Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient.

1st Dept of Medicine Hematology General University Hospital Prague 128 08 Prague Czech Republic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University 128 53 Prague Czech Republic

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Cheah C.Y., Seymour J.F., Wang M.L. Mantle Cell Lymphoma. J. Clin. Oncol. 2016;34:1256–1269. doi: 10.1200/JCO.2015.63.5904. PubMed DOI

Swerdlow S.H., Campo E., Pileri S.A., Harris N.L., Stein H., Siebert R., Advani R., Ghielmini M., Salles G.A., Zelenetz A.D., et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. doi: 10.1182/blood-2016-01-643569. PubMed DOI PMC

Klener P., Fronkova E., Berkova A., Jaksa R., Lhotska H., Forsterova K., Soukup J., Kulvait V., Vargova J., Fiser K., et al. Mantle cell lymphoma-variant Richter syndrome: Detailed molecular-cytogenetic and backtracking analysis reveals slow evolution of a pre-MCL clone in parallel with CLL over several years. Int. J. Cancer. 2016;139:2252–2260. doi: 10.1002/ijc.30263. PubMed DOI

Klener P., Salek D., Pytlik R., Mocikova H., Forsterova K., Blahovcova P., Campr V., Prochazka V., Obr A., Jaksa 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:E50–E53. doi: 10.1002/ajh.25362. PubMed DOI

Klener P., Fronkova E., Belada D., Forsterova K., Pytlik R., Kalinova M., Simkovic M., Salek D., Mocikova H., Prochazka V., et al. Alternating R-CHOP and R-cytarabine is a safe and effective regimen for transplant-ineligible patients with a newly diagnosed mantle cell lymphoma. Hematol. Oncol. 2018;36:110–115. doi: 10.1002/hon.2483. PubMed DOI

Cheah C.Y., George A., Gine E., Chiappella A., Kluin-Nelemans H.C., Jurczak W., Krawczyk K., Mocikova H., Klener P., Salek D., et al. Central nervous system involvement in mantle cell lymphoma: Clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network. Ann. Oncol. 2013;24:2119–2123. doi: 10.1093/annonc/mdt139. PubMed DOI

Hadzidimitriou A., Agathangelidis A., Darzentas N., Murray F., Delfau-Larue M.H., Pedersen L.B., Lopez A.N., Dagklis A., Rombout P., Beldjord K., et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood. 2011;118:3088–3095. doi: 10.1182/blood-2011-03-343434. PubMed DOI

Xochelli A., Sutton L.A., Agathangelidis A., Stalika E., Karypidou M., Marantidou F., Lopez A.N., Papadopoulos G., Supikova J., Groenen P., et al. Molecular evidence for antigen drive in the natural history of mantle cell lymphoma. Am. J. Pathol. 2015;185:1740–1748. doi: 10.1016/j.ajpath.2015.02.006. PubMed DOI

Wiestner A., Tehrani M., Chiorazzi M., Wright G., Gibellini F., Nakayama K., Liu H., Rosenwald A., Muller-Hermelink H.K., Ott G., et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood. 2007;109:4599–4606. doi: 10.1182/blood-2006-08-039859. PubMed DOI PMC

Dal Col J., Dolcetti R. GSK-3beta inhibition: At the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma. Cell Cycle. 2008;7:2813–2816. doi: 10.4161/cc.7.18.6733. PubMed DOI

Salaverria I., Royo C., Carvajal-Cuenca A., Clot G., Navarro A., Valera A., Song J.Y., Woroniecka R., Rymkiewicz G., Klapper W., et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1− mantle cell lymphoma. Blood. 2013;121:1394–1402. doi: 10.1182/blood-2012-08-452284. PubMed DOI PMC

Martin-Garcia D., Navarro A., Valdes-Mas R., Clot G., Gutierrez-Abril J., Prieto M., Ribera-Cortada I., Woroniecka R., Rymkiewicz G., Bens S., et al. CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma. Blood. 2019;133:940–951. doi: 10.1182/blood-2018-07-862151. PubMed DOI PMC

Zhang J., Jima D., Moffitt A.B., Liu Q., Czader M., Hsi E.D., Fedoriw Y., Dunphy C.H., Richards K.L., Gill J.I., et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood. 2014;123:2988–2996. doi: 10.1182/blood-2013-07-517177. PubMed DOI PMC

Bea S., Valdes-Mas R., Navarro A., Salaverria I., Martin-Garcia D., Jares P., Gine E., Pinyol M., Royo C., Nadeu F., et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl. Acad. Sci. USA. 2013;110:18250–18255. doi: 10.1073/pnas.1314608110. PubMed DOI PMC

Lovec H., Grzeschiczek A., Kowalski M.B., Moroy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J. 1994;13:3487–3495. doi: 10.1002/j.1460-2075.1994.tb06655.x. PubMed DOI PMC

Watson I.R., Takahashi K., Futreal P.A., Chin L. Emerging patterns of somatic mutations in cancer. Nat. Rev. Genet. 2013;14:703–718. doi: 10.1038/nrg3539. PubMed DOI PMC

Kridel R., Meissner B., Rogic S., Boyle M., Telenius A., Woolcock B., Gunawardana J., Jenkins C., Cochrane C., Ben-Neriah S., et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood. 2012;119:1963–1971. doi: 10.1182/blood-2011-11-391474. PubMed DOI

Rahal R., Frick M., Romero R., Korn J.M., Kridel R., Chan F.C., Meissner B., Bhang H.E., Ruddy D., Kauffmann A., et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat. Med. 2014;20:87–92. doi: 10.1038/nm.3435. PubMed DOI

Yang P., Zhang W., Wang J., Liu Y., An R., Jing H. Genomic landscape and prognostic analysis of mantle cell lymphoma. Cancer Gene Ther. 2018;25:129–140. doi: 10.1038/s41417-018-0022-5. PubMed DOI

Wu C., de Miranda N.F., Chen L., Wasik A.M., Mansouri L., Jurczak W., Galazka K., Dlugosz-Danecka M., Machaczka M., Zhang H., et al. Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. Oncotarget. 2016;7:38180–38190. doi: 10.18632/oncotarget.9500. PubMed DOI PMC

Onaindia A., Medeiros L.J., Patel K.P. Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms. Mod. Pathol. 2017;30:1338–1366. doi: 10.1038/modpathol.2017.58. PubMed DOI

Ahmed M., Zhang L., Nomie K., Lam L., Wang M. Gene mutations and actionable genetic lesions in mantle cell lymphoma. Oncotarget. 2016;7:58638–58648. doi: 10.18632/oncotarget.10716. PubMed DOI PMC

Delfau-Larue M.H., Klapper W., Berger F., Jardin F., Briere J., Salles G., Casasnovas O., Feugier P., Haioun C., Ribrag V., et al. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015;126:604–611. doi: 10.1182/blood-2015-02-628792. PubMed DOI

Greiner T.C., Moynihan M.J., Chan W.C., Lytle D.M., Pedersen A., Anderson J.R., Weisenburger D.D. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood. 1996;87:4302–4310. PubMed

Eskelund C.W., Dahl C., Hansen J.W., Westman M., Kolstad A., Pedersen L.B., Montano-Almendras C.P., Husby S., Freiburghaus C., Ek S., et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903–1910. doi: 10.1182/blood-2017-04-779736. PubMed DOI

Aukema S.M., Hoster E., Rosenwald A., Canoni D., Delfau-Larue M.H., Rymkiewicz G., Thorns C., Hartmann S., Kluin-Nelemans H., Hermine O., 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;131:417–420. doi: 10.1182/blood-2017-07-797019. PubMed DOI

Greiner T.C., Dasgupta C., Ho V.V., Weisenburger D.D., Smith L.M., Lynch J.C., Vose J.M., Fu K., Armitage J.O., Braziel R.M., et al. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Proc. Natl. Acad. Sci. USA. 2006;103:2352–2357. doi: 10.1073/pnas.0510441103. PubMed DOI PMC

Williamson C.T., Kubota E., Hamill J.D., Klimowicz A., Ye R., Muzik H., Dean M., Tu L., Gilley D., Magliocco A.M., et al. Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53. EMBO Mol. Med. 2012;4:515–527. doi: 10.1002/emmm.201200229. PubMed DOI PMC

Golla R.M., Li M., Shen Y., Ji M., Yan Y., Fu K., Greiner T.C., McKeithan T.W., Chan W.C. Inhibition of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks. Hematol. Oncol. 2012;30:175–179. doi: 10.1002/hon.1020. PubMed DOI

Yan W., Yang Y., Yang W. Inhibition of SKP2 Activity Impaired ATM-Mediated DNA Repair and Enhanced Sensitivity of Cisplatin-Resistant Mantle Cell Lymphoma Cells. Cancer Biother. Radiopharm. 2019 doi: 10.1089/cbr.2019.2787. PubMed DOI

Jares P., Colomer D., Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: Perspectives for new targeted therapeutics. Nat. Rev. Cancer. 2007;7:750–762. doi: 10.1038/nrc2230. PubMed DOI

Vincent-Fabert C., Fiancette R., Rouaud P., Baudet C., Truffinet V., Magnone V., Guillaudeau A., Cogne M., Dubus P., Denizot Y. A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphoma-like lymphoma formation in mice. Am. J. Pathol. 2012;180:1688–1701. doi: 10.1016/j.ajpath.2012.01.004. PubMed DOI

Choe J.Y., Yun J.Y., Na H.Y., Huh J., Shin S.J., Kim H.J., Paik J.H., Kim Y.A., Nam S.J., Jeon Y.K., et al. MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma. Histopathology. 2016;68:442–449. doi: 10.1111/his.12760. PubMed DOI

Li Y., Bouchlaka M.N., Wolff J., Grindle K.M., Lu L., Qian S., Zhong X., Pflum N., Jobin P., Kahl B.S., et al. FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene. 2016;35:6223–6234. doi: 10.1038/onc.2016.155. PubMed DOI PMC

Yi S., Zou D., Li C., Zhong S., Chen W., Li Z., Xiong W., Liu W., Liu E., Cui R., et al. High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival. Oncotarget. 2015;6:42362–42371. doi: 10.18632/oncotarget.5705. PubMed DOI PMC

Bea S., Salaverria I., Armengol L., Pinyol M., Fernandez V., Hartmann E.M., Jares P., Amador V., Hernandez L., Navarro A., et al. Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling. Blood. 2009;113:3059–3069. doi: 10.1182/blood-2008-07-170183. PubMed DOI PMC

