Circulating Tumor DNA to Monitor Therapy for Aggressive B-Cell Lymphomas

  • Mary Kwok
  • S. Peter Wu
  • Clifton Mo
  • Thomas Summers
  • Mark Roschewski
Lymphoma (JW Sweetenham, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lymphoma

Opinion statement

The goal of therapy for aggressive B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is to achieve cure. Combination chemotherapy with rituximab cures most patients, but those with recurrent disease have a poor prognosis. Medical imaging scans such as computed tomography (CT) and positron emission tomography (PET) are the principal methods to assess response and monitor for disease relapse after therapy but are fundamentally limited by risks of radiation, cost, and a lack of tumor specificity. Novel sequencing-based DNA monitoring methods are capable of quantifying small amounts of circulating tumor DNA (ctDNA) before, during, and after therapy for mature B-cell lymphomas. Detection of ctDNA encoding clonal rearranged variable-diversity-joining (VDJ) receptor gene sequences has demonstrated improved analytical sensitivity and enhanced tumor specificity compared to imaging scans in DLBCL, offering broad clinical applicability across a range of aggressive B-cell lymphomas. Molecular monitoring of ctDNA has vaulted into the spotlight as a promising non-invasive tool with immediate clinical impact on monitoring for recurrence after therapy prior to clinical symptoms. As these clinical observations are validated, ctDNA monitoring needs to be investigated as a tool for response-adapted therapy and as a marker of minimal residual disease upon completion of therapy in aggressive B-cell lymphomas. Molecular monitoring of ctDNA holds tremendous promise that may ultimately transform our ability to monitor disease in aggressive B-cell lymphomas.


Diffuse large B-cell lymphoma Circulating tumor DNA Minimal residual disease MRD Next-generation sequencing VDJ Liquid biopsy Surveillance imaging Response-adapted 

