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Standard of Care in First-Line Therapy of DLBCL

  • Greg Nowakowski
  • Fabian Frontzek
  • Norbert SchmitzEmail author
Chapter
Part of the Hematologic Malignancies book series (HEMATOLOGIC)

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity accounting for about 40% of the global lymphoma burden [1]. Approximately 60% of patients are cured with frontline chemoimmunotherapy, with most relapses occurring within the first 2 years from diagnosis. While some of the patients with relapsed disease can be salvaged with aggressive chemotherapy and transplant approaches, the majority of patients who relapse after modern frontline therapy will succumb to the disease [2, 3]. Not surprisingly, a great effort has been undertaken to improve outcomes of frontline treatment and increase cure rates in newly diagnosed DLBCL. DLBCL is unique with respect to the number and the quality of studies providing level 1 evidence which treatment should be considered. In addition to unmet clinical needs, two factors resulted in successful development of randomized studies in DLBCL: it is a common lymphoma enabling fast accrual to prospective studies and it runs an aggressive clinical course allowing for relatively quick readout of study endpoints. However, it is now recognized that DLBCL is a molecularly diverse disease, with several distinct molecular subtypes showing different outcomes and responsiveness to therapy [4]. These molecular subtypes described in Chap.  2 will drive future developments of novel therapies in DLBCL. Nonetheless, the large diversity of the clinical presentation of DLBCL including increasing patient age, comorbidities, and performance status will remain important variables affecting therapy selection and outcomes.