Pekarsky Y., Balatti V., Croce C.M. BCL2 and miR-15/16: From gene discovery to treatment. Cell Death Differ. 2018;25:21–26. doi: 10.1038/cdd.2017.159. PubMed DOI PMC

Khoury J.D., Medeiros L.J., Rassidakis G.Z., McDonnell T.J., Abruzzo L.V., Lai R. Expression of Mcl-1 in mantle cell lymphoma is associated with high-grade morphology, a high proliferative state, and p53 overexpression. J. Pathol. 2003;199:90–97. doi: 10.1002/path.1254. PubMed DOI

Tagawa H., Karnan S., Suzuki R., Matsuo K., Zhang X., Ota A., Morishima Y., Nakamura S., Seto M. Genome-wide array-based CGH for mantle cell lymphoma: Identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24:1348–1358. doi: 10.1038/sj.onc.1208300. PubMed DOI

Mestre-Escorihuela C., Rubio-Moscardo F., Richter J.A., Siebert R., Climent J., Fresquet V., Beltran E., Agirre X., Marugan I., Marin M., et al. Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas. Blood. 2007;109:271–280. doi: 10.1182/blood-2006-06-026500. PubMed DOI

Katz S.G., Labelle J.L., Meng H., Valeriano R.P., Fisher J.K., Sun H., Rodig S.J., Kleinstein S.H., Walensky L.D. Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood. 2014;123:884–893. doi: 10.1182/blood-2013-04-499079. PubMed DOI PMC

Prukova D., Andera L., Nahacka Z., Karolova J., Svaton M., Klanova M., Havranek O., Soukup J., Svobodova K., Zemanova Z., et al. Co-targeting of BCL2 with venetoclax and MCL1 with S63845 is synthetically lethal in vivo in relapsed mantle cell lymphoma. Clin. Cancer Res. 2019:3275. doi: 10.1158/1078-0432.Ccr-18-3275. PubMed DOI

Merolle M.I., Ahmed M., Nomie K., Wang M.L. The B cell receptor signaling pathway in mantle cell lymphoma. Oncotarget. 2018;9:25332–25341. doi: 10.18632/oncotarget.25011. PubMed DOI PMC

Rao E., Jiang C., Ji M., Huang X., Iqbal J., Lenz G., Wright G., Staudt L.M., Zhao Y., McKeithan T.W., et al. The miRNA-17 approximately 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia. 2012;26:1064–1072. doi: 10.1038/leu.2011.305. PubMed DOI

Kahl B.S., Spurgeon S.E., Furman R.R., Flinn I.W., Coutre S.E., Brown J.R., Benson D.M., Byrd J.C., Peterman S., Cho Y., et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL) Blood. 2014;123:3398–3405. doi: 10.1182/blood-2013-11-537555. PubMed DOI PMC

Thome M., Charton J.E., Pelzer C., Hailfinger S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb. Perspect. Biol. 2010;2:a003004. doi: 10.1101/cshperspect.a003004. PubMed DOI PMC

Zhang Q., Lenardo M.J., Baltimore D. 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology. Cell. 2017;168:37–57. doi: 10.1016/j.cell.2016.12.012. PubMed DOI PMC

Yang Y., Kelly P., Shaffer A.L., 3rd, Schmitz R., Yoo H.M., Liu X., Huang D.W., Webster D., Young R.M., Nakagawa M., et al. Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma. Cancer Cell. 2016;29:494–507. doi: 10.1016/j.ccell.2016.03.006. PubMed DOI PMC

Keats J.J., Fonseca R., Chesi M., Schop R., Baker A., Chng W.J., Van Wier S., Tiedemann R., Shi C.X., Sebag M., et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell. 2007;12:131–144. doi: 10.1016/j.ccr.2007.07.003. PubMed DOI PMC

Rossi D., Fangazio M., Rasi S., Vaisitti T., Monti S., Cresta S., Chiaretti S., Del Giudice I., Fabbri G., Bruscaggin A., et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012;119:2854–2862. doi: 10.1182/blood-2011-12-395673. PubMed DOI

Diop F., Moia R., Favini C., Spaccarotella E., De Paoli L., Bruscaggin A., Spina V., Terzi-di-Bergamo L., Arruga F., Tarantelli C., et al. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia. Haematologica. 2019:249550. doi: 10.3324/haematol.2019.219550. PubMed DOI PMC

Dai B., Grau M., Juilland M., Klener P., Horing E., Molinsky J., Schimmack G., Aukema S.M., Hoster E., Vogt N., et al. B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Blood. 2017;129:333–346. doi: 10.1182/blood-2016-05-718775. PubMed DOI

Kopan R., Ilagan M.X. The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell. 2009;137:216–233. doi: 10.1016/j.cell.2009.03.045. PubMed DOI PMC

Inamdar A.A., Goy A., Ayoub N.M., Attia C., Oton L., Taruvai V., Costales M., Lin Y.T., Pecora A., Suh K.S. Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents. Oncotarget. 2016;7:48692–48731. doi: 10.18632/oncotarget.8961. PubMed DOI PMC

Swaroop A., Oyer J.A., Will C.M., Huang X., Yu W., Troche C., Bulic M., Durham B.H., Wen Q.J., Crispino J.D., et al. An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene. 2019;38:671–686. doi: 10.1038/s41388-018-0474-y. PubMed DOI PMC

