NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023

Featured Updates to the NCCN Guidelines

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Andrew D. Zelenetz Memorial Sloan Kettering Cancer Center

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Leo I. Gordon Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Jeremy S. Abramson Massachusetts General Hospital Cancer Center

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Ranjana H. Advani Stanford Cancer Institute

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Babis Andreadis UCSF Helen Diller Family Comprehensive Cancer Center

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Nancy L. Bartlett Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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L. Elizabeth Budde City of Hope National Medical Center

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Paolo F. Caimi Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Julie E. Chang University of Wisconsin Carbone Cancer Center

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Beth Christian The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Sven DeVos UCLA Jonsson Comprehensive Cancer Center

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Bhagirathbhai Dholaria Vanderbilt-Ingram Cancer Center

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Luis E. Fayad The University of Texas MD Anderson Cancer Center

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Thomas M. Habermann Mayo Clinic Comprehensive Cancer Center

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Muhammad Saad Hamid St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center

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Francisco Hernandez-Ilizaliturri Roswell Park Comprehensive Cancer Center

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Boyu Hu Huntsman Cancer Institute at the University of Utah

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Mark S. Kaminski University of Michigan Rogel Cancer Center

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Yasmin Karimi University of Michigan Rogel Cancer Center

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Christopher R. Kelsey Duke Cancer Institute

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Rebecca King Mayo Clinic Comprehensive Cancer Center

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Susan Krivacic Consultant

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Ann S. LaCasce Dana-Farber/Brigham and Women’s Cancer Center

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Megan Lim Memorial Sloan Kettering Cancer Center

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Marcus Messmer Fox Chase Cancer Center

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Mayur Narkhede O’Neal Comprehensive Cancer Center at UAB

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Rachel Rabinovitch University of Colorado Cancer Center

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Praveen Ramakrishnan UT Southwestern Simmons Comprehensive Cancer Center

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Erin Reid UC San Diego Moores Cancer Center

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Kenneth B. Roberts Yale Cancer Center/Smilow Cancer Hospital

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Hayder Saeed Moffitt Cancer Center

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Stephen D. Smith Fred Hutchinson Cancer Center

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Jakub Svoboda Abramson Cancer Center at the University of Pennsylvania

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Lode J. Swinnen The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Joseph Tuscano UC Davis Comprehensive Cancer Center

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Julie M. Vose Fred & Pamela Buffett Cancer Center

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Mary A. Dwyer National Comprehensive Cancer Network

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Hema Sundar National Comprehensive Cancer Network

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Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

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  • 1.

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  • 3.

    Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res 2012;72:53075316.

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  • 4.

    Dreyling M, Klapper W, Rule S. Blastoid and pleomorphic mantle cell lymphoma: still a diagnostic and therapeutic challenge! Blood 2018;132:27222729.

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  • 7.

    Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 2017;130:19031910.

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  • 8.

    Obr A, Klener P, Furst T, et al. A high TP53 mutation burden is a strong predictor of primary refractory mantle cell lymphoma. Br J Haematol 2020;191:e103106.

  • 9.

    Ferrero S, Rossi D, Rinaldi A, et al. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study. Haematologica 2020;105:16041612.

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  • 10.

    Tam CS, Gregory GP, Ku M, et al. Recommendation for TP53 mutation testing in newly diagnosed mantle cell lymphoma: a statement from working groups sponsored by the Victorian Comprehensive Cancer Centre. Intern Med J 2022;52:12861287.

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  • 11.

    Graf SA, Stevenson PA, Holmberg LA, et al. Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann Oncol 2015;26:23232328.

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  • 12.

    Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem cell transplantation in mantle cell lymphoma. N Engl J Med 2017;377:12501260.

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    Klener P, Salek D, Pytlik R, et al. Rituximab maintenance significantly prolongs progression-free survival of patients with newly diagnosed mantle cell lymphoma treated with the Nordic MCL2 protocol and autologous stem cell transplantation. Am J Hematol 2019;94:E5053.

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  • 14.

    Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle cell lymphoma (MCL): long-term follow-up of the randomized European MCL Elderly Trial. J Clin Oncol 2020;38:248256.

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  • 15.

    Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: long-term follow-up of the randomized mantle cell lymphoma younger trial of the European Mantle Cell Lymphoma Network. J Clin Oncol 2023;41:479484.

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  • 16.

    Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle Trial by the European MCL Network. Blood 2022;140(Suppl 1):13.

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  • 17.

    Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol 2021;39:34413452.

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    Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2023;388:319332.

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    Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 2022;386:24822494.

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    Khouri IF, Saliba RM, Okoroji GJ, et al. Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first disease remission: the prognostic value of beta2-microglobulin and the tumor score. Cancer 2003;98:26302635.

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  • 21.

    Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005;105:26772684.

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  • 22.

    Zoellner AK, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol 2021;8:e648657.

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  • 23.

    Thieblemont C, Antal D, Lacotte-Thierry L, et al. Chemotherapy with rituximab followed by high-dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma. Cancer 2005;104:14341441.

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  • 24.

    Till BG, Gooley TA, Crawford N, et al. Effect of remission status and induction chemotherapy regimen on outcome of autologous stem cell transplantation for mantle cell lymphoma. Leuk Lymphoma 2008;49:10621073.

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  • 25.

    van’t Veer MB, de Jong D, MacKenzie M, et al. High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol 2009;144:524530.

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  • 26.

    Metzner B, Müller TH, Casper J, et al. Long-term outcome in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation. Eur J Haematol 2023;111:220228.

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  • 27.

    Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. Leukemia 2019;33:27622766.

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  • 28.

    Tam CS, Opat S, Simpson D, et al. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv 2021;5:25772585.

  • 29.

    Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 2012;13:716723.

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  • 30.

    Wang M, Schuster SJ, Phillips T, et al. Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004). J Hematol Oncol 2017;10:171.

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  • 31.

    Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507516.

  • 32.

    Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood 2015;126:739745.

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  • 33.

    Jain P, Romaguera J, Srour SA, et al. Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL). Br J Haematol 2018;182:404411.

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  • 34.

    Rule S, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia 2018;32:17991803.

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  • 35.

    McCulloch R, Lewis D, Crosbie N, et al. Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom real-world analysis of outcomes in 211 patients. Br J Haematol 2021;193:290298.

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  • 36.

    Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica 2019;104:e6871.

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  • 37.

    Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) — outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol 2020;95:623629.

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  • 38.

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  • 41.

    Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol 2023;41:555567.

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  • 42.

    Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood 2016;127:15591563.

  • 43.

    Jain P, Kanagal-Shamanna R, Zhang S, et al. Outcomes of relapsed mantle cell lymphoma patients after discontinuing acalabrutinib. Am J Hematol 2021;96:E137140.

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    Hess G, Dreyling M, Oberic L, et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: the SCHOLAR-2 retrospective chart review study. Br J Haematol 2022;202:749759.

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  • 45.

    Cohen JB, Shah NN, Alencar AJ, et al. MCL-133 pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Clin Lymphoma Myeloma Leuk 2022;22(Suppl 2):S394395.

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  • 46.

    Wang ML, Shah NN, Jurczak W, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pre-treated relapsed/refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1/2 BRUIN study. Blood 2022;140(Suppl 1):Abstract 623.

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  • 47.

    Munshi PN, Hamadani M, Kumar A, et al. American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation clinical practice recommendations for transplantation and cellular therapies in mantle cell lymphoma. Transplant Cell Ther 2021;27:720728.

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  • 48.

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    Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 2020;7:e511522.

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    Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 2023;141:23072315.

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    Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021;22:14031415.

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