NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019

Featured Updates to the NCCN Guidelines

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  • 1 Memorial Sloan Kettering Cancer Center;
  • | 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 3 Massachusetts General Hospital Cancer Center;
  • | 4 Stanford Cancer Institute;
  • | 5 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 6 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 7 University of Wisconsin Carbone Cancer Center;
  • | 8 Moffitt Cancer Center;
  • | 9 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 10 The University of Texas MD Anderson Cancer Center;
  • | 11 Huntsman Cancer Institute at the University of Utah;
  • | 12 Mayo Clinic Cancer Center;
  • | 13 Roswell Park Comprehensive Cancer Center;
  • | 14 University of Michigan Rogel Cancer Center;
  • | 15 Duke Cancer Institute;
  • | 16 Fox Chase Cancer Center;
  • | 17 Consultant;
  • | 18 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 19 O’Neal Comprehensive Cancer Center at UAB;
  • | 20 City of Hope National Medical Center;
  • | 21 University of Colorado Cancer Center;
  • | 22 Vanderbilt-Ingram Cancer Center;
  • | 23 UC San Diego Moores Cancer Center;
  • | 24 Yale Cancer Center/Smilow Cancer Hospital;
  • | 25 University of Washington/Seattle Cancer Care Alliance;
  • | 26 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 27 Fred & Pamela Buffett Cancer Center; and
  • | 28 National Comprehensive Cancer Network.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

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    Conconi A, Ponzio C, Lobetti-Bodoni C, et al.. Incidence, risk factors and outcome of histological transformation in follicular lymphoma. Br J Haematol 2012;157:188196.

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    Link BK, Maurer MJ, Nowakowski GS, et al.. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 2013;31:32723278.

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    Sarkozy C, Maurer MJ, Link BK, et al.. Cause of death in follicular lymphoma in the first decade of the rituximab era: a pooled analysis of french and US cohorts. J Clin Oncol 2019;37:144152.

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    Wagner-Johnston ND, Link BK, Byrtek M, et al.. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood 2015;126:851857.

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    Gleeson M, Hawkes EA, Peckitt C, et al.. Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013. Leuk Lymphoma 2017;58:18051813.

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    Casulo C, Byrtek M, Dawson KL, et al.. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol 2015;33:25162522.

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    Maurer MJ, Bachy E, Ghesquières H, et al.. Early event status informs subsequent outcome in newly diagnosed follicular lymphoma. Am J Hematol 2016;91:10961101.

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    Casulo C, Le-Rademacher J, Dixon J, et al.. Validation of POD24 as a robust early clinical endpoint of poor survival in follicular lymphoma: results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) investigation using individual data from 5,453 patients on 13 clinical trials [abstract]. Blood 2017;130:Abstract 412.

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    Gopal AK, Kahl BS, de Vos S, et al.. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370:10081018.

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    Salles G, Schuster SJ, de Vos S, et al.. Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: a subgroup analysis of a phase 2 study. Haematologica 2017;102:e156159.

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  • 13.

    Dreyling M, Santoro A, Mollica L, et al.. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 2017;35:38983905.

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  • 14.

    Dreyling M, Santoro A, Mollica L, et al.. Long-term efficacy and safety from the copanlisib CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma [abstract]. Blood 2018;132:Abstract 1595.

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  • 15.

    Flinn IW, Miller CB, Ardeshna KM, et al.. DYNAMO: a phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol 2019;37:912922.

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  • 16.

    Gopal AK, Kahl BS, Flowers CR, et al.. Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy. Blood 2017;129:30373039.

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  • 17.

    Philip T, Guglielmi C, Hagenbeek A, et al.. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995;333:15401545.

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  • 18.

    Vose JM, Zhang MJ, Rowlings PA, et al.. Autologous transplantation for diffuse aggressive non-Hodgkin’s lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 2001;19:406413.

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  • 19.

    Rodriguez J, Caballero MD, Gutierrez A, et al.. Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin’s lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience. Ann Oncol 2004;15:15041509.

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  • 20.

    Mounier N, Canals C, Gisselbrecht C, et al.. High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: an analysis based on data from the European Blood and Marrow Transplantation Registry. Biol Blood Marrow Transplant 2012;18:788793.

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  • 21.

    Farooq U, Maurer MJ, Thompson CA, et al.. Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy. Br J Haematol 2017;179:5060.

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  • 22.

    Hamlin PA, Zelenetz AD, Kewalramani T, et al.. Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2003;102:19891996.

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  • 23.

    Lerner RE, Thomas W, Defor TE, et al.. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin’s lymphoma in second complete or partial remission. Biol Blood Marrow Transplant 2007;13:486492.

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  • 24.

    Spaepen K, Stroobants S, Dupont P, et al.. Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. Blood 2003;102:5359.

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  • 25.

    Derenzini E, Musuraca G, Fanti S, et al.. Pretransplantation positron emission tomography scan is the main predictor of autologous stem cell transplantation outcome in aggressive B-cell non-Hodgkin lymphoma. Cancer 2008;113:24962503.

