Dismantling the Status Quo: Venetoclax in Mantle Cell Lymphoma

Main Article Content

Joshua ML Casan Mary Ann Anderson John F Seymour


Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma, and remains a clinically challenging disease entity, particularly in the relapsed setting where outcomes are poor. However, recent innovations in targeted therapeutics have expanded treatment options and demonstrate significant efficacy even in relapsed disease. MCL frequently harbours aberrations of apoptosis pathways including over-expression of the anti-apoptotic protein BCL2. Such aberrancy promotes and sustains lymphomagenesis, thus rendering MCL an attractive target for venetoclax, the highly specific, orally bioavailable inhibitor of BCL2. Pre-clinical and early clinical data of venetoclax monotherapy demonstrated high response rates in relapsed/refractory MCL, though the durability of response in high-risk patients appears modest. More recently, clinical trials deploying combination strategies that pair venetoclax with other novel agents have been undertaken, with some promising early data reported. In this article, we review the biological rationale for deploying venetoclax in MCL, as well as the emerging data from clinical trials of venetoclax monotherapy and novel combinations.

Article Details

How to Cite
CASAN, Joshua ML; ANDERSON, Mary Ann; SEYMOUR, John F. Dismantling the Status Quo: Venetoclax in Mantle Cell Lymphoma. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2843>. Date accessed: 13 apr. 2024. doi: https://doi.org/10.18103/mra.v10i6.2843.
Research Articles


1. Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Brit J Cancer. 2015;112(9):1575-1584. doi:10.1038/bjc.2015.94
2. Jain P, Dreyling M, Seymour JF, Wang M. High-Risk Mantle Cell Lymphoma: Definition, Current Challenges, and Management. J Clin Oncol. 2020;38(36):4302-4316. doi:10.1200/jco.20.02287
3. 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. Brit J Haematol. 2012;158(3):355-362. doi:10.1111/j.1365-2141.2012.09174.x
4. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575. doi:10.1016/s0140-6736(16)00739-x
5. Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood. 2013;121(1):48-53. doi:10.1182/blood-2011-09-370320
6. Fu S, Wang M, Lairson DR, Li R, Zhao B, Du XL. Trends and variations in mantle cell lymphoma incidence from 1995 to 2013: A comparative study between Texas and National SEER areas. Oncotarget. 2017;8(68):112516-112529. doi:10.18632/oncotarget.22367
7. Cao C, Feng J, Gu H, et al. Distribution of lymphoid neoplasms in Northwest China: Analysis of 3244 cases according to WHO classification in a single institution. Ann Diagn Pathol. 2018;34:60-65. doi:10.1016/j.anndiagpath.2017.05.005
8. Nair R, Arora N, Mallath MK. Epidemiology of Non-Hodgkin’s Lymphoma in India. Oncology. 2016;91(Suppl 1):18-25. doi:10.1159/000447577
9. Epperla N, Hamadani M, Fenske TS, Costa LJ. Incidence and survival trends in mantle cell lymphoma. Brit J Haematol. 2018;181(5):703-706. doi:10.1111/bjh.14699
10. Hsi ED, Martin P. Indolent mantle cell lymphoma. Leukemia Lymphoma. 2013;55(4):761-767. doi:10.3109/10428194.2013.815353
11. Pulte D, Weberpals J, Jansen L, et al. Survival for patients with rare haematologic malignancies: Changes in the early 21st century. Eur J Cancer. 2017;84:81-87. doi:10.1016/j.ejca.2017.07.014
12. 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. Brit J Haematol. 2016;175(3):410-418. doi:10.1111/bjh.14241