Zhang J., Lee Y.R., Dang F., Gan W., Menon A.V., Katon J.M., Hsu C.H., Asara J.M., Tibarewal P., Leslie N.R., et al. PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage. Cancer Discov. 2019:CD-18-0083. doi: 10.1158/2159-8290.CD-18-0083. PubMed DOI PMC

Jain P., Kanagal-Shamanna R., Zhang S., Ahmed M., Ghorab A., Zhang L., Ok C.Y., Li S., Hagemeister F., Zeng D., et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. Br. J. Haematol. 2018;183:578–587. doi: 10.1111/bjh.15567. PubMed DOI

Shen Y., Morishita M., Lee D., Kim S., Lee T., Mevius D., Roh Y., di Luccio E. Identification of LEM-14 inhibitor of the oncoprotein NSD2. Biochem. Biophys. Res. Commun. 2019;508:102–108. doi: 10.1016/j.bbrc.2018.11.037. PubMed DOI

Pasqualucci L., Trifonov V., Fabbri G., Ma J., Rossi D., Chiarenza A., Wells V.A., Grunn A., Messina M., Elliot O., et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 2011;43:830–837. doi: 10.1038/ng.892. PubMed DOI PMC

Chen R., Frankel P., Popplewell L., Siddiqi T., Ruel N., Rotter A., Thomas S.H., Mott M., Nathwani N., Htut M., et al. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica. 2015;100:357–362. doi: 10.3324/haematol.2014.117473. PubMed DOI PMC

Oki Y., Buglio D., Fanale M., Fayad L., Copeland A., Romaguera J., Kwak L.W., Pro B., de Castro Faria S., Neelapu S., et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin. Cancer Res. 2013;19:6882–6890. doi: 10.1158/1078-0432.CCR-13-1906. PubMed DOI PMC

Evens A.M., Balasubramanian S., Vose J.M., Harb W., Gordon L.I., Langdon R., Sprague J., Sirisawad M., Mani C., Yue J., et al. A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma. Clin. Cancer Res. 2016;22:1059–1066. doi: 10.1158/1078-0432.CCR-15-0624. PubMed DOI

Yazbeck V., Shafer D., Perkins E.B., Coppola D., Sokol L., Richards K.L., Shea T., Ruan J., Parekh S., Strair R., et al. A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma. Clin. LymphomaMyeloma Leuk. 2018;18:569–575. doi: 10.1016/j.clml.2018.05.023. PubMed DOI PMC

Shin D.Y., Kim S.J., Yoon D.H., Park Y., Kong J.H., Kim J.A., Kim B.S., Kim H.J., Won J.H., Park S.K., et al. Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: An interim analysis. Cancer Chemother. Pharmacol. 2016;77:865–873. doi: 10.1007/s00280-016-3005-y. PubMed DOI

Agarwal R., Chan Y.-C., Tam C.S., Hunter T., Vassiliadis D., Teh C.E., Thijssen R., Yeh P., Wong S.Q., Ftouni S., et al. Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 2019;25:119–129. doi: 10.1038/s41591-018-0243-z. PubMed DOI

Royo C., Navarro A., Clot G., Salaverria I., Gine E., Jares P., Colomer D., Wiestner A., Wilson W.H., Vegliante M.C., et al. Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia. 2012;26:1895–1898. doi: 10.1038/leu.2012.72. PubMed DOI PMC

Queiros A.C., Beekman R., Vilarrasa-Blasi R., Duran-Ferrer M., Clot G., Merkel A., Raineri E., Russinol N., Castellano G., Bea S., et al. Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage. Cancer Cell. 2016;30:806–821. doi: 10.1016/j.ccell.2016.09.014. PubMed DOI PMC

Vegliante M.C., Palomero J., Perez-Galan P., Roue G., Castellano G., Navarro A., Clot G., Moros A., Suarez-Cisneros H., Bea S., et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood. 2013;121:2175–2185. doi: 10.1182/blood-2012-06-438937. PubMed DOI

Ribera-Cortada I., Martinez D., Amador V., Royo C., Navarro A., Bea S., Gine E., de Leval L., Serrano S., Wotherspoon A., et al. Plasma cell and terminal B-cell differentiation in mantle cell lymphoma mainly occur in the SOX11-negative subtype. Mod. Pathol. 2015;28:1435–1447. doi: 10.1038/modpathol.2015.99. PubMed DOI

Kuo P.Y., Jatiani S.S., Rahman A.H., Edwards D., Jiang Z., Ahr K., Perumal D., Leshchenko V.V., Brody J., Shaknovich R., et al. SOX11 augments BCR signaling to drive MCL-like tumor development. Blood. 2018;131:2247–2255. doi: 10.1182/blood-2018-02-832535. PubMed DOI PMC

Palomero J., Vegliante M.C., Rodriguez M.L., Eguileor A., Castellano G., Planas-Rigol E., Jares P., Ribera-Cortada I., Cid M.C., Campo E., et al. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma. Blood. 2014;124:2235–2247. doi: 10.1182/blood-2014-04-569566. PubMed DOI

Balsas P., Palomero J., Eguileor A., Rodriguez M.L., Vegliante M.C., Planas-Rigol E., Sureda-Gomez M., Cid M.C., Campo E., Amador V. SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma. Blood. 2017;130:501–513. doi: 10.1182/blood-2017-04-776740. PubMed DOI

