title: Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing.
abstract: Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.
authors.affiliation: Division of Oncology, Department of Medicine, Department of Bioengineering.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0002-6382-4651
authors.initials: DM
authors.lastname: Kurtz
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Michael R
authors.identifier: http://orcid.org/0000-0001-6309-9472
authors.initials: MR
authors.lastname: Green
authors.affiliation: Department of Radiation Oncology, and.
authors.forename: Scott V
authors.initials: SV
authors.lastname: Bratman
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Florian
authors.initials: F
authors.lastname: Scherer
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Chih Long
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA;
authors.forename: Christian A
authors.initials: CA
authors.lastname: Kunder
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Glover
authors.affiliation: Princess Alexandra Hospital, Brisbane, QLD, Australia;
authors.forename: Colm
authors.initials: C
authors.lastname: Keane
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kihira
authors.affiliation: Department of Surgery, Stanford University, Stanford, CA;
authors.forename: Brendan
authors.initials: B
authors.lastname: Visser
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC, Australia;
authors.forename: Jason
authors.initials: J
authors.lastname: Callahan
authors.affiliation: Sequenta Inc., South San Francisco, CA;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kong
authors.affiliation: Sequenta Inc., South San Francisco, CA;
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Corbelli
authors.affiliation: Division of Blood and Bone Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA;
authors.forename: David
authors.initials: D
authors.lastname: Miklos
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.affiliation: Division of Oncology, Department of Medicine.
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC, Australia;
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: Department of Haematology, Westmead Hospital, Sydney, NSW, Australia;
authors.forename: Mark
authors.initials: M
authors.lastname: Hertzberg
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ohgami
authors.affiliation: Princess Alexandra Hospital, Brisbane, QLD, Australia; Blood Cancer Research, Diamantina Institute, Translational Research Institute, University of Queensland, Queensland, QLD, Australia;
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
authors.affiliation: Department of Radiation Oncology, and Institute for Stem Cell Biology and Regenerative Medicine, and Stanford Cancer Institute, Stanford University, Stanford, CA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Diehn
authors.affiliation: Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University, Stanford, CA.
authors.forename: Ash A
authors.identifier: http://orcid.org/0000-0002-5153-5625
authors.initials: AA
authors.lastname: Alizadeh
mesh_terms: D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007136:Immunoglobulins / Q000097:blood / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011446:Prospective Studies
chemical_list: D007136:Immunoglobulins; D007770:L-Lactate Dehydrogenase