In Follicular Lymphoma, Can MRD Predict Relapse or Define Cure?

Alexander M. Castellino, PhD

December 09, 2019

ORLANDO, Florida — A first-of-its-kind study has shown that for patients with follicular lymphoma (FL), measurements of minimal residual disease (MRD) can be used to predict risk for relapse.

Researchers at Georgetown University's Lombardi Comprehensive Cancer Center, in Washington, DC, showed that when MRD was at the 10-5 level of sensitivity (1 in 100,000 cells), the majority of the patients in their study who had been in remission for more than 2 years were free of disease.

"In patients with FL who were in remission for more than 2 years after their last therapy, monitoring for MRD status was likely to predict risk for relapse or the likelihood of a cure," lead author Maryam Sarraf Yazdy, MD, told Medscape Medical News.

"This disease has been considered incurable, but for some patients who have been disease free for at least 2 years after remission, our pilot study gives hope that calling the disease incurable may no longer be accurate," she added.

"FL is considered a treatable, but not curable, disorder. Nevertheless, many patients are without relapse for years or decades and die of other causes, leading to the concept that some patients may actually be cured," senior author Bruce Cheson, MD, Frank M. Ewing Foundation Chair in Hematology-Oncology, told Medscape Medical News.

Of five patients who were MRD positive, one experienced documented relapse. Of the 43 patients who were MRD negative, none had experienced relapse for more than 15 years, Cheson pointed out.

"This study is the first to examine patients in remission for more than 2 years using a sensitive next-generation assay for minimal residual disease," he added.

"This study is of importance in that patients with FL may no longer have to worry that death from their disease is inevitable," Cheson commented.

Approached for comment, Catherine S. M. Diefenbach, MD, director of the clinical lymphoma program at the Perlmutter Cancer Center at NYU Langone, New York City, commented that this was a single-institution study and that it will not change practice. "The follow-up is not long enough to confirm cure for the negative patients," she told Medscape Medical News. "It is an interesting finding that requires validation with longer follow-up and large independent datasets," she added.

Yazdy and Cheson agreed. "This is a pilot study in a small number of patients with a short follow-up time. We need to do more work, but this is an important first step," Yazdy said.

Laurie Sehn, MD, MPH, medical oncologist at the University of British Columbia in Vancouver, Canada, and chair of the Lymphoma Tumour Group as well as an associate editor of the journal Blood, also commented for Medscape Medical News.

"This is a fascinating study," she said. "Using a sophisticated NGS [next-generation sequencing], they were able to look for evidence of tumor burden in patients who have been in long-term remission."

However, she noted that every test has its limitations, and NGS-MRD may not be able to pick up all clonotypes associated with FL.

Study Details

Patients were recruited from the Lombardi Comprehensive Cancer Center clinic at Georgetown University. To be considered for the study, patients with FL had to have undergone treatment, achieved remission, and be free of disease progression for longer than 2 years since completing their last therapy.

Yazdy and colleagues used Adaptive Biotechnology's NGS-MRD assay first on original available biopsy specimens and then on peripheral blood to determine MRD status at sensitivity level of 10-5.

The NGS-MRD sequencing platform is specific for tracking the clonality of FL, including rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in Bcl1/2 IgH. NGD-MRD sequencing of the original biopsy sample established the clonality of FL. MRD status was then monitored by tracking the clonotype at enrollment in the study and every 6 months thereafter.

Sixty-eight patients were enrolled in the study; dominant clones were identified in 43 patients. Patients were excluded for several reasons, including insufficient sample for amplification, sample being polyclonal, or an inability to identify a dominant rearrangement.

The median age at diagnosis was 55 years, and 42% were women. Of the 43 patients, 30 patients had received one prior line of therapy, six patients had received two, six patients had received three, and one patient had received five.

Median follow-up since receiving the last line of therapy was 67 months (range: 25–183). "Median time in remission was more than 5 years, and some patients were in remission for as long as 15 years," Cheson noted.

For the 43 patients enrolled, the longest follow-up was 18 months; 34 patients had been followed for 6 months, and 25 for 1 year.

At enrollment, 38 of the 43 patients (88%) were MRD negative. By prior line of therapy:

  • 29 of 30 samples were negative following first-line treatment;

  • 3 of 6 samples were negative following second-line treatment;

  • 5 of 6 samples were negative following third-line treatment; and

  • 1 sample was negative following fifth-line treatment.

"We often think of a patient as refractory to treatment after five lines of therapy, but in our study, this patient continues to be in remission," Yazdy told Medscape Medical News.

"These data are the first to demonstrate that a high proportion of FL patients in a prolonged clinical remission have undetectable DNA by sensitive next-generation sequencing without evidence of clinical progression and are potentially cured of their disease," the researchers conclude.

The researchers are seeking to determine how the positive test results will correlate with eventual relapse.

"FL is lagging behind CLL [chronic lymphocytic leukemia]," Yazdy said. In CLL, MRD status is already being used in clinical trials to determine whether or not to further treat patients who have not shown documented clinical relapse, she explained.

Sehn noted that because CLL "floats in the blood," it has been possible to use far simpler technology, such as flow cytometry. "FL is a different disease from CLL and does not readily circulate in the blood. But with these newer technologies, we may be able to follow MRD in FL," she said.

"Moreover, this test [Adaptive's NGD-MRD] may be more sensitive than routine imaging to detect relapse and may antedate a positive scan. Whether early intervention at that point is of benefit would require a prospective clinical trial," Cheson told Medscape Medical News.

Yazdy receives honoraria from Bayer and is on its speakers bureau; has received research funding from Genentech; and has consulted for AbbVie and Octapharma. Cheson consults with TG Therapeutics, Genentech, Pharmacyclics, Celgene, AbbVie, and Acerta; is on the board of directors or on advisory committees for TG Therapeutics, Genentech, Pharmacyclics, Celgene, Symbios, AbbVie, AstraZeneca, and Morphosys; receives research funding from Epizyme, TG Therapeutics, Seattle Genetics, Bristol-Myers Squibb, Portola, Kite, Gilead, Genentech, Pharmacyclics, Celgene, AbbVie, Trillium, and Acerta; and owns equity in Symbios. Sehn consults with several pharmaceutics companies, including Verastem, Roche/Genentech, Morphosys, Takeda, Janssen, Lundbeck, Amgen, Teva, and AbbVie. Diefenbach has disclosed no relevant financial relationships.

American Society of Hematology (ASH) 2019: Abstract 2813. Presented December 8, 2019.

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