Skip to main content

Advertisement

SpringerLink
Log in

Double-Hit Large B Cell Lymphoma

  • Lymphomas (MR Smith, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of NHL cases. It is a heterogeneous group of diseases. BCL2, BCL6, and MYC are the most frequent mutated genes in DLBCL. Double-hit lymphoma (DHL) is an aggressive form of DLBCL with an unmet treatment need, in which MYC rearrangement is present with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass with B symptoms. DHL has been linked to very poor outcomes when treated with RCHOP chemotherapy. Dual-expressor lymphoma is a form of DLBCL with overexpression of MYC and BCL2/BCL6. There is a paucity of prospective trials evaluating the treatment of DHL. Retrospective series suggest that more aggressive treatment regimens such as DA-EPOCH and hyper CVAD may be more efficacious. However, there remains a lack of consensus regarding optimal treatment for DHL. Further clinical trials, including novel agents, are needed for improvement in outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Dunleavy K. Double-hit lymphomas: current paradigms and novel treatment approaches. Hematology Am Soc Hematol Educ Program. 2014;2014(1):107–12.

    PubMed  Google Scholar 

  2. Shustik J, Han G, Farinha P, et al. Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Haematologica. 2010;95(1):96–101.

    Article  CAS  PubMed  Google Scholar 

  3. Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114(11):2273–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021–31. quiz 4250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wagner SD, Amen F, Trivedi PS, Horncastle D, Elderfield K, Naresh KN. Bcl-6 and c-Myc are rarely co-expressed in adult diffuse large B-cell lymphoma. Leuk Lymphoma. 2007;48(8):1510–3.

    Article  CAS  PubMed  Google Scholar 

  6. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.

    Article  CAS  PubMed  Google Scholar 

  8. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937–47.

    Article  PubMed  Google Scholar 

  9. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275–82.

    Article  CAS  PubMed  Google Scholar 

  10. Iqbal J, Meyer PN, Smith LM, et al. BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. Clin Cancer Res. 2011;17(24):7785–95.

    Article  CAS  PubMed  Google Scholar 

  11. Chisholm KM, Bangs CD, Bacchi CE, Molina-Kirsch H, Cherry A, Natkunam Y. Expression profiles of MYC protein and MYC gene rearrangement in lymphomas. Am J Surg Pathol. 2015;39(3):294–303.

    Article  PubMed  Google Scholar 

  12. Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114(17):3533–7.

    Article  CAS  PubMed  Google Scholar 

  13. Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013;98(10):1554–62.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Škunca Ž, Domimis M, Plninc-Peraica A, Jakšić B. Clinical features in DLBCL and translocation BCL2/c-MYC “double hit” lymphoma. Acta Med Croatica. 2014;68(3):299–305.

    PubMed  Google Scholar 

  15. Pedersen MO, Gang AO, Poulsen TS, et al. MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations. Eur J Haematol. 2014;92(1):42–8.

    Article  CAS  PubMed  Google Scholar 

  16. Pillai RK, Sathanoori M, Van Oss SB, Swerdlow SH. Double-hit B-cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphomas. Am J Surg Pathol. 2013;37(3):323–32.

    Article  PubMed  Google Scholar 

  17. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319–31.

    Article  CAS  PubMed  Google Scholar 

  18. Snuderl M, Kolman OK, Chen YB, et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol. 2010;34(3):327–40.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Friedberg JW. Double-hit diffuse large B-cell lymphoma. J Clin Oncol. 2012;30(28):3439–43.

    Article  CAS  PubMed  Google Scholar 

  20. Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121(12):2253–63.

    Article  CAS  PubMed  Google Scholar 

  21. Momose S, Weissbach S, Pischimarov J, et al. The diagnostic gray zone between Burkitt lymphoma and diffuse large B-cell lymphoma is also a gray zone of the mutational spectrum. Leukemia England. 2015;29:1789–91.

    Article  CAS  Google Scholar 

  22. Gebauer N, Bernard V, Gebauer W, Thorns C, Feller AC, Merz H. TP53 mutations are frequent events in double-hit B-cell lymphomas with MYC and BCL2 but not MYC and BCL6 translocations. Leuk Lymphoma. 2015;56(1):179–85.

    Article  CAS  PubMed  Google Scholar 

  23. De Jong D, Voetdijk BM, Beverstock GC, van Ommen GJ, Willemze R, Kluin PM. Activation of the c-myc oncogene in a precursor-B-cell blast crisis of follicular lymphoma, presenting as composite lymphoma. N Engl J Med. 1988;318(21):1373–8.

    Article  PubMed  Google Scholar 

  24. Gauwerky CE, Haluska FG, Tsujimoto Y, Nowell PC, Croce CM. Evolution of B-cell malignancy: pre-B-cell leukemia resulting from MYC activation in a B-cell neoplasm with a rearranged BCL2 gene. Proc Natl Acad Sci U S A. 1988;85(22):8548–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kluk MJ, Chapuy B, Sinha P, et al. Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas. PLoS One. 2012;7(4):e33813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim S, Nam SJ, Kwon D, et al. MYC and BCL2 overexpression is associated with a higher class of Memorial Sloan-Kettering Cancer Center prognostic model and poor clinical outcome in primary diffuse large B-cell lymphoma of the central nervous system. BMC Cancer. 2016;16:363.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ye Q, Xu-Monette ZY, Tzankov A, et al. Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma. Oncotarget. 2016;7(3):2401–16.

    Article  PubMed  Google Scholar 

  28. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Copie-Bergman C, Cuilliere-Dartigues P, Baia M, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood. 2015;126(22):2466–74.

    Article  CAS  PubMed  Google Scholar 

  30. Zelenetz AD, Gordon LI, Wierda WG, et al. Diffuse large B-cell lymphoma version 1.2016. J Natl Compr Cancer Netw. 2016;14(2):196–231.

    Article  Google Scholar 

  31. Tilly H, da Gomes Silva M, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v116–25.

    Article  PubMed  Google Scholar 

  32. • Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354–61.

  33. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia. 2009;23(4):777–83.

    Article  CAS  PubMed  Google Scholar 

  34. Landsburg DJ, Nasta SD, Svoboda J, Morrissette JJ, Schuster SJ. ‘Double-Hit’ cytogenetic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients. Br J Haematol. 2014;166(3):369–74.

    Article  CAS  PubMed  Google Scholar 

  35. McHugh DJ GP, Quinn J, Thornton P, Bird B, Sukor S, Fortune A, Parera K, Bacon E, Vandenberghe E, Flavin R, Grant C. Prevalence, clinico-pathological features and outcomes of ‘double-hit’ high-grade B-cell non-Hodgkins lymphoma (NHL): a single institution experience. Ann Oncol 2016; 27(suppl_6).

  36. Pedersen MO, Gang AO, Poulsen TS, et al. Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma—a single centre’s experience. Eur J Haematol. 2012;89(1):63–71.

    Article  PubMed  Google Scholar 

  37. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354–61.

    Article  CAS  PubMed  Google Scholar 

  38. Lin P, et al. Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Cancer. 2012;118(6):1566–73.

    Article  CAS  PubMed  Google Scholar 

  39. • Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891–901. Describes the utility of intensive treatment regimens as compared to RCHOP for DHL.

    Article  CAS  PubMed  Google Scholar 

  40. Tomita N, et al. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica. 2009;94(7):935–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Steven LG, et al. The clinical presentation and prognosis of diffuse large B-cell lymphoma with t (14; 18) and 8q24/c-MYC rearrangement. Haematologica. 2007;92(10):1335–42.

    Article  Google Scholar 

  42. Kanungo A, et al. Lymphoid neoplasms associated with concurrent t (14; 18) and 8q24/c-MYC translocation generally have a poor prognosis. Mod Pathol. 2006;19(1):25.

  43. Dunleavy K, Fanale M, LaCasce A, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Blood. 2014;124:395.

  44. • Cohen JB, Geyer SM, Lozanski G, et al. Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival. Cancer. 2014;120(11):1677–85. Mainly describes the importance of first CR.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Nabhan C, Karrison T, Kline J, Cohen K, Bishop MR, Karmali R, et al. Prospective phase I multi-center trial incorporating lenalidomide (LEN) into dose-adjusted epoch plus rituximab (DA-EPOCH-R) in patients with double hit (DHL) or double expressing (DEL) lymphomas: final results. Blood. 2016;128:4191.

