Updates on Circulating Tumor DNA Assessment in Lymphoma

Current Hematologic Malignancy Reports volume 13, pages348–355(2018)Cite this article

Abstract

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 Findings

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.

Summary

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.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. 1.

    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.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    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.

    Article  PubMed  Google Scholar 

  3. 3.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    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.

    Article  PubMed  Google Scholar 

  6. 6.

    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.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    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.

    Article  PubMed  Google Scholar 

  8. 8.

    • 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.

    Article  PubMed  Google Scholar 

  9. 9.

    • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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.

  11. 11.

    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.

  12. 12.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    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.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    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.

  16. 16.

    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.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    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.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    • 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    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.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    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.

  22. 22.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    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.

  24. 24.

    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.

  25. 25.

    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.

  26. 26.

    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.

  27. 27.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    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.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    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.

  31. 31.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    •• 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.

    Article  PubMed  Google Scholar 

  34. 34.

    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.

    Article  Google Scholar 

  35. 35.

    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.

  36. 36.

    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.

    CAS  Article  PubMed  Google Scholar 

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Author information

Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA

    Justin M. Darrah & Alex F. Herrera

  2. Department of Hematology and Oncology, Harbor-UCLA Medical Center, Torrance, CA, USA

    Justin M. Darrah

Authors
  1. Justin M. Darrah
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  2. Alex F. Herrera
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Correspondence to Alex F. Herrera.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma

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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

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Keywords

  • Circulating tumor DNA
  • Minimal residual disease
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma