Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing

Abstract

Key Points• DLBCL can be detected in the blood by immunoglobulin high-throughput sequencing (Ig-HTS) with high specificity.• Although DLBCL can be detected in leukocytes or plasma by Ig-HTS, plasma has greater sensitivity and more accurately reflects disease.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 5 173). 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 5 .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P 5 .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 5 .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission. (Blood. 2015;125(24):3679-3687)

Liquid Biopsy in Liquid Tumors

“…The 3-years follow-up period showed that total level of ccfDNA at diagnosis, had prognosis value in terms of DFS, since it was shorter in the group of patients that had a ccfDNA concentration over 46 ng/ml [58]. [62]. So far, including this paper, clonotypic sequences identified in ctDNA and CTCs, has to be compared to the sequences found in fresh or frozen tissue samples from the same patient.…”

Personalized Medicine in Lymphoma: Tailoring Treatment According to Minimal Residual Disease

“…Therefore, ctDNA analysis might overcome some limitations of the current MRD approach in NHL. First, it can avoid falsenegative MRD results: as ctDNA gives a better representation of tumor masses (lymph nodes) rather than leukemic disease, ctDNA might help in localized relapses, not detectable either in PB or in BM; in addition, it may extend the application of MRD to non-or less leukemic disorders, such as DLBCL (102,103), primary central nervous system lymphoma (PCNSL) (104), stage I FL or WM (105); finally, it is likely to decrease or avoid invasive diagnostic procedures (BM biopsy or lumbar puncture) to monitor MRD.…”

Multimodality Technologies in the Assessment of Hematolymphoid Neoplasms

“…Currently, most clinical laboratories take a targeted gene panel approach instead of performing whole-exome or whole-genome sequencing to identify clonal markers to aid in diagnosis, evaluation of prognosis, choice of molecular targets, and treatment monitoring. [101][102][103][104][105][106] For example, at Emory we are validating and will soon implement a targeted gene panel for myeloid neoplasms. This laboratory-developed NGS test protocol is based on a well-validated research use-only kit that targets 54 genes, including all exons of 15 genes (BCOR, BCORL1, CDKN2A, CEBPA, CUX1, DNMT3A, ETV6, EZH2, IKZF1, KDM6A, PHF6, RAD21, RUNX1, STAG2, and ZRSR2) and hot spot exons/regions of 39 genes (ABL1, ASXL1, ATRX, BRAF, CALR, CBL, CBLB, CBLC, CSF3R, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, JAK2, JAK3, KIT, KMT2A/MLL, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PTEN, PTPN11, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, TET2, TP53, U2AF1, and WT1).…”