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A test tube rack is filled with vials of blood.

Blood test predicts chances of lymphoma relapse after therapy

Stanford Medicine Scientists have devised a blood test to predict some cancer relapses after patients have already been treated.

Tools that track circulating tumor DNA, or ctDNA -- teeny fragments of genetic material released into the blood by dying cancer cells -- are giving doctors a clearer picture of which cancer patients respond to treatment and how quickly they do so.

Now, Stanford Medicine researchers have shown that such tracking is highly useful in gauging the success of CAR-T cell therapy, one of oncology's most advanced weapons, when treating a blood cancer called large B-cell lymphoma.

ctDNA monitoring is a non-invasive simple blood test, also called a liquid biopsy, from which a patient's ctDNA, if any exists, is collected and analyzed. The method has become a valuable way to keep tabs on cancers such as lymphomas and leukemias, in which small numbers of cancerous cells that may remain after treatment -- called minimal residual disease, or MRD -- can increase a patient's risk of relapse. 

"We've known for a long time that the DNA of the immune receptor on B and T cells can rearrange itself and basically give us a barcode," said David Miklos, MD, PhD, a professor of medicine. That barcode helps scientists distinguish malignant cells from normal ones. The advent of highly advanced DNA sequencing technologies then allowed Miklos and others "to figure out how to read these barcodes, so we could better assess MRD in patients." 

Tracking treatment results

To understand whether ctDNA tracking might hint at relapse, Miklos, who heads Stanford Medicine's Blood and Marrow Transplantation and Cellular Therapy division, Matthew Frank MD, PhD assistant professor of medicine, and their labs enrolled 72 patients with large B-cell lymphoma, who had received CAR-T cell therapy, which involves genetically engineering certain immune cells to find and eliminate specific cancer cells. They found that weekly blood tests could predict how a patient would fare after treatment.

"We saw a very clean separation of patients who go on to respond well, versus those whose disease progresses," Miklos said. Among 33 responders, 70% already had undetectable ctDNA by the second week of treatment, and they did not relapse. Meanwhile, even four weeks after treatment, residual disease stubbornly lingered in 31 patients who, although they briefly responded to the therapy, eventually relapsed. The remaining eight patients didn't complete the study.

The researchers published their findings recently in the Journal of Clinical Oncology.

Imaging techniques like PET and CT have regularly been used to monitor CAR-T cell therapy response and detect early relapse. But these scans are not always definitive or entirely reliable. Routinely including ctDNA monitoring could increase precision, Miklos said.

"It's difficult to explain to patients that after lying on the table for an hour for scans, they end up with test results that look like abstract art and are difficult to interpret," he said. "Instead, imagine being able to tell them, 'You have no detectable ctDNA, the number is zero.' It's infinitely more accessible information."

A decade-long odyssey

For Miklos, this paper is the culmination of a decade of research to advance blood cancer care at Stanford by leveraging advanced DNA sequencing technologies to suss out rogue cancer cells remaining after treatment.

In 2009, Miklos and Andrew Fire, PhD, sat at a faculty lunch and talked science instead of listening to a fundraising speech. Their conversation led to a task for Scott Boyd, MD, PhD, then a research fellow in Fire's lab: Demonstrate the power of a new approach, called next-generation sequencing, in tracking cancer.

With help from two other colleagues, Ronald Davis, PhD, and James Zehnder, MD, Boyd, Miklos, and Fire fine-tuned the technology's earliest version for this purpose. Then, as the field of genomic sequencing evolved, they began establishing the usefulness of newer next-generation sequencing in leukemia.

"Since 2006, we'd been banking blood samples from every patient in the Blood and Marrow Transplantation and Cellular Therapy program," Miklos said. "So we had plenty to work with." The researchers validated this other method and it became the first ctDNA test to be authorized by the Food and Drug Administration for tracking residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia and multiple myeloma.   

The technology continued to evolve, eventually allowing for easier sequencing of ctDNA from plasma -- the liquid that surrounds cells in whole blood. The Stanford Medicine crew used this strategy in a pilot study of large B-cell lymphoma in 2018, which led to the recent 72-patient trial. The data will now be used to seek FDA clearance for expanding ctDNA testing to track this blood cancer after CAR-T cell therapy has been administered, Miklos said.  

Because lymphomas are more prevalent than leukemias, Miklos hopes the use of ctDNA monitoring becomes standard, in time.

"It spares patients unnecessary tissue biopsies, while still providing specific, quantitative assessments of tumor burden," he said. "CAR-T therapy is powerful and can rapidly influence the disease trajectory. We need a test that keeps up with this impact, or lack thereof."

Photo the National Institutes of Health

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