This prospective feasibility study evaluates a minimal residual disease (MRD)-adapted treatment strategy in patients with diffuse large B-cell lymphoma (DLBCL) receiving frontline chemoimmunotherapy. Circulating tumor DNA (ctDNA)-based MRD testing and interim positron emission tomography (PET) imaging after two cycles of therapy are used to guide treatment decisions. Patients with detectable MRD may receive low-dose radiation therapy (LDRT) to residual PET-avid disease sites in addition to standard systemic therapy, while patients with undetectable MRD continue standard frontline chemoimmunotherapy. The study aims to assess the feasibility and safety of integrating MRD-guided radiation therapy into frontline treatment of DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is commonly treated with frontline chemoimmunotherapy regimens such as R-CHOP or related combinations. Early response assessment using positron emission tomography (PET) imaging provides prognostic information but may not fully capture minimal residual disease. Circulating tumor DNA (ctDNA)-based MRD assays allow for sensitive detection of molecular residual disease during treatment.

This study evaluates an MRD-adapted treatment strategy that integrates interim PET imaging and ctDNA MRD testing during frontline therapy for DLBCL. Patients receiving standard-of-care chemoimmunotherapy undergo MRD testing and PET imaging after cycle 2 of treatment. Patients with detectable MRD may receive low-dose radiation therapy (LDRT) directed at residual PET-avid disease sites, while patients with undetectable MRD continue standard therapy without radiation.

Inclusion Criteria:

1. Adults ≥19 years of age
2. Biopsy-proven newly diagnosed DLBCL, transformed from indolent lymphoma, Follicular lymphoma grade 3B, post-transplant lymphoproliferative disorder, or any other subtypes of Large B-cell lymphoma under WHO-HAEM5 classification who are eligible and plan to receive 6 cycles of R-chemoimmunotherapy. Note: patients may receive up to one cycle of R-chemoimmunotherapy prior to enrollment.
3. Planned to receive 6 cycles of frontline R-chemoimmunotherapy for diseases mentioned in criterion 2
4. Presence of measurable disease on imaging, nodal lesion >1.5cm or extra-nodal lesion >1 cm prior to initiation of R-chemoimmunotherapy
5. Availability of sufficient and viable baseline FFPE tumor tissue to allow development of a personalized MRD assay

Exclusion Criteria:

1. Limited stage (Ann Arbor stage I-II) DLBCL, requiring less than 6 cycles of R-chemoimmunotherapy
2. Primary or secondary CNS lymphoma
3. Subject has exceeded maximum lifelong cumulative doses of radiation therapy or is unsafe for radiation therapy as determined by the investigator and/or radiation oncologist
4. Pregnant and lactating patients
5. Has received two or more cycles of R-chemoimmunotherapy relating to this disease