Remission Assessment by Circulating Tumor DNA in Large B-Cell Lymphoma

Author(s): Mark Roschewski, MD¹; David M. Kurtz, MD, PhD^2,3,4; Jason R. Westin, MD⁵; Ryan C. Lynch, MD⁶; Ajay K. Gopal, MD⁶; Stefan K. Alig, MD, PhD^2,7; Brian J. Sworder, MD, PhD⁸; Hua-Jay J. Cherng, MD⁹; Christian Kuffer, PhD¹⁰; Derek Blair, PhD¹⁰; Krystal Brown, PhD⁴; Jordan S. Goldstein, MD²; Andre Schultz, PhD⁴; Sandra Close, PhD⁴; Jacob J. Chabon, PhD⁴; Maximilian Diehn, MD, PhD^3,11,12; Wyndham H. Wilson, MD, PhD¹; Ash A. Alizadeh, MD, PhD^2,3,11;

Source: DOI: 10.1200/JCO-25-01534

Dr. Maen Hussein's Thoughts

Minimal residual disease (MRD) testing after two cycles of therapy and at the end of treatment predicted 2-year progression-free survival (PFS) (96% in MRD-negative patients vs 67% in MRD-positive patients). MRD status was more predictive of treatment outcomes than radiographic imaging in this patient population.

PURPOSE

Large B-cell lymphomas (LBCLs) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal residual disease (MRD) may improve the determination of remission.

METHODS

We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL. Tumor-specific phased variants were identified from pretreatment samples and monitored landmark time points. Serial plasma specimens were blindly analyzed for detectable ctDNA as MRD. MRD status was compared with conventional response criteria for prognosis of progression-free survival (PFS).

RESULTS

We studied ctDNA-MRD in 137 patients by monitoring 409 plasma specimens over time. Detectable ctDNA rates decreased during therapy with 55% and 78% of patients achieving undetectable ctDNA after two cycles and the end of therapy, respectively. After a median follow-up of 37 months, the 2-year PFS for patients with detectable versus undetectable ctDNA after two cycles was 67% versus 96% (P = .0025; hazard ratio [HR], 6.9) and after therapy was 29% versus 97% (P < .0001; HR, 28.7), respectively. Ninety-two (94%) patients with undetectable ctDNA the end of therapy remained alive without progression, while 19 (68%) patients with detectable ctDNA progressed or died. MRD status the end of therapy had greater prognostic utility than conventional lymphoma response criteria using positron emission tomography (PET) scans (HR, 3.6 for positive PET and 28.3 for detectable ctDNA).

CONCLUSION

Ultrasensitive ctDNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined definition of remission with ctDNA-MRD may improve clinical and psychological outcomes for patients with LBCL.

Author Affiliations

¹Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD; ²Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; ³Stanford Cancer Institute, Stanford University, Stanford, CA; ⁴Foresight Diagnostics, Boulder, CO; ⁵Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; ⁶Division of Hematology Oncology, Department of Medicine, University of Washington School of Medicine Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; ⁷Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany; ⁸Division of Hematology Oncology, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA; ⁹Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY; ¹⁰MorphoSys, a Novartis Company, Planegg, Germany; ¹¹Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA; ¹²Department of Radiation Oncology, Stanford University, Stanford, CA

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