Early prediction of outcomes in DLBCL clinical trials through MRD testing
When assessing the risk of relapse in patients treated for diffuse large B-cell lymphoma, combining imaging data with tests that detect tumor DNA can result in an earlier and more accurate prognosis.
The presence or absence of minimal residual disease (MRD) can provide a valuable prognostic marker in many cancers. In general, when MRD is found at detectable levels post-treatment, the risk of relapse is significantly higher than for patients with negative MRD test results. In several blood cancers, new technologies can identify tumor cells at levels as low as a single cell in a million sampled cells. In lymphoid cancers, where tumor cells aren’t routinely found in the blood, next-generation sequencing (NGS) can be used to measure circulating tumor DNA (ctDNA) and provide a more accurate prognosis.
The usefulness of MRD testing now extends to diffuse large B-cell lymphoma (DLBCL). This is the most common type of non-Hodgkin’s lymphoma, with more than 25,000 new cases diagnosed each year in the U.S. alone.1 The disease occurs when B cells of the adaptive immune system undergo a malignant transformation and proliferate. These tumor cells accumulate in the lymph nodes where they originate and can eventually spread throughout the lymphatic system and beyond. A standard frontline therapy is R-CHOP—a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone—which is often effective in early-stage disease. However, for roughly 40% of patients with DLBCL, refractory disease or relapse occurs, and second-line treatments are needed.2
While DLBCL is a lymphoid cancer, the tumor cells often stay in the lymph nodes or collect in organs such as the liver and spleen. Imaging technologies such as positron emission tomography (PET) and computed tomography (CT) are standard tools for diagnosing the disease and assessing a patient’s response to therapy.
Adding clarity to imaging results
Imaging provides crucial information for determining what stage of disease a patient has progressed to and where the cancer has spread. However, the technology is known to capture false-positive results, particularly in post-treatment evaluations. Imaging can pick up artifacts that resemble tumor sites but are not malignant, including inflamed or necrotic tissue left behind once an actual tumor is gone. In many cases, a biopsy is needed to extract tissue for genetic sequencing or a pathology report, which may reveal that the suspected lesion is benign.
These false positives can be clarified by using a liquid biopsy that measures ctDNA. Individual B cells have unique receptors with unique genetic sequences, and these DNA signatures remain stable even in malignant cells and their subclones. These molecular barcodes can be used to identify lymphoma-related DNA in the blood, revealing the presence of MRD. NGS MRD provides an orthogonal information stream that complements imaging to give a fuller picture of disease burden at a given point in time.
A 2021 study by Frank et al. underscored the prognostic value of adding MRD testing to PET/CT imaging in patients undergoing therapy for relapsed or refractory DLBCL.3 The study followed 72 patients who had a median of three lines of prior therapy (range 1-7). These patients received B cell-depleting chemotherapy followed by infusion of axicabtagene ciloleucel (axi-cel), a CAR-T cell therapy. The results showed that patients with higher pre-treatment levels of ctDNA had significantly poorer post-treatment outcomes in terms of progression-free survival and overall survival.3
MRD testing was also more accurate in predicting disease progression at 28 days post-treatment in a subset of patients with a partial treatment response or stable disease. In this subset, just one of 10 who tested MRD-negative went on to suffer a relapse, while 15 of 17 patients who tested MRD-positive relapsed (P=.0001). In the broader study population, all patients with a durable treatment response tested MRD-negative within three months or sooner after CAR T therapy. In patients who relapsed, 29 of 30 had a positive MRD test before or concurrently with the detection of relapse via imaging.3
In another study by Phillips et al., that evaluated the bispecific antibody epcoritamab in 157 patients with DLBCL and related non-Hodgkin’s lymphomas, MRD negativity was also strongly predictive of durable, progression-free survival.4
Highly sensitive and specific MRD testing
Both the axi-cel and epcoritamab studies employed a ctDNA assay from Adaptive Biotechnologies, a leader in the development of MRD testing technology for lymphoid malignancies. The DLBCL assay uses a tumor-informed approach and works by identifying the dominant lymphoma clonotype in each patient and selecting a unique sequence of receptor DNA from that clonotype to serve as an MRD marker. In running the assay, Adaptive sequences the patient’s entire B-cell repertoire and provides a precise count of all tumor-related molecules in the sample.
The assay is highly sensitive and specific, with a limit of detection of 1.9 and a limit of blank, or background, of 0. In practical terms, this means that the assay can detect one or two molecules of lymphoma-related DNA in up to 10 mililiters of plasma, with little to no risk of a false positive. The test can’t completely rule out the risk of relapse, because the cancer might still be present in the body at levels so low that a single sample may not be MRD-positive. However, a negative result indicates a very low risk of relapse.
MRD testing has several other key advantages that make it a valuable addition to imaging for DLBCL. In the Frank et al. study, researchers took MRD measurements at 10 time points over the course of one year to better understand MRD dynamics.3 Imaging can’t be conducted with such frequency, due to radiation exposure limits, as well as cost and reimbursement constraints. Given the desire to monitor DLBCL more closely, liquid biopsies open the door to more frequent post-treatment assessments to improve long-term surveillance.
In clinical practice, Adaptive’s DLBCL assay, clonoSEQ, is validated under the Clinical Laboratory Improvement Amendments (CLIA) and is eligible for Medicare reimbursement. In the clinical development arena, more than 30 clinical trials are currently employing NGS MRD as an endpoint to study DLBCL and other B-cell lymphomas.
To learn more about MRD testing in DLBCL, contact email@example.com.
1Susanibar‐Adaniya S, Barta SK. 2021 update on diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and management. American Journal of Hematology. 2021;96(5):617-629. doi: 10.1002/ajh.26151
2Sarkozy C, Sehn LH. Management of relapsed/refractory DLBCL. Best Practice & Research Clinical Haematology. 2018;31(3):209-216. doi: 10.1016/j.beha.2018.07.014
3Frank MJ, et al. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: Results of a prospective multi-institutional trial. Journal of Clinical Oncology. 2021;39(27):3034-3043. doi: 10.1200/JCO.21.00377
4Phillips T, et al. Epcoritamab monotherapy provides deep and durable responses including minimal residual disease (MRD) negativity: Novel subgroup analyses in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Blood. 2022;140(Supplement 1):9443-9445. doi: 10.1182/blood-2022-158245