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Retrospective Analysis Shows ctDNA Superior to CT Scan for Predicting Relapse in Lymphoma Patients


NEW YORK (GenomeWeb) – A retrospective analysis of over 100 patients with diffuse large B-cell lymphoma demonstrated that a noninvasive sequencing-based assay to analyze circulating tumor DNA could predict relapse months in advance of detection via CT scan.

The results, which were published this week in Lancet Oncology and need to be validated in a larger cohort and in prospective trials, nonetheless demonstrate the clinical utility of a more sensitive screen for detecting minimal residual disease.

"The clinical value is clear," Jian Han, a faculty investigator with HudsonAlpha Institute of Biotechnology and CEO of immune sequencing firm iRepertoire who was not involved with the study, told GenomeWeb. "I think the clinical study design, the methods, and results are all very good," he added.

Sequenta, the immune sequencing firm that spearheaded the current study in Lancet Oncology, had previously published findings that MRD detection is clinically relevant for acute lymphoid leukemia, chronic lymphoid leukemia, and multiple myeloma, and had been offering a clinical laboratory developed test for MRD in those malignancies, ClonoSight. It had also presented preliminary data of its work in diffuse large B-cell lymphoma.

However, the recent study "is the first in which we've been able to connect the appearance of MRD in blood to correlation with relapse" in DBCL, Tom Willis, formerly CEO of Sequenta but now senior vice president and general manager of diagnostics at Adaptive Biotechnologies, told GenomeWeb.

Adaptive Biotechnologies acquired Sequenta in January, but Sequenta conducted this study prior to the acquisition as part of a collaboration with the National Cancer Institute.

The study had two aims. The first was to compare the ctDNA assay to CT scanning for its ability to monitor residual disease that could lead to relapse. The second tested the ability of the ctDNA assay to predict the likelihood that a patient would relapse within five years after receiving chemotherapy treatment.

In addition, while Sequenta's previous studies have evaluated MRD in blood-based cancers, this study looked at a solid tumor. "What we tested in this study was not circulating white blood cells," Willis said, "but DNA that is found in the cell-free compartment of blood."

The assay is based on the LymphoSight technology developed at Sequenta but now rebranded under Adaptive Biotechnologies' ClonoSeq name. Essentially, the assay uses proprietary multiplex PCR to amplify immune cell receptor rearrangements in T cells and B cells from blood and tissue.

The team retrospectively analyzed 126 patients enrolled in a clinical trial of three different first line protocols: etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) with or without rituximab. All three protocols included the prospective collection of research serum samples before treatment, before each chemotherapy cycle, at the end of treatment, and at every staging assessment.

The protocols also included assessment with whole-body CT scans before treatment; after cycles two or four; after the last cycle of treatment; and after treatment surveillance assessment every three months for the first year, every four months for the second year, every six months for the third year, and once a year for the next two years.

First, the researchers evaluated biopsy samples for all the patients to identify patient-specific clonotypes on which to base the LymphoSight assay. For patients without biopsies, they evaluated pre-treatment serum samples.

Han said that an alternative approach would be to evaluate larger groups of patients to identify groups of clonotypes shared among patients, but not controls, that could serve as public signatures of disease. Such an approach would not require an initial biopsy sample to establish a "calibration reference," he said.

The Sequenta team evaluated patients for two different purposes: to compare the assay to CT scans for its ability to monitor patients for MRD and relapse, and to test whether running the assay after two cycles of chemotherapy could essentially declare a patient cured or not.

The researchers serially evaluated 107 patients to monitor for disease recurrence, 17 of whom eventually relapsed. The patients had all achieved complete remission following treatment. On average, the LymphoSight assay detected ctDNA 3.5 months before the CT scan detected disease. In addition, the assay had a positive predictive value of 88.2 percent and a negative predictive value of 97.8 percent.

"What we show is not only are we able to do this in the blood, obviating the need for radiation exposure in scans, but the test allows us to catch earlier phases of relapse," Willis said.

For the second portion of the study, they evaluated 108 patients, 24 of whom eventually progressed. The goal of this portion was not to monitor patients but to predict whether, after treatment, the patient was likely to relapse within five years. For patients without detectable ctDNA, 80.2 percent did not have disease progression within five years, compared to just 41.7 percent of patients that did have detectable levels of ctDNA. For this type of test, ctDNA had a positive predictive value of 62.5 percent and a negative predictive value of 79.8 percent.

Willis said that for determining whether a patient is "cured," the ctDNA assay alone would not be sufficient, but "it is clearly a risk factor to have MRD remaining after two cycles of chemotherapy." He said that this assay could be used in conjunction with other determinants of risk, like PET scans, to better help identify patients that are failing.

He added that the team has now started validating the results and is working on prospective studies.

Once the assay is validated for clinical use in monitoring MRD, he said it could be used to help physicians make treatment decisions. Currently, the standard intervention for patients that relapse is a stem cell transplant. "That's a pretty intensive, invasive regimen," Willis said, so it is unlikely that physicians will immediately start using this test to make decisions about whether or not to give a patient a stem cell transplant, even though the test demonstrated a high PPV. However, Willis said, there are many new therapeutics in the pipeline for lymphomas, and "it's more tractable to imagine intervening with those agents that have better safety profiles."