MRD-Adapted Low-Dose Radiation Therapy During Frontline Chemoimmunotherapy for Diffuse Large B-Cell Lymphoma

Feasibility of MRD-Adapted Mid-Cycle Low-Dose Radiation Combined With Frontline R-Chemoimmunotherapy in Diffuse Large B-Cell Lymphoma (MRD XRT)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Radiation: Low-Dose Radiation Therapy (LDRT); Other: Standard Frontline Chemoimmunotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Krishna vamsi Gottipati, MS; Phone Number: (402) 5593518; Email: krgottipati@unmc.edu
• Study Contact Backup: Name: IIT Office Clinical Trails Office; Phone Number: (402) 5590963; Email: IITOFFICE@unmc.edu

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Fred & Pamela Buffet Cancer Center
      • Contact: Snegha Ananth, MBBS; Phone Number: (402)559-3848; Email: sananth@unmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm- A: MRD-Detectable with Protocol-Directed LDRT Consideration; Patients with detectable circulating tumor DNA minimal residual disease (ctDNA MRD) after cycle 2 of frontline chemoimmunotherapy and residual PET-avid disease may receive low-dose radiation therapy (LDRT) to PET-positive sites in addition to standard systemic therapy.	Radiation: Low-Dose Radiation Therapy (LDRT); Low-dose radiation therapy delivered to residual PET-avid disease sites identified after interim assessment with PET imaging and MRD testing.; Other: Standard Frontline Chemoimmunotherapy; Standard-of-care frontline chemoimmunotherapy regimens for diffuse large B-cell lymphoma, including R-CHOP, Pola-R-CHP, DA-EPOCH-R, R-CEOP, or related regimens as determined by the treating physician.
Active Comparator: Arm- B: MRD-Undetectable Standard Therapy; Patients with undetectable ctDNA MRD after cycle 2 of frontline chemoimmunotherapy continue standard systemic therapy without the addition of radiation therapy.	Other: Standard Frontline Chemoimmunotherapy; Standard-of-care frontline chemoimmunotherapy regimens for diffuse large B-cell lymphoma, including R-CHOP, Pola-R-CHP, DA-EPOCH-R, R-CEOP, or related regimens as determined by the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of Real-Time MRD-Guided Treatment Strategy	The proportion of enrolled patients who successfully complete protocol-specified ctDNA MRD testing after 2 cycles of frontline chemoimmunotherapy. Among patients with detectable MRD after cycle 2, the proportion who successfully receive protocol-defined low-dose radiation therapy (LDRT).	From initiation of study treatment through completion of frontline therapy (approximately 6 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR), Including Complete Response (CR) and Partial Response (PR) Rates	Proportion of patients achieving complete response (CR) or overall response (CR+PR) based on PET-CT and imaging criteria	From initiation of study treatment through completion of frontline therapy (approximately 6 months)
Progression-Free Survival (PFS)	Time from initiation of frontline therapy until disease progression or death from any cause. will be analyzed using Kaplan-Meier curves	From initiation of study treatment until disease progression or death, assessed up to 24 months
Overall Survival (OS)	Time from initiation of frontline therapy until death from any cause. will be analyzed using Kaplan-Meier curves	From initiation of study treatment until death from any cause, assessed up to 24 months
Impact of Low-Dose Radiation Therapy on Delivery of Systemic Chemoimmunotherapy	Assessment of the impact of mid-cycle low dose radiation therapy on the delivery of planned systemic chemoimmunotherapy.	From initiation of study treatment through completion of frontline Chemoimmunotherapy (approximately 6 months)
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	Patient-reported quality of life assessed using the EORTC QLQ-C30 questionnaire.	From baseline through end of treatment, assessed up to 24 months

Collaborators and Investigators

• Sponsor: University of Nebraska
• Investigators: Principal Investigator: Snegha Ananth, MBBS, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Estimated): June 12, 2026
• Primary Completion (Estimated): November 12, 2030
• Study Completion (Estimated): November 12, 2032

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: April 3, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: ctDNA; Minimal Residual Disease; PET-CT; Low-Dose Radiation Therapy; MRD-guided therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Neoplastic Processes; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasm, Residual; Lymphoma, Large B-Cell, Diffuse; Therapeutics; Radiotherapy
• Other Study ID Numbers: MRD XRT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No