Mantle Cell Lymphoma: Evolving Frontline Treatment Strategies

Authors

  • Inna Y. Gong, MD Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • John Kuruvilla, MD Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  • Michael Crump, MD Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada

DOI:

https://doi.org/10.58931/cht.2024.3251

Abstract

Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma (NHL) that accounts for 3-10% of new NHL cases in Canada. The clinical course of MCL is heterogeneous, ranging from indolent behavior that does not require therapy for years, to highly aggressive disease with limited prognosis. As such, the 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications subdivide MCL into two categories: 1) indolent MCL, which is characterized by blood involvement, splenomegaly without nodal involvement, or low-burden nodal involvement (mutated immunoglobulin heavy chain [IGHV], SOX11 negative, low Ki67 proliferative index); and 2) aggressive MCL, which is characterized by pleomorphic and blastoid morphologic appearance, TP53 aberrancy, high Ki67, and unmutated IGHV.

While traditionally, patients with MCL had a median overall survival (OS) of only 3 to 5 years, there has been significant improvement over the last two decades, owing to chemoimmunotherapy with rituximab, cytarabine-based induction regimens, addition of consolidative autologous stem cell transplant (ASCT), rituximab maintenance, and the advent of novel targeted therapies (including Bruton kinase inhibitors [BTKi], venetoclax, and lenalidomide) in the relapsed setting. Despite these advances, MCL remains incurable even with aggressive therapy, and most patients will invariably relapse. As such, prospective studies integrating novel therapies with either a chemotherapy backbone or evaluating chemotherapy-free regimens are ongoing, aiming to improve outcomes and reduce toxicities. This review summarizes the current understanding of disease prognostication, treatment options, and novel therapeutic strategies that will reshape the treatment paradigm of MCL in the near future.

Author Biographies

Inna Y. Gong, MD, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Dr. Inna Gong is a Lymphoma fellow completing a combined clinical and post-doctoral fellowship focused on advanced therapies for lymphoid malignancies at Princess Margaret Hospital. She is enrolled in the Eliot Philipson Clinician Scientist Training Program and Clinical Investigator Program at University of Toronto. She has earned a PhD in Clinical Pharmacology from Western University and an MD from the University of Toronto, followed by recent completion of her Royal College certification in Internal Medicine and Hematology. Her research focuses on delineating immuno-metabolomic variation among patients with lymphoid malignancies, as well as identifying new immune-based biomarkers for predicting therapeutic outcomes.

John Kuruvilla, MD, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Dr. John Kuruvilla is an Associate Professor of Medicine at the University of Toronto and a hematologist in the Division of Medical Oncology and Hematology at the Princess Margaret Cancer Centre in Toronto. He is a member of the Lymphoma, Autologous Transplant and Immune Effector Cell Therapy programs. Dr. Kuruvilla’s research interest is the development of novel therapeutics in lymphoid malignancies and incorporating translational research into clinical trials. He is the Lymphoma Co-chair for the Canadian Cancer Trials Group (CCTG) as well as the Chair of the Scientific Advisory Board of Lymphoma Canada.

Michael Crump, MD, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Dr. Michael Crump is a Hematologist in the Division of Medical Oncology and Hematology at Princess Margaret Cancer Centre, and Professor of Medicine at the University of Toronto. He was the Co-chair of the Hematology Site Group of the CCTG for many years and the Co-chair of the Lymphoma working group. His research interests include the development of new therapies for lymphomas including bispecific antibodies and chimeric antigen receptor CAR T-cells and the application of autologous stem cell transplantation.

References

WHO. WHO Classification of Tumours Editorial Board. Hematolymphoid tumors: International Agency for Research on Cancer.

Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647-1656.

Armitage JO, Longo DL. Mantle-Cell Lymphoma. New England Journal of Medicine. 2022;386(26):2495-2506.

Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-1748.

Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140(11):1229-1253.

Bock AM, Gile JJ, Larson MC, et al. Evolving treatment patterns and improved outcomes in relapsed/refractory mantle cell lymphoma: a prospective cohort study. Blood Cancer Journal. 2023;13(1):169.

Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418.

Hoster E, Rosenwald A, Berger F, et al. Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386-1394.

Scheubeck G, Jiang L, Hermine O, et al. Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression). Leukemia. 2023;37(9):1887-1894.