13. Romaguera JE, Fayad LE, Feng L, et al. Ten‐year follow‐up after intense chemoimmunotherapy with Rituximab‐HyperCVAD alternating with Rituximab‐high dose methotrexate/cytarabine (R‐MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Brit J Haematol. 2010;150(2):200-208. doi:10.1111/j.1365-2141.2010.08228.x
14. 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. doi:10.1182/blood-2004-10-3883
15. Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687-2693. doi:10.1182/blood-2008-03-147025
16. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of Older Patients with Mantle-Cell Lymphoma. New Engl J Medicine. 2012;367(6):520-531. doi:10.1056/nejmoa1200920
17. Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Harris AW, Adams JM. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. Embo J. 1994;13(9):2124-2130. doi:10.1002/j.1460-2075.1994.tb06488.x
18. Gladden AB, Diehl JA. The Cyclin D1-dependent Kinase Associates with the Pre-replication Complex and Modulates RB·MCM7 Binding*. J Biol Chem. 2003;278(11):9754-9760. doi:10.1074/jbc.m212088200
19. Bienvenu F, Jirawatnotai S, Elias JE, et al. Transcriptional role of cyclin D1 in development revealed by a genetic–proteomic screen. Nature. 2010;463(7279):374-378. doi:10.1038/nature08684
20. Jirawatnotai S, Hu Y, Michowski W, et al. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature. 2011;474(7350):230-234. doi:10.1038/nature10155
21. Albero R, Enjuanes A, Demajo S, et al. Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms. J Clin Invest. 2018;128(9):4132-4147. doi:10.1172/jci96520
22. Martín-Garcia D, Navarro A, Valdés-Mas R, et al. CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma. Blood. 2019;133(9):940-951. doi:10.1182/blood-2018-07-862151
23. Lovec H, Grzeschiczek A, Kowalski MB, Möröy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. Embo J. 1994;13(15):3487-3495.
24. Greiner TC, Dasgupta C, Ho VV, et al. Mutation and genomic deletion status of ataxia telangiectasia mutated ( ATM ) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc National Acad Sci. 2006;103(7):2352-2357. doi:10.1073/pnas.0510441103
25. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ. Inhibition of Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells Leads to Induction of Cell Cycle Arrest and Apoptosis. J Immunol. 2003;171(1):88-95. doi:10.4049/jimmunol.171.1.88
26. Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-κB–targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20(1):87-92. doi:10.1038/nm.3435
27. Zhang J, Jima D, Moffitt AB, et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123(19):2988-2996. doi:10.1182/blood-2013-07-517177
28. 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. doi:10.1182/blood-2011-11-391474
29. Lai R, Rassidakis GZ, Medeiros LJ, Leventaki V, Keating M, Mcdonnell TJ. Expression of STAT3 and its phosphorylated forms in mantle cell lymphoma cell lines and tumours. J Pathology. 2003;199(1):84-89. doi:10.1002/path.1253
30. Baran-Marszak F, Boukhiar M, Harel S, et al. Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica. 2010;95(11):1865-1872. doi:10.3324/haematol.2009.019745
31. Rudelius M, Pittaluga S, Nishizuka S, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood. 2006;108(5):1668-1676. doi:10.1182/blood-2006-04-015586
32. Rizzatti EG, Falcão RP, Panepucci RA, et al. Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K‐AKT, WNT and TGFβ signalling pathways. Brit J Haematol. 2005;130(4):516-526. doi:10.1111/j.1365-2141.2005.05630.x
33. Psyrri A, Papageorgiou S, Liakata E, et al. Phosphatidylinositol 3′-Kinase Catalytic Subunit α Gene Amplification Contributes to the Pathogenesis of Mantle Cell Lymphoma. Clin Cancer Res. 2009;15(18):5724-5732. doi:10.1158/1078-0432.ccr-08-3215
34. Gelebart P, Anand M, Armanious H, et al. Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma. Blood. 2008;112(13):5171-5179. doi:10.1182/blood-2008-02-139212
35. Beà S, Salaverria I, Armengol L, et al. Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling. Blood. 2009;113(13):3059-3069. doi:10.1182/blood-2008-07-170183
36. Hartmann EM, Campo E, Wright G, et al. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. Blood. 2010;116(6):953-961. doi:10.1182/blood-2010-01-263806
37. Tagawa H, Karnan S, Suzuki R, et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24(8):1348-1358. doi:10.1038/sj.onc.1208300
38. Li Y, Bouchlaka MN, Wolff J, et al. FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene. 2016;35(48):6223-6234. doi:10.1038/onc.2016.155
39. Beltran E, Fresquet V, Martinez-Useros J, et al. A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma. Proc National Acad Sci. 2011;108(30):12461-12466. doi:10.1073/pnas.1018941108
40. Khoury JD, Medeiros LJ, Rassidakis GZ, McDonnell TJ, Abruzzo LV, Lai R. Expression of Mcl‐1 in mantle cell lymphoma is associated with high‐grade morphology, a high proliferative state, and p53 overexpression. J Pathology. 2003;199(1):90-97. doi:10.1002/path.1254
41. Dengler MA, Weilbacher A, Gutekunst M, et al. Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles’ heel in mantle cell lymphoma. Cell Death Dis. 2014;5(1):e1013. doi:10.1038/cddis.2013.552
42. Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Bio. 2019;20(3):175-193. doi:10.1038/s41580-018-0089-8
43. Llambi F, Moldoveanu T, Tait SWG, et al. A Unified Model of Mammalian BCL-2 Protein Family Interactions at the Mitochondria. Mol Cell. 2011;44(4):517-531. doi:10.1016/j.molcel.2011.10.001
44. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Bio. 2014;15(1):49-63. doi:10.1038/nrm3722
45. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013
46. Zaman S, Wang R, Gandhi V. Targeting the apoptosis pathway in hematologic malignancies. Leukemia Lymphoma. 2014;55(9):1980-1992. doi:10.3109/10428194.2013.855307
47. Bannerji R, Kitada S, Flinn IW, et al. Apoptotic-Regulatory and Complement-Protecting Protein Expression in Chronic Lymphocytic Leukemia: Relationship to In Vivo Rituximab Resistance. J Clin Oncol. 2003;21(8):1466-1471. doi:10.1200/jco.2003.06.012
48. Certo M, Moore VDG, Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351-365. doi:10.1016/j.ccr.2006.03.027
49. Tse C, Shoemaker AR, Adickes J, et al. ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor. Cancer Res. 2008;68(9):3421-3428. doi:10.1158/0008-5472.can-07-5836
50. Roberts AW, Seymour JF, Brown JR, et al. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease. J Clin Oncol. 2011;30(5):488-496. doi:10.1200/jco.2011.34.7898
51. Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149-1159. doi:10.1016/s1470-2045(10)70261-8
52. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375-388. doi:10.1016/j.ccr.2006.10.006
53. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208. doi:10.1038/nm.3048
54. Salem AH, Agarwal SK, Dunbar M, et al. Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor. J Clin Pharmacol. 2016;56(11):1355-1361. doi:10.1002/jcph.741
55. Agarwal SK, Hu B, Chien D, Wong SL, Salem AH. Evaluation of Rifampin’s Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL‐2 Inhibitor: Results of a Single‐ and Multiple‐Dose Study. J Clin Pharmacol. 2016;56(11):1335-1343. doi:10.1002/jcph.730
56. Lasica M, Anderson MA. Review of Venetoclax in CLL, AML and Multiple Myeloma. J Personalized Medicine. 2021;11(6):463. doi:10.3390/jpm11060463
57. 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. Brit J Haematol. 2015;168(5):765-768. doi:10.1111/bjh.13149
58. Ackler S, Oleksijew A, Chen J, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspectives. 2015;3(5):e00178. doi:10.1002/prp2.178
59. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016;127(25):3215-3224. doi:10.1182/blood-2016-01-688796
60. Davids MS, Roberts AW, Seymour JF, et al. Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol. 2017;35(8):JCO.2016.70.432. doi:10.1200/jco.2016.70.4320
61. 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(2):e68-e71. doi:10.3324/haematol.2018.198812
62. 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(6):623-629. doi:10.1002/ajh.25796
63. Sawalha Y, Goyal S, Switchenko JM, et al. Outcomes of Patients with Relapsed Mantle Cell Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis. Blood. 2020;136(Supplement 1):4-6. doi:10.1182/blood-2020-138878
64. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387(10020):770-778. doi:10.1016/s0140-6736(15)00667-4
65. Axelrod M, Ou Z, Brett LK, et al. Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia. 2014;28(2):407-410. doi:10.1038/leu.2013.249
66. Portell CA, Axelrod M, Brett LK, et al. Synergistic Cytotoxicity of Ibrutinib and the BCL2 Antagonist, ABT-199(GDC-0199) in Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL): Molecular Analysis Reveals Mechanisms of Target Interactions. Blood. 2014;124(21):509-509. doi:10.1182/blood.v124.21.509.509
67. Chiron D, Dousset C, Brosseau C, et al. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget. 2015;6(11):8750-8759. doi:10.18632/oncotarget.3275
68. Chang BY, Francesco M, Rooij MFMD, et al. Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood. 2013;122(14):2412-2424. doi:10.1182/blood-2013-02-482125
69. Davids MS, Keudell G von, Portell CA, et al. Revised Dose Ramp-Up to Mitigate the Risk of Tumor Lysis Syndrome When Initiating Venetoclax in Patients With Mantle Cell Lymphoma. J Clin Oncol. 2018;36(35):JCO.18.00359. doi:10.1200/jco.18.00359
70. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. New Engl J Medicine. 2018;378(13):1211-1223. doi:10.1056/nejmoa1715519
71. Handunnetti SM, Anderson MA, Burbury K, et al. Three Year Update of the Phase II ABT-199 (Venetoclax) and Ibrutinib in Mantle Cell Lymphoma (AIM) Study. Blood. 2019;134(Supplement_1):756-756. doi:10.1182/blood-2019-126619
72. Wang ML, Rule S, Martin P, et al. Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma. New Engl J Medicine. 2013;369(6):507-516. doi:10.1056/nejmoa1306220
73. Wang M, Ramchandren R, Chen R, et al. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021;14(1):179. doi:10.1186/s13045-021-01188-x
74. Portell CA, Wages NA, Kahl BS, et al. Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Blood Adv. 2022;6(5):1490-1498. doi:10.1182/bloodadvances.2021005357
75. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113(19):4604-4613. doi:10.1182/blood-2008-10-185827
76. Burger JA, Ford RJ. The microenvironment in mantle cell lymphoma: Cellular and molecular pathways and emerging targeted therapies. Semin Cancer Biol. 2011;21(5):308-312. doi:10.1016/j.semcancer.2011.09.006
77. Hostager BS, Bishop GA. CD40-Mediated Activation of the NF-κB2 Pathway. Front Immunol. 2013;4:376. doi:10.3389/fimmu.2013.00376
78. Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G. NF-κB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc National Acad Sci. 1999;96(16):9136-9141. doi:10.1073/pnas.96.16.9136
79. Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin’s lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res. 2005;65(1):264-276.
80. Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302-e306. doi:10.3324/haematol.2015.124560
81. Gouill SL, Morschhauser F, Chiron D, et al. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021;137(7):877-887. doi:10.1182/blood.2020008727
82. Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphomas. J Clin Oncol. 1999;17(4):1244-1244. doi:10.1200/jco.1999.17.4.1244
83. Wang M, Robak T, Maddocks KJ, et al. Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL). Blood. 2021;138(Supplement 1):2416-2416. doi:10.1182/blood-2021-146615
84. Song Y, Zhou K, Zou D hui, et al. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. Published online 2022. doi:10.1182/blood.2021014162
85. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/s0140-6736(17)33108-2
86. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014;32(27):3059-3067. doi:10.1200/jco.2013.54.8800
87. Habermann TM, Lossos IS, Justice G, et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Brit J Haematol. 2009;145(3):344-349. doi:10.1111/j.1365-2141.2009.07626.x
88. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22(7):1622-1627. doi:10.1093/annonc/mdq626
89. Goy A, Sinha R, Williams ME, et al. Single-Agent Lenalidomide in Patients With Mantle-Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: Phase II MCL-001 (EMERGE) Study. J Clin Oncol. 2013;31(29):3688-3695. doi:10.1200/jco.2013.49.2835
90. 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(7):716-723. doi:10.1016/s1470-2045(12)70200-0
91. Morrison VA, Jung SH, Johnson J, et al. Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501). Leukemia Lymphoma. 2014;56(4):958-964. doi:10.3109/10428194.2014.938333
92. Yamshon S, Martin P, Shah B, et al. Initial Treatment with Lenalidomide Plus Rituximab for Mantle Cell Lymphoma (MCL): 7-Year Analysis from a Multi-Center Phase II Study. Blood. 2020;136(Supplement 1):45-46. doi:10.1182/blood-2020-138731
93. 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. doi:10.1182/blood-2016-03-704023
94. Epstein-Peterson ZD, Batlevi CL, Caron P, et al. Frontline Sequential Immunochemotherapy Plus Lenalidomide for Mantle Cell Lymphoma Incorporating MRD Evaluation: Phase II, Investigator-Initiated, Single-Center Study. Blood. 2020;136(Supplement 1):11-12. doi:10.1182/blood-2020-136565
95. Jerkeman M, Kolstad A, Niemann CU, et al. Venetoclax, Lenalidomide and Rituximab for Patients with Relapsed or Refractory Mantle Cell Lymphoma - Data from the Nordic Lymphoma Group NLG-MCL7 (VALERIA) Phase I Trial: Stopping Treatment in Molecular Remission Is Feasible. Blood. 2020;136(Supplement 1):15-15. doi:10.1182/blood-2020-133273
96. Ma S, Seymour JF, Brander DM, et al. Efficacy of venetoclax plus rituximab for relapsed CLL: 5-year follow-up of continuous or limited- duration therapy. Blood. 2021;138(10):836-846. doi:10.1182/blood.2020009578
97. Agarwal R, Chan YC, Tam CS, et al. Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat Med. 2019;25(1):119-129. doi:10.1038/s41591-018-0243-z
98. Steinbrecher D, Seyfried F, Tausch E, et al. Venetoclax Resistance in Mantle Cell Lymphoma Is Mediated By BCL-XL and Can be Circumvent By Inhibiting the BH4 Domain of BCL-2. Blood. 2019;134(Supplement_1):1507-1507. doi:10.1182/blood-2019-127931
99. Choudhary GS, Al-harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6(1):e1593. doi:10.1038/cddis.2014.525
100. Guièze R, Liu VM, Rosebrock D, et al. Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Cancer Cell. 2019;36(4):369-384.e13. doi:10.1016/j.ccell.2019.08.005
101. Phillips DC, Xiao Y, Lam LT, et al. Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199). Blood Cancer J. 2016;6(3):e403. doi:10.1038/bcj.2016.12
102. Haselager MV, Kielbassa K, Burg J ter, et al. Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL. Blood. 2020;136(25):2918-2926. doi:10.1182/blood.2019004326
103. Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep-uk. 2016;6(1):27696. doi:10.1038/srep27696
104. Teh TC, Nguyen NY, Moujalled DM, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32(2):303-312. doi:10.1038/leu.2017.243
105. Huang S, Liu Y, Chen Z, Wang M, Jiang VC. PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. Am J Cancer Res. 2022;12(3):1102-1115.
106. Blombery P, Anderson MA, Gong J nan, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2018;9(3):CD-18-1119. doi:10.1158/2159-8290.cd-18-1119
107. Tausch E, Close W, Dolnik A, et al. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019;104(9):e434-e437. doi:10.3324/haematol.2019.222588
108. Birkinshaw RW, Gong J nan, Luo CS, et al. Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nat Commun. 2019;10(1):2385. doi:10.1038/s41467-019-10363-1
109. Thompson ER, Nguyen T, Kankanige Y, et al. Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors. Blood Adv. 2022;6(2):503-508. doi:10.1182/bloodadvances.2021006211
110. Anderson MA, Tam C, Lew TE, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129(25):3362-3370. doi:10.1182/blood-2017-01-763003