References

  1. 1.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Publications; 2017.Google Scholar
  2. 2.
    Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, et al. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014;15(7):757–66.CrossRefGoogle Scholar
  3. 3.
    Glass B, Dohm AJ, Truemper LH, Pfreundschuh M, Bleckmann A, Wulf GG, et al. Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial. Ann Oncol. 2017;28(12):3058–64.PubMedGoogle Scholar
  4. 4.
    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.CrossRefGoogle Scholar
  5. 5.
    McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38(4):1484–93.CrossRefGoogle Scholar
  6. 6.
    Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002–6.CrossRefGoogle Scholar
  7. 7.
    Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, MacPherson N, O’Reilly SE, et al. Introduction of combined CHOP-rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma (DLBC) in British Columbia (BC). Blood. 2003;102(11):88a.Google Scholar
  8. 8.
    Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.CrossRefGoogle Scholar
  9. 9.
    Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7(5):379–91.CrossRefGoogle Scholar
  10. 10.
    Pfreundschuh M, Kloess M, Zeynalava E, Lengfelder E, Franke A, Reiser M, et al. Six vs. eight cycles of bi-weekly CHOP-14 with or without rituximab for elderly patients with diffuse large B-cell lymphoma (DLBCL): results of the completed RICOVER-60 trial of the German high-grade non-Hodgkin lymphoma study group (DSHNHL). Blood. 2006;108:205 abstract.Google Scholar
  11. 11.
    Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121–7.CrossRefGoogle Scholar
  12. 12.
    Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373–80.CrossRefGoogle Scholar
  13. 13.
    Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–61.CrossRefGoogle Scholar
  14. 14.
    Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837–42.CrossRefGoogle Scholar
  15. 15.
    Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22–32.CrossRefGoogle Scholar
  16. 16.
    Pasqualucci L, Dalla-Favera R. The genetic landscape of diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):67–76.CrossRefGoogle Scholar
  17. 17.
    Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362(15):1417–29.CrossRefGoogle Scholar
  18. 18.
    Staiger AM, Ziepert M, Horn H, Scott DW, Barth TFE, Bernd HW, et al. Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German high-grade non-Hodgkin’s lymphoma study group. J Clin Oncol. 2017;35(22):2515–26.CrossRefGoogle Scholar
  19. 19.
    Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381(9880):1817–26.CrossRefGoogle Scholar
  20. 20.
    Davies AJ, Caddy J, Maishman T, Barrans S, Mamot C, Care M, et al. A prospective randomised trial of targeted therapy for diffuse large B-cell lymphoma (DLBCL) based upon real-time gene expression profiling: the Remodl-B Study of the UK NCRI and SAKK Lymphoma Groups (ISRCTN51837425). Blood. 2015;126(23):812.Google Scholar
  21. 21.
    Dave SS, Fu K, Wright GW, Lam LT, Kluin P, Boerma EJ, et al. Molecular diagnosis of Burkitt's lymphoma. N Engl J Med. 2006;354(23):2431–42.CrossRefGoogle Scholar
  22. 22.
    Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360–5.CrossRefGoogle Scholar
  23. 23.
    Swerdlow S, Campo E, Harris N, Jaffe ES, Pileri A, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008.Google Scholar
  24. 24.
    Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam 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 250CrossRefGoogle Scholar
  25. 25.
    Perry AM, Alvarado-Bernal Y, Laurini JA, Smith LM, Slack GW, Tan KL, et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014;165(3):382–91.CrossRefGoogle Scholar
  26. 26.
    Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, 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.CrossRefGoogle Scholar
  27. 27.
    Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460–7.CrossRefGoogle Scholar
  28. 28.
    Young RM, Shaffer AL 3rd, Phelan JD, Staudt LM. B-cell receptor signaling in diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):77–85.CrossRefGoogle Scholar
  29. 29.
    Jiang Y, Melnick A. The epigenetic basis of diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):86–96.CrossRefGoogle Scholar
  30. 30.
    Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, 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.CrossRefGoogle Scholar
  31. 31.
    Petrich AM, Gandhi M, Jovanovic B, Castillo JJ, Rajguru S, Yang DT, 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.CrossRefGoogle Scholar
  32. 32.
    Dunleavy K, Fanale M, LaCasce A, Noy A, Caimi P, Parekh S, 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:abstract 395.Google Scholar
  33. 33.
    Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012;13(12):1250–9.CrossRefGoogle Scholar
  34. 34.
    Wilson WH, Sin-Ho J, Pitcher BN, Hsi ED, Friedberg J, Cheson B, et al. Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. Blood. 2016;128(22):469.Google Scholar
  35. 35.
    Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117(22):5058–66.CrossRefGoogle Scholar
  36. 36.
    Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251–7.CrossRefGoogle Scholar
  37. 37.
    Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15(7):730–7.CrossRefGoogle Scholar
  38. 38.
    Yang Y, Shaffer AL 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723–37.CrossRefGoogle Scholar
  39. 39.
    Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922–6.CrossRefGoogle Scholar
  40. 40.
    Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, Amorim S, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014;15(9):1019–26.CrossRefGoogle Scholar
  41. 41.
    Leonard JP, Kolibaba KS, Reeves JA, Tulpule A, Flinn IW, Kolevska T, et al. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3538–46.CrossRefGoogle Scholar
  42. 42.
    van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: The ORCHARRD Study. J Clin Oncol. 2017;35(5):544–51.CrossRefGoogle Scholar
  43. 43.
    Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393–402.CrossRefGoogle Scholar
  44. 44.
    Vitolo U, Trneny M, Belada D, Burke JM, Carella AM, Chua N, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529–37.CrossRefGoogle Scholar