Hoster E., Dreyling M., Klapper W., Gisselbrecht C., van Hoof A., Kluin-Nelemans H.C., Pfreundschuh M., Reiser M., Metzner B., Einsele H., et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111:558–565. doi: 10.1182/blood-2007-06-095331. PubMed DOI

Hoster E., Klapper W., Hermine O., Kluin-Nelemans H.C., Walewski J., van Hoof A., Trneny M., Geisler C.H., Di Raimondo F., Szymczyk M., et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J. Clin. Oncol. 2014;32:1338–1346. doi: 10.1200/JCO.2013.52.2466. PubMed DOI

Greenwell I.B., Staton A.D., Lee M.J., Switchenko J.M., Saxe D.F., Maly J.J., Blum K.A., Grover N.S., Mathews S.P., Gordon M.J., et al. Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy. Cancer. 2018;124:2306–2315. doi: 10.1002/cncr.31328. PubMed DOI PMC

Sarkozy C., Terre C., Jardin F., Radford I., Roche-Lestienne C., Penther D., Bastard C., Rigaudeau S., Pilorge S., Morschhauser F., et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index. Genes Chromosom. Cancer. 2014;53:106–116. doi: 10.1002/gcc.22123. PubMed DOI

Determann O., Hoster E., Ott G., Wolfram Bernd H., Loddenkemper C., Leo Hansmann M., Barth T.E., Unterhalt M., Hiddemann W., Dreyling M., et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: Results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008;111:2385–2387. doi: 10.1182/blood-2007-10-117010. PubMed DOI

Hoster E., Rosenwald A., Berger F., Bernd H.W., Hartmann S., Loddenkemper C., Barth T.F., Brousse N., Pileri S., Rymkiewicz G., 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;34:1386–1394. doi: 10.1200/JCO.2015.63.8387. PubMed DOI

Dreyling M., Klapper W., Rule S. Blastoid and pleomorphic mantle cell lymphoma: Still a diagnostic and therapeutic challenge! Blood. 2018;132:2722–2729. doi: 10.1182/blood-2017-08-737502. PubMed DOI

Ruan J., Martin P., Shah B., Schuster S.J., Smith S.M., Furman R.R., Christos P., Rodriguez A., Svoboda J., Lewis J., et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. N. Engl. J. Med. 2015;373:1835–1844. doi: 10.1056/NEJMoa1505237. PubMed DOI PMC

Kumar A., Ying Z., Alperovich A., Dogan A., Hamlin P., Moskowitz C., Pichardo J., Portlock C., Sha F., Zelenetz A.D., et al. Clinical presentation determines selection of patients for initial observation in mantle cell lymphoma. Haematologica. 2019;104:e163–e166. doi: 10.3324/haematol.2018.201350. PubMed DOI PMC

Hermine O., Hoster E., Walewski J., Bosly A., Stilgenbauer S., Thieblemont C., Szymczyk M., Bouabdallah R., Kneba M., Hallek M., 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;388:565–575. doi: 10.1016/s0140-6736(16)00739-x. PubMed DOI

Geisler C.H., Kolstad A., Laurell A., Andersen N.S., Pedersen L.B., Jerkeman M., Eriksson M., Nordstrom M., Kimby E., Boesen A.M., 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;112:2687–2693. doi: 10.1182/blood-2008-03-147025. PubMed DOI PMC

Geisler C.H., Kolstad A., Laurell A., Jerkeman M., Raty R., Andersen N.S., Pedersen L.B., Eriksson M., Nordstrom M., Kimby E., 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;158:355–362. doi: 10.1111/j.1365-2141.2012.09174.x. PubMed DOI

Lenz G., Dreyling M., Hoster E., Wormann B., Duhrsen U., Metzner B., Eimermacher H., Neubauer A., Wandt H., Steinhauer H., et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG) J. Clin. Oncol. 2005;23:1984–1992. doi: 10.1200/jco.2005.08.133. PubMed DOI

Gerson J.N., Barta S.K. Mantle Cell Lymphoma: Which Patients Should We Transplant? Curr. Hematol. Malig. Rep. 2019;14:239–246. doi: 10.1007/s11899-019-00520-0. PubMed DOI

Le Gouill S., Thieblemont C., Oberic L., Moreau A., Bouabdallah K., Dartigeas C., Damaj G., Gastinne T., Ribrag V., Feugier P., et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. N. Engl. J. Med. 2017;377:1250–1260. doi: 10.1056/NEJMoa1701769. PubMed DOI

Dietrich S., Weidle J., Rieger M., Meissner J., Radujkovic A., Ho A.D., Dreger P., Witzens-Harig M. Rituximab maintenance therapy after autologous stem cell transplantation prolongs progression-free survival in patients with mantle cell lymphoma. Leukemia. 2014;28:708–709. doi: 10.1038/leu.2013.332. PubMed DOI

Graf S.A., Stevenson P.A., Holmberg L.A., Till B.G., Press O.W., Chauncey T.R., Smith S.D., Philip M., Orozco J.J., Shustov A.R., et al. Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann. Oncol. 2015;26:2323–2328. doi: 10.1093/annonc/mdv364. PubMed DOI PMC

Mei M.G., Cao T.M., Chen L., Song J.Y., Siddiqi T., Cai J.L., Farol L.T., Al Malki M.M., Salhotra A., Aldoss I., et al. Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 2017;23:1861–1869. doi: 10.1016/j.bbmt.2017.07.006. PubMed DOI PMC

