Purpose of Review
The use of circulating tumor DNA (ctDNA) for the purposes of diagnosis, prognosis, assessment of treatment response, and monitoring for relapse is a new and developing field in lymphoma. This review aims to summarize many of the most recent advances in ctDNA applications.
Recent studies have demonstrated the use of ctDNA assessment across many lymphoma subtypes including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, and T-cell lymphoma. In addition, many novel applications of ctDNA assessment have been described such as the development of new prognostic models, investigation of clonal evolution and heterogeneity, early assessment of treatment response, and prediction of response to targeted therapy as a form of personalized medicine.
The use of ctDNA has been shown to be feasible across many lymphoma subtypes and has shown significant promise for several new applications. Additional studies will be needed to validate these findings prior to routine use in clinical practice.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
Han HS, Escalon MP, Hsiao B, Serafini A, Lossos IS. High incidence of false-positive PET scans in patients with aggressive non-Hodgkin’s lymphoma treated with rituximab-containing regimens. Ann Oncol. 2009;20(2):309–18. https://doi.org/10.1093/annonc/mdn629.
El-Galaly T, Prakash V, Christiansen I, Madsen J, Johansen P, Boegsted M, et al. Efficacy of routine surveillance with positron emission tomography/computed tomography in aggressive non-Hodgkin lymphoma in complete remission: status in a single center. Leuk Lymphoma. 2011;52(4):597–603. https://doi.org/10.3109/10428194.2010.547642.
Moskowitz CH, Schoder H, Teruya-Feldstein J, Sima C, Iasonos A, Portlock CS, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in advanced-stage diffuse large B-cell lymphoma. J Clin Oncol. 2010;28(11):1896–903. https://doi.org/10.1200/JCO.2009.26.5942.
Ansell SM, Armitage JO. Positron emission tomographic scans in lymphoma: convention and controversy. Mayo Clin Proc. 2012;87(6):571–80. https://doi.org/10.1016/j.mayocp.2012.03.006.
Berrington de Gonzalez A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, et al. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med. 2009;169(22):2071–7. https://doi.org/10.1001/archinternmed.2009.440.
Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277–84. https://doi.org/10.1056/NEJMra072149.
Huntington SF, Svoboda J, Doshi JA. Cost-effectiveness analysis of routine surveillance imaging of patients with diffuse large B-cell lymphoma in first remission. J Clin Oncol. 2015;33(13):1467–74. https://doi.org/10.1200/JCO.2014.58.5729.
• Herrera AF, Armand P. Minimal residual disease assessment in lymphoma: methods and applications. J Clin Oncol. 2017;35(34):3877–87. https://doi.org/10.1200/JCO.2017.74.5281. This article provides a thorough review of prior applications of circulating tumor DNA and serves as a background for this review.
• Roschewski M, Dunleavy K, Pittaluga S, Moorhead M, Pepin F, Kong K, et al. Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol. 2015;16(5):541–9. https://doi.org/10.1016/S1470-2045(15)70106-3. This study applied IgNGS to analyze ctDNA in patients with DLBCL and demonstrated the ability to identify patients at risk of recurrence prior to clinical evidence of disease.
Kurtz DM, Jin M, Soo J, Scherer F, Craig A, Chabon JJ, et al. Circulating tumor DNA is a reliable measure of tumor burden at diagnosis of diffuse large B cell lymphoma: an international reproducibility study. ASH 59th Annual Meeting; Atlanta, GA Blood; 2017. p. 310.
Schroers-Martin JG, Kurtz DM, Soo J, Jin M, Scherer F, Craig A, et al. Determinants of circulating tumor DNA levels across lymphoma histologic subtypes. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 4018.
Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016;128(2):185–94. https://doi.org/10.1182/blood-2016-02-699520.
Kurtz DM, Green MR, Bratman SV, Scherer F, Liu CL, Kunder CA, et al. Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood. 2015;125(24):3679–87. https://doi.org/10.1182/blood-2015-03-635169.
Armand P, Oki Y, Neuberg DS, Faham M, Cummings C, Klinger M, et al. Detection of circulating tumour DNA in patients with aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2013;163(1):123–6. https://doi.org/10.1111/bjh.12439.
Hartert K, Tadros S, Bouska A, Moore D, Pak C, Heavican T, et al. DNA copy number gains of TCF4 (E2-2) are associated with poor outcome in diffuse large B-cell lymphoma. ASH 58th Annual Meeting; San Diego, CA: Blood; 2016. p. 2686.
van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia. 2003;17(6):1013–34. https://doi.org/10.1038/sj.leu.2402922.
Drandi D, Kubiczkova-Besse L, Ferrero S, Dani N, Passera R, Mantoan B, et al. Minimal residual disease detection by droplet digital PCR in multiple myeloma, mantle cell lymphoma, and follicular lymphoma: a comparison with real-time PCR. J Mol Diagn. 2015;17(6):652–60. https://doi.org/10.1016/j.jmoldx.2015.05.007.
Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54. https://doi.org/10.1038/nm.3519.
• Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AF, Esfahani MS, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8(364):364ra155. https://doi.org/10.1126/scitranslmed.aai8545. This study demonstrates the application of CAPP-Seq analysis of ctDNA in patients with DLBCL.