  45. 45.
    Murawski N, Pfreundschuh M, Zeynalova S, Poeschel V, Hanel M, Held G, et al. Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL. Ann Oncol. 2014;25(9):1800–6.CrossRefGoogle Scholar
  46. 46.
    Pfreundschuh M, Poeschel V, Zeynalova S, Hanel M, Held G, Schmitz N, et al. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German high-grade non-Hodgkin lymphoma study group. J Clin Oncol. 2014;32(36):4127–33.CrossRefGoogle Scholar
  47. 47.
    Pfreundschuh M, Murawski N, Zeynalova S, Ziepert M, Loeffler M, Hanel M, et al. Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients. Br J Haematol. 2017;179(3):410–20.CrossRefGoogle Scholar
  48. 48.
    Schmitz N, Nickelsen M, Ziepert M, Haenel M, Viardot A, Dreyling MH, et al. Optimization of rituximab for treatment of DLBCL in young, high-risk patients-results of the dense-R-CHOEP trial of the German high-grade lymphoma study group. Blood. 2015;126(23):474.Google Scholar
  49. 49.
    Lugtenburg PJ, Brown PDN, van der Holt B, D’Amore F, Koene HR, Berenschot HW, et al. Randomized phase III study on the effect of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab or no maintenance in patients with diffuse large B-cell lymphoma: results from a HOVON-Nordic Lymphoma Group study. J Clin Oncol. 2016;34(15):7504.CrossRefGoogle Scholar
  50. 50.
    Held G, Murawski N, Ziepert M, Fleckenstein J, Poschel V, Zwick C, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112–8.CrossRefGoogle Scholar
  51. 51.
    Le Gouill S, Milpied NJ, Lamy T, Delwail V, Gressin R, Guyotat D, et al. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: preliminary results of the GOELAMS 075 prospective multicenter randomized trial. J Clin Oncol. 2011;29(15):8003.CrossRefGoogle Scholar
  52. 52.
    Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, et al. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017;18(8):1076–88.CrossRefGoogle Scholar
  53. 53.
    Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, et al. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013;369(18):1681–90.CrossRefGoogle Scholar
  54. 54.
    Schmitz N, Ziepert M, Vitolo U, German High-Grade Non-Hodgkin’s Lymphoma Study Group, Fondazione Italiana Linfomi. The role of myeloablation for lymphoma. N Engl J Med. 2014;370(6):574–5.CrossRefGoogle Scholar
  55. 55.
    Crump M, Leppa S, Fayad L, Lee JJ, Di Rocco A, Ogura M, et al. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016;34(21):2484–92.CrossRefGoogle Scholar
  56. 56.
    Witzig TE, Tobinai K, Rigacci L, Ikeda T, Vanazzi A, Hino M, et al. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol. 2018;29(3):707–14.CrossRefGoogle Scholar
  57. 57.
    Thieblemont C, Tilly H, Gomes da Silva M, Casasnovas RO, Fruchart C, Morschhauser F, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017;35(22):2473–81.CrossRefGoogle Scholar
  58. 58.
    Jaeger U, Trneny M, Melzer H, Praxmarer M, Nawarawong W, Ben Yehuda D, et al. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015;100(7):955–63.CrossRefGoogle Scholar
  59. 59.
    Muller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynalova S, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119(14):3276–84.CrossRefGoogle Scholar
  60. 60.
    Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2009;113(17):3896–902.CrossRefGoogle Scholar
  61. 61.
    Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13(7):1099–107.CrossRefGoogle Scholar
  62. 62.
    Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, Savage KJ. Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol. 2010;21(5):1046–52.CrossRefGoogle Scholar
  63. 63.
    Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34(26):3150–6.CrossRefGoogle Scholar
  64. 64.
    El-Galaly TC, Villa D, Michaelsen TY, Hutchings M, Mikhaeel NG, Savage KJ, et al. The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: an international multicenter study of 1532 patients treated with chemoimmunotherapy. Eur J Cancer. 2017;75:195–203.CrossRefGoogle Scholar
  65. 65.
    Schmitz N, Nickelsen M, Savage KJ. Central nervous system prophylaxis for aggressive B-cell lymphoma who, what, and when? Hematol Oncol Clin N. 2016;30(6):1277–91.CrossRefGoogle Scholar
  66. 66.
    Savage KJ, Slack GW, Mottok A, Sehn LH, Villa D, Kansara R, et al. Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. Blood. 2016;127(18):2182–8.CrossRefGoogle Scholar
  67. 67.
    Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833–43 e5.CrossRefGoogle Scholar
  68. 68.
    Houillier C, Choquet S, Touitou V, Martin-Duverneuil N, Navarro S, Mokhtari K, et al. Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology. 2015;84(3):325–6.CrossRefGoogle Scholar
  69. 69.
    Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998;339(1):21–6.CrossRefGoogle Scholar
  70. 70.
    Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, et al. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008;26(14):2258–63.CrossRefGoogle Scholar
  71. 71.
    Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018;131(2):174–81.CrossRefGoogle Scholar
  72. 72.
    Zettl F, Ziepert M, Altmann B, Zeynalova S, Loeffler M, Schmitz N, et al. Age-dependent analysis of toxicity, mortality, and implementation of an anti-infective prophylaxis in 1171 elderly patients (pts) with aggressive B-cell lymphoma (aNHL): data from consecutive phase II and III trials of the DSHNHL. J Clin Oncol. 2016;34(15):7539.CrossRefGoogle Scholar
  73. 73.
    Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460–8.CrossRefGoogle Scholar
  74. 74.
    Moccia AA, Schaff K, Hoskins P, Klasa R, Savage KJ, Shenkier T, et al. R-CHOP with etoposide substituted for doxorubicin (R-CEOP): excellent outcome in diffuse large B cell lymphoma for patients with a contraindication to anthracyclines. Blood. 2009;114(22):170.Google Scholar
  75. 75.
    Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014;93(3):403–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Greg Nowakowski
    • 1
  • Fabian Frontzek
    • 2
  • Norbert Schmitz
    • 2
    Email author
  1. 1.Mayo ClinicRochesterUSA
  2. 2.Department of Medicine A, Hematology, Oncology, Hemostaseology and PneumonologyUniversity Hospital of MuensterMuensterGermany

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