Kumar A., Sha F., Toure A., Dogan A., Ni A., Batlevi C.L., Palomba M.L.M., Portlock C., Straus D.J., Noy A., et al. Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: Progressive shortening in response duration and survival after each relapse. Blood Cancer J. 2019;9:50. doi: 10.1038/s41408-019-0209-5. PubMed DOI PMC

Gerson J.N., Handorf E., Villa D., Gerrie A.S., Chapani P., Li S., Medeiros L.J., Wang M.I., Cohen J.B., Calzada O., et al. Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era. J. Clin. Oncol. 2019;37:471–480. doi: 10.1200/JCO.18.00690. PubMed DOI PMC

Visco C., Finotto S., Zambello R., Paolini R., Menin A., Zanotti R., Zaja F., Semenzato G., Pizzolo G., D’Amore E.S., et al. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J. Clin. Oncol. 2013;31:1442–1449. doi: 10.1200/JCO.2012.45.9842. PubMed DOI

Rummel M.J., Niederle N., Maschmeyer G., Banat G.A., von Grunhagen U., Losem C., Kofahl-Krause D., Heil G., Welslau M., Balser C., 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;381:1203–1210. doi: 10.1016/S0140-6736(12)61763-2. PubMed DOI

Robak T., Jin J., Pylypenko H., Verhoef G., Siritanaratkul N., Drach J., Raderer M., Mayer J., Pereira J., Tumyan G., 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, open-label, phase 3 study. Lancet. Oncol. 2018;19:1449–1458. doi: 10.1016/s1470-2045(18)30685-5. PubMed DOI

Kluin-Nelemans H.C., Hoster E., Hermine O., Walewski J., Trneny M., Geisler C.H., Stilgenbauer S., Thieblemont C., Vehling-Kaiser U., Doorduijn J.K., et al. Treatment of older patients with mantle-cell lymphoma. N. Engl. J. Med. 2012;367:520–531. doi: 10.1056/NEJMoa1200920. PubMed DOI

Visco C., Chiappella A., Nassi L., Patti C., Ferrero S., Barbero D., Evangelista A., Spina M., Molinari A., Rigacci L., et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: A multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4:e15–e23. doi: 10.1016/S2352-3026(16)30185-5. PubMed DOI

Obr A., Prochazka V., Papajik T., Klener P., Jr., Janikova A., Salek D., Belada D., Pytlik R., Sykorova A., Mocikova H., et al. Maintenance rituximab in newly diagnosed mantle cell lymphoma patients: A real world analysis from the Czech lymphoma study group registry(dagger) Leuk. Lymphoma. 2019;60:748–755. doi: 10.1080/10428194.2018.1508672. PubMed DOI

Chen R.W., Palmer J.M., Tomassetti S., Popplewell L.L., Alluin J., Chomchan P., Nademanee A.P., Siddiqi T., Tsai N.C., Chen L., et al. Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation. J. Hematol. Oncol. 2018;11:87. doi: 10.1186/s13045-018-0631-3. PubMed DOI PMC

Till B.G. Maintenance Therapy in Diffuse Large B Cell Lymphoma and Mantle Cell Lymphoma. Curr. Treat. Options Oncol. 2018;19:45. doi: 10.1007/s11864-018-0561-x. PubMed DOI

Klener P., Fronkova E., Kalinova M., Belada D., Forsterova K., Pytlik R., Blahovcova P., Simkovic M., Salek D., Mocikova H., et al. Potential loss of prognostic significance of minimal residual disease assessment after R-CHOP-based induction in elderly patients with mantle cell lymphoma in the era of rituximab maintenance. Hematol. Oncol. 2018;36:773–778. doi: 10.1002/hon.2550. PubMed DOI

Visco C., Tisi M.C., Evangelista A., Di Rocco A., Zoellner A.K., Zilioli V.R., Hohaus S., Sciarra R., Re A., Tecchio C., et al. Time to progression of mantle cell lymphoma after high-dose cytarabine-based regimens defines patients risk for death. Br. J. Haematol. 2019;185:940–944. doi: 10.1111/bjh.15643. PubMed DOI

Pott C., Hoster E., Delfau-Larue M.H., Beldjord K., Bottcher S., Asnafi V., Plonquet A., Siebert R., Callet-Bauchu E., Andersen N., et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: A European MCL intergroup study. Blood. 2010;115:3215–3223. doi: 10.1182/blood-2009-06-230250. PubMed DOI PMC

Andersen N.S., Pedersen L.B., Laurell A., Elonen E., Kolstad A., Boesen A.M., Pedersen L.M., Lauritzsen G.F., Ekanger R., Nilsson-Ehle H., et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J. Clin. Oncol. 2009;27:4365–4370. doi: 10.1200/JCO.2008.21.3116. PubMed DOI

Pott C., Bruggemann M., Ritgen M., van der Velden V.H.J., van Dongen J.J.M., Kneba M. MRD Detection in B-Cell Non-Hodgkin Lymphomas Using Ig Gene Rearrangements and Chromosomal Translocations as Targets for Real-Time Quantitative PCR. Methods Mol. Biol. (CliftonN.J.) 2019;1956:199–228. doi: 10.1007/978-1-4939-9151-8_9. PubMed DOI

Smith A., Roman E., Appleton S., Howell D., Johnson R., Burton C., Patmore R. Impact of novel therapies for mantle cell lymphoma in the real world setting: A report from the UK’s Haematological Malignancy Research Network (HMRN) Br. J. Haematol. 2018;181:215–228. doi: 10.1111/bjh.15170. PubMed DOI PMC

