorporating circulating tumor DNA at the end of therapy assessment identifies patients who do not require surveillance monitoring and introduces paradigms of treating measurable residual disease within clinical trials. Practical barriers, including standardization of collection, availability, turnaround times, and cost, remain hurdles preventing widespread implementation into clinical practice.