The FDA granted marketing authorization to the first-ever next-generation sequencing assay for detecting minimal residual disease in patients with acute lymphoblastic leukemia or multiple myeloma.

The first assay to use next-generation sequencing (NGS) to test for residual cancer cells post-treatment in patients with blood cancer has obtained marketing clearance in the United States. The FDA granted the authorization at the end of September for clonoSEQ, from Adaptive Biotechnologies of Seattle, WA, to detect and monitor disease burden in patients with multiple myeloma and acute lymphoblastic leukemia.

Currently, most clinicians look for trace amounts of cancer in patients’ bone marrow following treatment, either through cytomorphology under the microscope, which can accurately pick up cancer cells lurking above a frequency of one in 20, or through more sensitive analytic techniques. These typically involve flow cytometry, which makes use of molecular markers found on the surface of tumor cells to detect malignant plasma cells at levels as low as one in 10,000 or one in 100,000 bone marrow cells, depending on the technology.

ClonoSEQ offers greater sensitivity. By sequencing across immunoglobulin receptor gene sequences, as well as frequently translocated regions of the genome, the NGS platform has been shown to pick up cancer down to one cell in a million—and it can probably do even better. “The sensitivity of this assay is only limited by the amount of DNA that is analyzed,” says Lanny Kirsch, MD, senior vice president of translational medicine at Adaptive.

Measuring so-called minimal residual disease (MRD) at such low levels offers real prognostic value, says Nikhil Munshi, MD, of Dana-Farber Cancer Institute in Boston, MA, because even a few remaining cancer cells post-treatment can lead to disease recurrence.

Munshi, together with colleagues in France, reported in late September that MRD negativity as calculated by NGS was a stronger predictor of long-term survival among patients with myeloma receiving combination therapy than MRD negativity as determined by flow cytometry. That's because nearly half of the patients who tested negative with flow cytometry later tested positive with the more sensitive NGS assay, Munshi explains, and “getting deeper MRD negativity provides better outcomes,” he says.

More important perhaps than the added sensitivity is the broad availability of a standardized molecular MRD test that the clearance of clonoSEQ brings, says Christopher Hourigan, MD, PhD, of the National Heart, Lung, and Blood Institute in Bethesda, MD. Although many clinics today offer flow cytometry assays, these tests generally require considerable expertise to analyze correctly, and they've rarely been benchmarked externally. Now, says Hourigan, “no matter where you are, you potentially have access to world-class MRD assessment that's highly reproducible.”

That access could help inform future clinical trials and drug approvals. Many physicians are now pushing the FDA to accept MRD negativity as a surrogate endpoint for progression-free survival to expedite drug approvals. At the same time, the agency is looking at MRD positivity as an actionable indicator to guide treatment decisions. Earlier this year, the FDA for the first time expanded the approval of a leukemia drug—the CD19/CD3 bispecific antibody blinatumomab (Blincyto; Amgen)—to include patients who are technically in remission but still have measurable residual disease.

Thanks to MRD testing, “there's this opportunity to treat patients who you know are going to have a bad outcome,” says Gregory Friberg, MD, head of global development at Amgen, which partnered with Adaptive on clonoSEQ's development. “This is a test that allows physicians to have a road map so they can make decisions knowing what's coming ahead of them.” –Elie Dolgin