References and Recommended Reading

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

  1. 1.
    Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010;116(12):2040–5.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, et al. A cancer and leukemia group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012;97(5):758–65.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, et al. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med. 2013;369(20):1915–25.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rizzieri DA, Johnson JL, Byrd JC, Lozanski G, Blum KA, Powell BL, et al. Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and leukemia group B study 10 002. Br J Haematol. 2014;165(1):102–11.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dunleavy K, Pittaluga S, Maeda LS, Advani R, Chen CC, Hessler J, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408–16.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(27):4184–90.CrossRefGoogle Scholar
  7. 7.
    Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat Rev Clin Oncol. 2014;11(1):12–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Roschewski M, Dunleavy K, Wilson WH. Moving beyond rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for diffuse large B-cell lymphoma. Leuk Lymphoma. 2014;55(11):2428–37.CrossRefPubMedGoogle Scholar
  9. 9.
    Weeks JC, Yeap BY, Canellos GP, Shipp MA. Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission. J Clin Oncol Off J Am Soc Clin Oncol. 1991;9(7):1196–203.Google Scholar
  10. 10•.
    Thompson CA, Ghesquieres H, Maurer MJ, Cerhan JR, Biron P, Ansell SM, et al. Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(31):3506–12 .A large retrospective study that demonstrated routine use of post-therapy surveillance imaging with CT scans was unable to improve clinical outcomes in patients with diffuse large B-cell lymphomaGoogle Scholar
  11. 11.
    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 Off J Am Soc Clin Oncol. 2015;33(13):1467–74.CrossRefGoogle Scholar
  12. 12.
    Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A, et al. The ASH choosing wisely(R) campaign: five hematologic tests and treatments to question. Blood. 2013;122(24):3879–83.CrossRefPubMedGoogle Scholar
  13. 13•.
    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 Off J Am Soc Clin Oncol. 2010;28(11):1896–903 .An important study that demonstrated that many positive PET scans performed during therapy do not have active tumor tissue when biopsies are performed.Google Scholar
  14. 14.
    Cheah CY, Hofman MS, Dickinson M, Wirth A, Westerman D, Harrison SJ, et al. Limited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy. Br J Cancer. 2013;109(2):312–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16••.
    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 .Landmark study in patients with diffuse large B-cell lymphoma followed with both serum samples and CT scans. Demonstrates a lead-time for surveillance ctDNA and that interim ctDNA predicts outcomesCrossRefPubMedPubMedCentralGoogle Scholar
  17. 17••.
    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. .Another important paper of ctDNA in DLBCL that demonstrated it was superior to cell-based assays of immunoglobulin receptor DNA. Also demonstrated a lead-time for ctDNA compared to PET scans.Google Scholar
  18. 18.
    Morin RD, Assouline S, Alcaide M, Mohajeri A, Johnston RL, Chong L, et al. Genetic landscapes of relapsed and refractory diffuse large B-Cell lymphomas. Clin Cancer Res. 2016;22(9):2290–300.Google Scholar
  19. 19.
    Mandel P, Metais P. Not available. C R Seances Soc Biol Fil. 1948;142(3–4):241–3.PubMedGoogle Scholar
  20. 20.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.PubMedGoogle Scholar
  21. 21.
    Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646–50.PubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.CrossRefPubMedGoogle Scholar
  24. 24•.
    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24 .A paper that extensively demonstrated the utlizity of ctDNA testing in a variety of malignancies. Detailed explanations regarding the benefits of ctDNA including various modalities and technical considerationsCrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Arnold A, Cossman J, Bakhshi A, Jaffe ES, Waldmann TA, Korsmeyer SJ. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med. 1983;309(26):1593–9.CrossRefPubMedGoogle Scholar
  26. 26•.
    Roschewski M, Staudt LM, Wilson WH. Dynamic monitoring of circulating tumor DNA in non-Hodgkin lymphoma. Blood. 2016;127:3127–32. A recent review that discusses current uses of ctDNA for both aggressive and indolent forms of non-Hodgkin lymphoma including future research applications that are emerging.Google Scholar
  27. 27.
    Horning SJ, Galili N, Cleary M, Sklar J. Detection of non-Hodgkin's lymphoma in the peripheral blood by analysis of antigen receptor gene rearrangements: results of a prospective study. Blood. 1990;75(5):1139–45.PubMedGoogle Scholar
  28. 28.
    Frickhofen N, Muller E, Sandherr M, Binder T, Bangerter M, Wiest C, et al. Rearranged Ig heavy chain DNA is detectable in cell-free blood samples of patients with B-cell neoplasia. Blood. 1997;90(12):4953–60.PubMedGoogle Scholar
  29. 29.
    Ladetto M, Bruggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28(6):1299–307.CrossRefPubMedGoogle Scholar
  30. 30.
    Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012;120(26):5173–80.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Liedtke M, Hamlin PA, Moskowitz CH, Zelenetz AD. Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population. Ann Oncol. 2006;17(6):909–13.CrossRefPubMedGoogle Scholar
  32. 32.
    El-Galaly TC, Jakobsen LH, Hutchings M, de Nully BP, Nilsson-Ehle H, Szekely E, et al. Routine imaging for diffuse large B-cell lymphoma in first complete remission does not improve post-treatment survival: a Danish-Swedish population-based study. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(34):3993–8.CrossRefGoogle Scholar
  33. 33.
    Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med. 2007;357(22):2277–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A. 2003;100(24):13761–6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Smith-Bindman R, Lipson J, Marcus R, Kim KP, Mahesh M, Gould R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med. 2009;169(22):2078–86.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Armitage JO. Who benefits from surveillance imaging? J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(21):2579–80.CrossRefGoogle Scholar
  37. 37.
    Armitage JO, Vose JM. To surveil or not to surveil. J Clin Oncol. 2015;33:3983–4.Google Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    Lin C, Itti E, Haioun C, Petegnief Y, Luciani A, Dupuis J, et al. Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med. 2007;48(10):1626–32.CrossRefPubMedGoogle Scholar
  40. 40.
    Pregno P, Chiappella A, Bello M, Botto B, Ferrero S, Franceschetti S, et al. Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP. Blood. 2012;119(9):2066–73.CrossRefPubMedGoogle Scholar
  41. 41•.
    Cashen AF, Dehdashti F, Luo J, Homb A, Siegel BA, Bartlett NL. 18F-FDG PET/CT for early response assessment in diffuse large B-cell lymphoma: poor predictive value of international harmonization project interpretation. J Nucl Med. 2011;52(3):386–92 .A prospective and rigorous study of interim PET scans which demonstrates a low positive predictive value for risk of progresionGoogle Scholar
  42. 42.
    Pardal E, Coronado M, Martin A, Grande C, Marin-Niebla A, Panizo C, et al. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014;167(3):327–36.CrossRefPubMedGoogle Scholar
  43. 43.
    Duehrsen UHA, Müller S, et al. Positron emission tomography (PET) guided therapy of aggressive lymphomas—a randomized controlled trial comparing different treatment approaches based on interim PET results (PETAL trial). Blood. 2014;124:391.Google Scholar
  44. 44.
    Sehn LH, Hardy ELG, Gill KK, Al-Tourah AJ, Shustik J, Macpherson NA, et al. Phase 2 trial of interim PET scan-tailored therapy in patients with advanced stage diffuse large B-cell lymphoma (DLBCL) in British Columbia (BC). Blood. 2014;124(21):392.Google Scholar
  45. 45.
    Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68.Google Scholar
  46. 46.
    Adams HJ, Nievelstein RA, Kwee TC. Prognostic value of complete remission status at end-of-treatment FDG-PET in R-CHOP-treated diffuse large B-cell lymphoma: systematic review and meta-analysis. Br J Haematol. 2015;170(2):185–91.CrossRefPubMedGoogle Scholar
  47. 47•.
    Newman AMBS, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20:548–54 .A novel assay of monitoring circulating tumor DNA being tested in lymphoma that combines immunoglobulin receptor DNA with somatic mutations and other genetic aberrations in lymphomas.Google Scholar
  48. 48.
    Kurtz DM, Scherer F, Newman AM, Lovejoy AF, Klass DM, Chabon JJ, et al. Dynamic noninvasive genomic monitoring for outcome prediction in diffuse large B-cell lymphoma. Blood. 2015;126(23):130.Google Scholar
  49. 49.
    Scherer F, Kurtz DM, Newman AM, Stehr H, Liu CL, Zhou L, et al. Noninvasive genotyping and assessment of treatment response in diffuse large B cell lymphoma. Blood. 2015;126(23):114.Google Scholar
  50. 50.
    Rasi S, Monti S, Zanni M, Ciardullo C, Diop F, Martuscelli L, et al. Liquid biopsy as a tool for monitoring the genotype of diffuse large B-cell lymphoma. Blood. 2015;126(23):127.Google Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  • Mary Kwok
    • 1
  • S. Peter Wu
    • 2
  • Clifton Mo
    • 1
  • Thomas Summers
    • 3
  • Mark Roschewski
    • 4
  1. 1.Hematology-Oncology DepartmentJohn P. Murtha Cancer Center, Walter Reed National Military Medical CenterBethesdaUSA
  2. 2.Internal Medicine DepartmentPerlmutter Cancer Center, New York University Langone Medical CenterNew YorkUSA
  3. 3.Pathology DepartmentUniformed Services University of the Health SciencesBethesdaUSA
  4. 4.Lymphoid Malignancies Branch, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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