Blood test may predict response to CAR T-cell therapy
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Patients with diffuse large B-cell lymphoma who achieved a durable response to axicabtagene ciloleucel showed evidence of lower circulating tumor DNA levels before and after treatment, according to results of a prospective study.
Patients who achieved minimal residual disease (MRD) negativity by day 28 after axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) infusion — with no evidence of circulating tumor DNA (ctDNA) — had significantly longer PFS and OS than those who were MRD-positive.
Nearly half of all patients who receive axicabtagene ciloleucel — a CD19-directed chimeric antigen receptor T-cell therapy — experience disease relapse, according to David B. Miklos, MD, PhD, clinical director of cancer cell therapy and professor in the department of medicine at Stanford University. The ability to identify which patients are more likely to progress after CAR T-cell therapy would be valuable for guiding treatment, he added.
Circulating tumor DNA measurement of blood plasma uses so-called “next-generation sequencing” technology that has been employed for years to quantify MRD status of cell-based blood cancers, such as acute lymphoblastic leukemia and multiple myeloma. However, it has not yet been cleared by the FDA for use with lymphocytic malignancies, including large B-cell lymphoma.
“This is a commercially available diagnostic that already has been validated for over 8 years for measuring leukemia and could now be applied to supplement or replace PET scans in the next year,” Miklos told Healio. “Our experience tells me that we should be doing this test at day 28 and follow-up with PET CT scans if the ctDNA becomes detectable to locate the malignancy.”
The multicenter study was led by Frederick L. Locke, MD, of Moffitt Cancer Center, Saurabh Dahiya, MD, of University of Maryland School of Medicine and Matthew J. Frank, MD, PhD, of Stanford, who approached the assay’s manufacturer — Adaptive Biotechnologies — looking to expand its use into lymphoma.
Researchers enrolled 72 patients (median age, 62 years; range, 19-79; 60% men) with relapsed or refractory large B-cell lymphoma who underwent a median three(range, 1-7) previous lines of therapy. Sixty percent of patients had three or more lines of previous therapy.
The primary analysis included 64 patients, 33 of whom achieved durable response to axicabtagene ciloleucel and 31 of whom experienced disease progression after infusion.
The investigators used highly sensitive next-generation sequence-based assays that identify lymphoma-specific variable, diversity and joining gene segments (VDJ) clonotype sequences in a patients’ blood plasma. Samples were collected before apheresis, before lymphodepletion, and at several intervals after infusion, including 28 days, 3 months and 1 year.
Ninety-six percent of patients had adequate DNA samples to complete the assays.
Results showed patients who achieved durable response to axicabtagene ciloleucel had lower prelymphodepletion levels than patients who experienced disease progression (8 LG/mL [range, 0-1,327] vs. 581 LG/mL [range, 0-17,903]; P < .0001).
Twenty-three (70%) of the patients who achieved durable response had no detectable ctDNA by 3 months after infusion, compared with only four (14%) of the patients who experienced disease progression (P < .0001).
Prelymphodepletion ctDNA concentrations appeared predictive of durable response to therapy.
Researchers reported median OS of 19 months for patients with concentrations between 100 LG/mL and 1,000 LG/mL, compared with 7.4 months for patients with concentrations above 1,000 LG/mL.
Patients who did not have detectable ctDNA at 28-day evaluation achieved significantly better survival outcomes than those who had detectable ctDNA (median PFS, not reached vs. 19 months; P = .0080; median OS, not reached vs. 3 months; P < .0001).
MRD status predicted disease progression among 85% of patients who experienced partial response or stable disease by day 28 after infusion. Patients who were MRD-positive had a positive predictive value of 88% for disease relapse.
All patients who achieved a durable response to therapy at 3-month follow-up also had undetectable ctDNA.
Researchers are using ctDNA “to evaluate the new therapies and advances in the field of CAR-T with ctDNA,” Miklos said.
These same three research groups are evaluating three commercially available CAR T-cell therapies for large B-cell lymphoma, in addition to patients with mantle cell lymphoma and follicular lymphoma.
“In my treatment of patients going forward, having this measurement will identify who needs to be followed closely for disease progression,” Miklos told Healio. “In the future, I believe we'll be performing ctDNA blood testing until we see MRD progression and then we'll do a PET scan to see where the tumor is, as opposed to the opposite, where we do PET scans with low specificity that expose people to radiation.”
For more information:
David B. Miklos, MD, PhD, can be reached at Stanford University, Division of Blood and Marrow Transplantation and Cellular Therapy, 269 W. Campus Drive, CCSR 2205, Stanford, CA 94305; email: dmiklos@stanford.edu.
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