Obr A, Procházka V, Jirkuvová A, et al. TP53 Mutation and Complex Karyotype Portends a Dismal Prognosis in Patients With Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(11):762-768.

Beà S, Valdés-Mas R, Navarro A, et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(45):18250-18255.

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(6):1604-1612.

Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119(9):1963-1971.

Ek S, Dictor M, Jerkeman M, Jirström K, Borrebaeck CA. Nuclear expression of the non B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma.Blood. 2008;111(2):800-805.

Jain P, Tang G, Yin CC, et al. Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients. Blood. 2020;136(Supplement 1):32-33.

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(17):1903-1910.

Aukema SM, Hoster E, Rosenwald A, et al. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network. Blood. 2018;131(4):417-420.

Rodrigues JM, Hassan M, Freiburghaus C, et al. p53 is associated with high-risk and pinpoints TP53 missense mutations in mantle cell lymphoma. Br J Haematol. 2020;191(5):796-805.

Nolan J, Murphy C, Dinneen K, et al. p53 immunohistochemistry must be confirmed by TP53 next generation sequencing for accurate risk stratification of patients with mantle cell lymphoma. Leuk Lymphoma. 2022;63(14):3504-3507.

Kumar A, Ying Z, Alperovich A, et al. Clinical presentation determines selection of patients for initial observation in mantle cell lymphoma. Haematologica. 2019;104(4):e163-e166.

Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27(8):1209-1213.

Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017;28(10):2489-2495.

Mangel J, Leitch HA, Connors JM, et al. Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis. Ann Oncol. 2004;15(2):283-290.

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(7):2677-2684.

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(9):e648-e657.

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(3):479-484.

Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012;158(3):355-362.

Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23(28):7013-7023.

Bernstein SH, Epner E, Unger JM, et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013;24(6):1587-1593.

Chen RW, Li H, Bernstein SH, et al. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017;176(5):759-769.

Kamdar M, Li H, Chen RW, et al. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019;3(20):3132-3135.

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(13):1250-1260.

Falcone U, Jiang H, Bashir S, et al. Effectiveness and tolerability of first-line autologous stem cell transplant and maintenance rituximab for mantle cell lymphoma. Bone Marrow Transplant. 2018;53(3):347-351.

Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of Older Patients with Mantle-Cell Lymphoma. New England Journal of Medicine. 2012;367(6):520-531.

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(3):248-256.

Robak T, Huang H, Jin J, et al. Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma. New England Journal of Medicine. 2015;372(10):944-953.

Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, openlabel, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458.

Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in firstline treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952.

Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210.

Tisi MC, Moia R, Patti C, et al. Long-term follow-up of rituximab plus bendamustine and cytarabine in older patients with newly diagnosed MCL. Blood Adv.2023;7(15):3916-3924.

Visco C, Tisi MC, Evangelista A, et al. Time to progression of mantle cell lymphoma after highdose cytarabine-based regimens defines patients risk for death. British Journal of Haematology. 2019;185(5):940-944.

Hill BT, Switchenko JM, Martin P, et al. Maintenance Rituximab Improves Outcomes in Mantle Cell Lymphoma Patients Who Respond to Induction Therapy with Bendamustine + Rituximab without Autologous Transplant. Blood. 2019;134(Supplement_1):1525-1525.

Martin P, Cohen JB, Wang M, et al. Treatment Outcomes and Roles of Transplantation and Maintenance Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts. J Clin Oncol. 2023;41(3):541-554.

Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306

Villa D, Larouche J-F, Cheung MC, et al. Rituximab Combined with Chemotherapy and Acalabrutinib Prior to Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: The Rectangle Trial. Blood. 2023;142:3042.

Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. New England Journal of Medicine. 2022;386(26):2482-2494.

Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica. 2019;104(5):e211-e214.

Wang ML, Blum KA, Martin P, et al. Long-term followup of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739-745.

Jain P, Zhao S, Lee HJ, et al. Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma. J Clin Oncol. 2022;40(2):202-212.

Dreyling M, Tam CS, Wang M, et al. A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. Future Oncol. 2021;17(3):255-262.

Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016-2025.

Phillips TJ, Bond D, Takiar R, et al. Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023;7(16):4518-4527.

Zhao X, Bodo J, Sun D, et al. Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways. Br J Haematol. 2015;168(5):765-768.

Trněný M, Lamy T, Walewski J, et al. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol.2016;17(3):319-331.