Epperla N., Hamadani M., Fenske T.S., Costa L.J. Incidence and survival trends in mantle cell lymphoma. Br. J. Haematol. 2018;181:703–706. doi: 10.1111/bjh.14699. PubMed DOI

Klanova M., Lorkova L., Vit O., Maswabi B., Molinsky J., Pospisilova J., Vockova P., Mavis C., Lateckova L., Kulvait V., et al. Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogs gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents. Mol. Cancer. 2014;13:159. doi: 10.1186/1476-4598-13-159. PubMed DOI PMC

Wang Y., Zhang L.L., Champlin R.E., Wang M.L. Targeting Bruton’s tyrosine kinase with ibrutinib in B-cell malignancies. Clin. Pharmacol. Ther. 2015;97:455–468. doi: 10.1002/cpt.85. PubMed DOI

Wang M., Rule S., Zinzani P.L., Goy A., Casasnovas O., Smith S.D., Damaj G., Doorduijn J., Lamy T., Morschhauser F., et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): A single-arm, multicentre, phase 2 trial. Lancet. 2018;391:659–667. doi: 10.1016/S0140-6736(17)33108-2. PubMed DOI PMC

Wang M.L., Rule S., Martin P., Goy A., Auer R., Kahl B.S., Jurczak W., Advani R.H., Romaguera J.E., Williams M.E., et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 2013;369:507–516. doi: 10.1056/NEJMoa1306220. PubMed DOI PMC

Dreyling M., Jurczak W., Jerkeman M., Silva R.S., Rusconi C., Trneny M., Offner F., Caballero D., Joao C., Witzens-Harig 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;387:770–778. doi: 10.1016/S0140-6736(15)00667-4. PubMed DOI

Martin P., Maddocks K., Leonard J.P., Ruan J., Goy A., Wagner-Johnston N., Rule S., Advani R., Iberri D., Phillips T., et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559–1563. doi: 10.1182/blood-2015-10-673145. PubMed DOI

Cheah C.Y., Chihara D., Romaguera J.E., Fowler N.H., Seymour J.F., Hagemeister F.B., Champlin R.E., Wang M.L. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann. Oncol. 2015;26:1175–1179. doi: 10.1093/annonc/mdv111. PubMed DOI

Epperla N., Hamadani M., Cashen A.F., Ahn K.W., Oak E., Kanate A.S., Calzada O., Cohen J.B., Farmer L., Ghosh N., et al. Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a “real world” study. Hematol. Oncol. 2017;35:528–535. doi: 10.1002/hon.2380. PubMed DOI

Dreger P., Michallet M., Bosman P., Dietrich S., Sobh M., Boumendil A., Nagler A., Scheid C., Cornelissen J., Niederwieser D., et al. Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: A study by the EBMT Chronic Malignancies and Lymphoma Working Parties. Bone Marrow Transplant. 2019;54:44–52. doi: 10.1038/s41409-018-0207-4. PubMed DOI

Rule S., Cook G., Russell N.H., Hunter A., Robinson S., Morley N., Sureda A., Patrick P., Clifton-Hadley L., Adedayo T., et al. Allogeneic stem cell transplantation as part of front line therapy for Mantle cell lymphoma. Br. J. Haematol. 2019;184:999–1005. doi: 10.1111/bjh.15723. PubMed DOI

Ma J., Lu P., Guo A., Cheng S., Zong H., Martin P., Coleman M., Wang Y.L. Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells. Br. J. Haematol. 2014;166:849–861. doi: 10.1111/bjh.12974. PubMed DOI

Hershkovitz-Rokah O., Pulver D., Lenz G., Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: Clinical, molecular and treatment aspects. Br. J. Haematol. 2018;181:306–319. doi: 10.1111/bjh.15108. PubMed DOI

Chiron D., Di Liberto M., Martin P., Huang X., Sharman J., Blecua P., Mathew S., Vijay P., Eng K., Ali S., et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–1035. doi: 10.1158/2159-8290.CD-14-0098. PubMed DOI PMC

Zhao X., Lwin T., Silva A., Shah B., Tao J., Fang B., Zhang L., Fu K., Bi C., Li J., et al. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat. Commun. 2017;8:14920. doi: 10.1038/ncomms14920. PubMed DOI PMC

Compagno M., Wang Q., Pighi C., Cheong T.C., Meng F.L., Poggio T., Yeap L.S., Karaca E., Blasco R.B., Langellotto F., et al. Phosphatidylinositol 3-kinase delta blockade increases genomic instability in B cells. Nature. 2017;542:489–493. doi: 10.1038/nature21406. PubMed DOI PMC

Martin P., Bartlett N.L., Blum K.A., Park S., Maddocks K., Ruan J., Ridling L., Dittus C., Chen Z., Huang X., et al. A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma. Blood. 2019;133:1201–1204. doi: 10.1182/blood-2018-11-886457. PubMed DOI PMC

Wang M.L., Lee H., Chuang H., Wagner-Bartak N., Hagemeister F., Westin J., Fayad L., Samaniego F., Turturro F., Oki Y., et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: A single-centre, open-label, phase 2 trial. Lancet. Oncol. 2016;17:48–56. doi: 10.1016/S1470-2045(15)00438-6. PubMed DOI