Hohaus S, Giachelia M, Massini G, Mansueto G, Vannata B, Bozzoli V, et al. Cell-free circulating DNA in Hodgkin’s and non-Hodgkin’s lymphomas. Ann Oncol. 2009;20(8):1408–13. https://doi.org/10.1093/annonc/mdp006.
Kurtz DM, Scherer F, Jin M, Soo J, Craig A, Esfahani MS, et al. Development of a dynamic model for personalized risk assessment in large B-cell lymphoma. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 826.
Suehara Y, Sakata-Yanagimoto M, Hattori K, Nanmoku T, Itoh T, Kaji D, et al. Liquid biopsy for the identification of intravascular large B-cell lymphoma. Haematologica. 2018;103:e241–4. https://doi.org/10.3324/haematol.2017.178830.
Quesada AE, Desai P, Tang G, Lin P, Westin JR, Seegmiller AC, et al. MYC copy number aberrancies predict a worse prognosis in patients with diffuse large B-cell lymphoma. ASH 58th Annual Meeting; San Diego, CA: Blood; 2016. p. 154.
Jin M, Kurtz DM, Esfahani MS, Soo J, Craig A, Scherer F, et al. Clinical impact of somatic copy number alterations in circulating tumor DNA from diverse lymphoma subtypes. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 2747.
Pott C, Knecht H, Herzog A, Genuardi E, Unterhalt M, Mantoan B, et al. Standardized IGH-based next-generation sequencing for MRD detection in follicular lymphoma. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 1491.
Soo J, Scherer F, Kurtz DM, Schroers-Martin JG, Jin M, Craig A, et al. Reproducibility of m7-FLIPI risk scores in follicular lymphoma using tumor biopsies and blood specimens. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 1466.
Delfau-Larue MH, van der Gucht A, Dupuis J, Jais JP, Nel I, Beldi-Ferchiou A, et al. Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma. Blood Adv. 2018;2(7):807–16. https://doi.org/10.1182/bloodadvances.2017015164.
Sarkozy C, Seymour JF, Ferme C, Caballero D, Ghesquieres H, Leppa S, et al. Rituximab maintenance obviates the poor prognosis associated with circulating lymphoma cells in patients with follicular lymphoma. Blood. 2014;123(17):2740–2. https://doi.org/10.1182/blood-2014-02-553693.
Sarkozy C, Huet S, Carlton VE, Fabiani B, Delmer A, Jardin F, et al. The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma. Oncotarget. 2017;8(5):8765–74. https://doi.org/10.18632/oncotarget.14448.
Daigle S, McDonald AA, Morschhauser F, Salles G, Ribrag V, McKay P, et al. Discovery of candidate predictors of response to tazemetostat in diffuse large B-cell lymphoma and follicular lymphoma using NGS technology on ctDNA samples collected pre-treatment. ASH 59th Annual Meeting; Atlanta, GA: Blood; 2017. p. 4013.
Oki Y, Neelapu SS, Fanale M, Kwak LW, Fayad L, Rodriguez MA, et al. Detection of classical Hodgkin lymphoma specific sequence in peripheral blood using a next-generation sequencing approach. Br J Haematol. 2015;169(5):689–93. https://doi.org/10.1111/bjh.13349.
Herrera AF, Kim HT, Kong KA, Faham M, Sun H, Sohani AR, et al. Next-generation sequencing-based detection of circulating tumour DNA after allogeneic stem cell transplantation for lymphoma. Br J Haematol. 2016;175(5):841–50. https://doi.org/10.1111/bjh.14311.
•• Spina V, Bruscaggin A, Cuccaro A, Martini M, Di Trani M, Forestieri G, et al. Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood. 2018;131(22):2413–25. https://doi.org/10.1182/blood-2017-11-812073. While tumor genotyping has been historically difficult in Hodgkin lymphoma, this study demonstrates the feasibility of identifying ctDNA by using the CAPP-Seq sequencing method.
Kurtz DM, Scherer F, Newman AM, Craig AFM, Khodadoust MS, Lovejoy AF, et al. Prediction of therapeutic outcomes in DLBCL from circulating tumor DNA dynamics. J Clin Oncol. 2016;34(15_suppl):7511. https://doi.org/10.1200/JCO.2016.34.15_suppl.7511.
Melani C, Pittaluga S, Yee L, Lucas A, Shovlin M, Jacob A, et al. Next-generation sequencing based monitoring of circulating-tumor DNA in untreated peripheral T-cell lymphoma. ASH 59th Annual Meeting; Atlanta, GA Blood; 2017. p. 2728.
Sakata-Yanagimoto M, Nakamoto-Matsubara R, Komori D, Nguyen TB, Hattori K, Nanmoku T, et al. Detection of the circulating tumor DNAs in angioimmunoblastic T-cell lymphoma. Ann Hematol. 2017;96(9):1471–5. https://doi.org/10.1007/s00277-017-3038-2.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma
About this article
Cite this article
Darrah, J.M., Herrera, A.F. Updates on Circulating Tumor DNA Assessment in Lymphoma. Curr Hematol Malig Rep 13, 348–355 (2018). https://doi.org/10.1007/s11899-018-0468-4
- Circulating tumor DNA
- Minimal residual disease
- Non-Hodgkin lymphoma
- Hodgkin lymphoma