Ladetto M, Cortelazzo S, Ferrero S, et al. Lenalidomide maintenance after autologous haematopoietic stemcell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial. Lancet Haematol. 2021;8(1):e34-e44.

Karmali R, Abramson JS, Stephens DM, et al. Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma. Blood Adv. 2023;7(23):7361-7368.

Kumar A, Soumerai J, Abramson JS, et al. A Multicenter Phase 2 Trial of Zanubrutinib, Obinutuzumab, and Venetoclax (BOVen) in Patients with Treatment-Naïve, TP53-Mutant Mantle Cell Lymphoma. Blood. 2023;142(Supplement 1):738-738.

Wang M, Jain P, Lee HJ, et al. Ibrutinib Plus Rituximab and Venetoclax (IRV) Followed By Risk-Stratified Observation or Short Course R-Hypercvad/MTX in Young Patients with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-2 Clinical Trial. Blood. 2021;138(Supplement 1):3525-3525.

Blombery P, Cheah CY. Predicting the future in MCL with MRD. Blood. 2022;140(12):1332-1333.

Hoster E, Delfau-Larue M-H, Macintyre E, et al. Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial. Journal of Clinical Oncology. 2024;42(5):538-549.

Hoster E, Pott C. Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment. Hematology Am Soc Hematol Educ Program. 2016;2016(1):437-445.

Jung D, Jain P, Yao Y, Wang M. Advances in the assessment of minimal residual disease in mantle cell lymphoma. Journal of Hematology & Oncology. 2020;13(1):127.

Gerson JN, Handorf E, Villa D, et al. Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era. J Clin Oncol. 2019;37(6):471-480.

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(3):555-567.

Wang Y, Jain P, Locke FL, et al. Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. Journal of Clinical Oncology. 2023;41(14):2594-2606.

Phillips TJ, Dickinson M, Morschhauser F, et al. Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma. Blood. 2022;140(Supplement 1):178-180.

Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma(WINDOW-1): a single-arm, phase 2 trial. Lancet Oncol. 2022;23(3):406-415.

Guy D, Watkins M, Wan F, et al. A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma. Blood. 2020;136:8-9.

Greenwell IB, Switchenko JM, Craig AFM, et al. Bendamustine, Obinutuzumab and Venetoclax Results in High Complete Response Rates in Untreated Mantle Cell Lymphoma. Blood. 2022;140(Supplement 1):9373-9374.

Smith MR, Jegede O, Martin P, et al. Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411. Blood. 2022;140(Supplement 1):186-188.

Smith MR, Jegede O, Martin P, et al. ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab (BR)-based induction followed by rituximab (R) ± lenalidomide (L) consolidation for Mantle cell lymphoma: Effect of adding bortezomib to front-line BR induction on PFS. Journal of Clinical Oncology. 2021;39(15_suppl):7503-7503.

Epstein-Peterson ZD, Drill E, Aypar U, et al. Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation. Haematologica. 2023.

Albertsson-Lindblad A, Kolstad A, Laurell A, et al. Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma. Blood. 2016;128(14):1814-1820.

Gressin R, Daguindau N, Tempescul A, et al. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. Haematologica. 2019;104(1):138-146.

Portell CA, Jegede O, Bennani NN, et al. Primary Analysis and Results of Bendamustine, Rituximab, and Venetoclax (BR-VEN) for Initial Treatment of Mantle Cell Lymphoma in Subjects over 60 Years of Age (PrE0405). Blood. 2023;142(Supplement 1):733-733.

Wang M, Belada D, Cheah C, et al. A PHASE 3 STUDY OF ACALABRUTINIB PLUS BENDAMUSTINE AND RITUXIMAB IN ELDERLY (AGED ≥65 Years) TREATMENT-NAIVE PATIENTS WITH MANTLE CELL LYMPHOMA. Hematological Oncology. 2019;37(S2):554-555.

Downloads

Published

2024-06-27

How to Cite

1.
Gong IY, Kuruvilla J, Crump M. Mantle Cell Lymphoma: Evolving Frontline Treatment Strategies. Can Hematol Today [Internet]. 2024 Jun. 27 [cited 2024 Sep. 8];3(2):5–21. Available from: https://canadianhematologytoday.com/article/view/3-2-gong_et_al

Issue

Volume 3, Issue 2, Summer 2024

Section

Articles

License

Copyright (c) 2024 Canadian Hematology Today

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.