Tam C.S., Anderson M.A., Pott C., Agarwal R., Handunnetti S., Hicks R.J., Burbury K., Turner G., Di Iulio J., Bressel M., et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N. Engl. J. Med. 2018;378:1211–1223. doi: 10.1056/NEJMoa1715519. PubMed DOI

Robak P., Robak T. Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later. Drugs RD. 2019;19:73–92. doi: 10.1007/s40268-019-0269-9. PubMed DOI PMC

Fisher R.I., Bernstein S.H., Kahl B.S., Djulbegovic B., Robertson M.J., de Vos S., Epner E., Krishnan A., Leonard J.P., Lonial S., et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 2006;24:4867–4874. doi: 10.1200/JCO.2006.07.9665. PubMed DOI

Lamm W., Kaufmann H., Raderer M., Hoffmann M., Chott A., Zielinski C., Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica. 2011;96:1008–1014. doi: 10.3324/haematol.2011.041392. PubMed DOI PMC

Friedberg J.W., Vose J.M., Kelly J.L., Young F., Bernstein S.H., Peterson D., Rich L., Blumel S., Proia N.K., Liesveld J., et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011;117:2807–2812. doi: 10.1182/blood-2010-11-314708. PubMed DOI PMC

Zinzani P.L., Vose J.M., Czuczman M.S., Reeder C.B., Haioun C., Polikoff J., Tilly H., Zhang L., Prandi K., Li J., et al. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: Subset analysis of the NHL-003 study. Ann. Oncol. 2013;24:2892–2897. doi: 10.1093/annonc/mdt366. PubMed DOI PMC

Goy A., Sinha R., Williams M.E., Kalayoglu Besisik S., Drach J., Ramchandren R., Zhang L., Cicero S., Fu T., Witzig T.E. 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;31:3688–3695. doi: 10.1200/JCO.2013.49.2835. PubMed DOI PMC

Trneny M., Lamy T., Walewski J., Belada D., Mayer J., Radford J., Jurczak W., Morschhauser F., Alexeeva J., Rule S., 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;17:319–331. doi: 10.1016/S1470-2045(15)00559-8. PubMed DOI

Hagner P.R., Chiu H., Ortiz M., Apollonio B., Wang M., Couto S., Waldman M.F., Flynt E., Ramsay A.G., Trotter M., et al. Activity of lenalidomide in mantle cell lymphoma can be explained by NK cell-mediated cytotoxicity. Br. J. Haematol. 2017;179:399–409. doi: 10.1111/bjh.14866. PubMed DOI

Hess G., Herbrecht R., Romaguera J., Verhoef G., Crump M., Gisselbrecht C., Laurell A., Offner F., Strahs A., Berkenblit A., et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J. Clin. Oncol. 2009;27:3822–3829. doi: 10.1200/JCO.2008.20.7977. PubMed DOI

Davids M.S., Roberts A.W., Seymour J.F., Pagel J.M., Kahl B.S., Wierda W.G., Puvvada S., Kipps T.J., Anderson M.A., Salem A.H., et al. Phase I First-in-Human Study of Venetoclax in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma. J. Clin. Oncol. 2017;35:826–833. doi: 10.1200/JCO.2016.70.4320. PubMed DOI PMC

Eyre T.A., Walter H.S., Iyengar S., Follows G., Cross M., Fox C.P., Hodson A., Coats J., Narat S., Morley N., et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica. 2019;104:e68–e71. doi: 10.3324/haematol.2018.198812. PubMed DOI PMC

Andorsky D.J., Kolibaba K.S., Assouline S., Forero-Torres A., Jones V., Klein L.M., Patel-Donnelly D., Smith M., Ye W., Shi W., et al. An open-label phase 2 trial of entospletinib in indolent non-Hodgkin lymphoma and mantle cell lymphoma. Br. J. Haematol. 2019;184:215–222. doi: 10.1111/bjh.15552. PubMed DOI PMC

Morschhauser F., Seymour J.F., Kluin-Nelemans H.C., Grigg A., Wolf M., Pfreundschuh M., Tilly H., Raemaekers J., van’t Veer M.B., Milpied N., et al. A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann. Oncol. 2008;19:247–253. doi: 10.1093/annonc/mdm463. PubMed DOI

Xu-Monette Z.Y., Zhou J., Young K.H. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131:68–83. doi: 10.1182/blood-2017-07-740993. PubMed DOI PMC

Levin A., Shah N.N. Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. Am. J. Hematol. 2019;94:S18–S23. doi: 10.1002/ajh.25403. PubMed DOI

Montico B., Lapenta C., Ravo M., Martorelli D., Muraro E., Zeng B., Comaro E., Spada M., Donati S., Santini S.M., et al. Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy. Oncoimmunology. 2017;6:e1356964. doi: 10.1080/2162402X.2017.1356964. PubMed DOI PMC

Cox M.C., Castiello L., Mattei M., Santodonato L., D’Agostino G., Muraro E., Martorelli D., Lapenta C., Di Napoli A., Di Landro F., et al. Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNalpha-Dendritic Cells and Rituximab. Clin. Cancer Res. 2019:0709. doi: 10.1158/1078-0432.ccr-19-0709. PubMed DOI

Concurrent TP53 and CDKN2A Gene Aberrations in Newly Diagnosed Mantle Cell Lymphoma Correlate with Chemoresistance and Call for Innovative Upfront Therapy