  46. Puvvada SD, Stiff PJ, Leblanc M, et al. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016;174(5):686–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. • Landsburg DJ, et al. Outcomes of patients with double-hit lymphoma who achieve first complete remission. J Clin Oncol 2017; JCO-2017.

  48. Schuster SSJ, Dwivedy Nasta S, Chong EA, Winchell N, Landsburg DJ, Porter DL, June CH. Treatment with chimeric antigen receptor modified T cells directed against CD19 (CTL019) results in durable remissions in patients with relapsed or refractory diffuse large B cell lymphomas of germinal center and non-germinal center origin, “Double Hit” diffuse large b cell lymphomas, and transformed follicular to diffuse large B cell lymphomas. Web site. https://ash.confex.com/ash/2016/webprogram/Paper93934.html. Published 2016. Updated.

  49. • Locke FL NS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). 2017. Describes utility of CAR-19 in treatment of DLBCL in second line, this will likely be practice changing.

  50. Herrera AF, Mei M, Low L, et al. Relapsed or refractory double-expressor and double-hit lymphomas have inferior progression-free survival after autologous stem-cell transplantation. J Clin Oncol. 2017;35(1):24–31.

    Article  PubMed  Google Scholar 

  51. Dashnamoorthy R, Kandela I, Bhalla S, Mazar A, Evens AM. Evaluation of potency and the associated biology of the investigational proteasome inhibitor, ixazomib: redox, autophagic, and MAPK-dependent cell death in T-cell lymphoma (TCL) and hodgkin lymphoma (HL) cell lines and human lymphoma xenograft models. Blood. 2013;122:4407.

    Google Scholar 

  52. Assouline SE, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4(10):e251.8.

    Article  Google Scholar 

  53. Wall M, et al. The mTORC1 inhibitor everolimus prevents and treats Eμ-Myc lymphoma by restoring oncogene-induced senescence. Cancer Discov. 2013;3(1):82–95.

    Article  CAS  PubMed  Google Scholar 

  54. Smith SM, et al. Temsirolimus has activity in non–mantle cell non-Hodgkin's lymphoma subtypes: the University of Chicago Phase II Consortium. J Clin Oncol. 2010;28(31):4740–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Davids MS, Seymour JF, Gerecitano JF, Kahl BS, Pagel JM, Wierda WG, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. ASCO Meeting Abstr. 2014;32(15_suppl):8522.

    Google Scholar 

  56. Tam CS, Bassett R, Ledesma C, et al. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113(18):4144–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kretzner L, et al. Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels. Cancer Res. 2011;71(11):3912–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fanale MA, Hagemeister FB, Fayad L, Oki Y, Fowler N, Romaguera J, et al. A phase I trial of alisertib plus romidepsin for relapsed/refractory aggressive B- and T-cell lymphomas. Blood. 2014;124:1744.

  59. Friedberg JW, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B-and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2013;32(1):44–50.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Delmore JE, Issa GC, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Novero A, Ravella PM, Chen Y, Dous G, Liu D. Ibrutinib for B cell malignancies. Exp Hematol Oncol. 32014:4.

  62. Lannutti BJ, et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Furman RR, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kochenderfer JN, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122(25):4129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cerchietti LC, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17(4):400–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sun K, Atoyan R, Borek MA, et al. Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers. Mol Cancer Ther. 2017;16(2):285–99.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Marshall University School of Medicine-Edwards Comprehensive Cancer Center, 1400 Hal Greer Boulevard, Huntington, WV, 25701, USA

    Yousef Khelfa, Yehuda Lebowicz & Muhammad Omer Jamil

Authors
  1. Yousef Khelfa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yehuda Lebowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad Omer Jamil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muhammad Omer Jamil.

Ethics declarations

Conflict of Interest

Yousef Khelfa, Yehuda Lebowicz, and Muhammad Omer Jamil 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.

Additional information

This article is part of the Topical Collection on Lymphomas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khelfa, Y., Lebowicz, Y. & Jamil, M.O. Double-Hit Large B Cell Lymphoma. Curr Oncol Rep 19, 74 (2017). https://doi.org/10.1007/s11912-017-0629-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-017-0629-y

Keywords

Search

Navigation