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  • 26.

    Hoppe BS, Moskowitz CH, Zhang Z, et al.. The role of FDG-PET imaging and involved field radiotherapy in relapsed or refractory diffuse large B-cell lymphoma. Bone Marrow Transplant 2009;43:941948.

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  • 27.

    Hoppe BS, Moskowitz CH, Filippa DA, et al.. Involved-field radiotherapy before high-dose therapy and autologous stem-cell rescue in diffuse large-cell lymphoma: long-term disease control and toxicity. J Clin Oncol 2008;26:18581864.

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  • 28.

    Mounier N, El Gnaoui T, Tilly H, et al.. Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica 2013;98:17261731.

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  • 29.

    Ohmachi K, Niitsu N, Uchida T, et al.. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2013;31:21032109.

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  • 30.

    Vacirca JL, Acs PI, Tabbara IA, et al.. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol 2014;93:403409.

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  • 31.

    Jacobsen ED, Sharman JP, Oki Y, et al.. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125:13941402.

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  • 32.

    Nowakowski GS, LaPlant B, Macon WR, 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;33:251257.

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  • 33.

    Czuczman MS, Trněný M, Davies A, et al.. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator’s choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res 2017;23:41274137.

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  • 34.

    Wilson WH, Young RM, Schmitz R, et al.. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015;21:922926.

  • 35.

    Crump M, Neelapu SS, Farooq U, et al.. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 2017;130:18001808.

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  • 36.

    Neelapu SS, Locke FL, Bartlett NL, et al.. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:25312544.

  • 37.

    Locke FL, Ghobadi A, Jacobson CA, et al.. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 2019;20:3142.

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  • 38.

    Schuster SJ, Bishop MR, Tam CS, et al.. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019;380:4556.

  • 39.

    Neelapu SS, Tummala S, Kebriaei P, et al.. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol 2018;15:4762.

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    Montoto S, Davies AJ, Matthews J, et al.. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007;25:24262433.

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    Sarkozy C, Trneny M, Xerri L, et al.. Risk factors and outcomes for patients with follicular lymphoma who had histologic transformation after response to first-line immunochemotherapy in the PRIMA trial. J Clin Oncol 2016;34:25752582.

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  • 42.

    Ardeshna KM, Qian W, Smith P, et al.. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 2014;15:424435.

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  • 43.

    Gordon LI, Witzig T, Molina A, et al.. Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high response rates and durable remissions in patients with previously treated B-cell lymphoma. Clin Lymphoma 2004;5:98101.

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  • 44.

    Mei M, Wondergem MJ, Palmer JM, et al.. Autologous transplantation for transformed non-Hodgkin lymphoma using an yttrium-90 ibritumomab tiuxetan conditioning regimen. Biol Blood Marrow Transplant 2014;20:20722075.

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    Smith SD, Bolwell BJ, Advani AS, et al.. High rate of survival in transformed lymphoma after autologous stem cell transplant: pathologic analysis and comparison with de novo diffuse large B-cell lymphoma. Leuk Lymphoma 2009;50:16251631.

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  • 46.

    Ban-Hoefen M, Kelly JL, Bernstein SH, et al.. High-dose therapy and autologous stem cell transplant for transformed non-Hodgkin lymphoma in the rituximab era. Leuk Lymphoma 2012;53:830835.

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    Reddy N, Oluwole O, Greer JP, et al.. Superior long-term outcome of patients with early transformation of non-Hodgkin lymphoma undergoing stem cell transplantation. Clin Lymphoma Myeloma Leuk 2012;12:406411.

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  • 48.

    Ban-Hoefen M, Vanderplas A, Crosby-Thompson AL, et al.. Transformed non-Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database. Br J Haematol 2013;163:487495.

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  • 49.

    Villa D, Crump M, Panzarella T, et al.. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian Blood and Marrow Transplant Group. J Clin Oncol 2013;31:11641171.

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    Villa D, Crump M, Keating A, et al.. Outcome of patients with transformed indolent non-Hodgkin lymphoma referred for autologous stem-cell transplantation. Ann Oncol 2013;24:16031609.

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    Wirk B, Fenske TS, Hamadani M, et al.. Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma. Biol Blood Marrow Transplant 2014;20:951959.

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  • 52.

    Madsen C, Pedersen MB, Vase MO, et al.. Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation. Ann Oncol 2015;26:393399.

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  • 53.

    Clavert A, Le Gouill S, Brissot E, et al.. Reduced-intensity conditioning allogeneic stem cell transplant for relapsed or transformed aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma 2010;51:15021508.

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  • 54.

    Kridel R, Mottok A, Farinha P, et al.. Cell of origin of transformed follicular lymphoma. Blood 2015;126:21182127.

  • 55.

    McPhail ED, Maurer MJ, Macon WR, et al.. Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements. Haematologica 2018;103:18991907.

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