##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 147 No. 3738 (2017)

New treatment for non-Hodgkin B-cell lymphomas with a special focus on the impact of junctional adhesion molecules

  • Beat A. Imhof
  • Thomas Matthes
Cite this as:
Swiss Med Wkly. 2017;147:w14487
Published
12.09.2017

Summary

Current therapeutic modalities used for B-cell lymphoma include chemotherapy, immunotherapy, and radiation therapy. Chemotherapy together with anti-CD20 monoclonal antibodies forms the cornerstone of therapy and has a curative, as well as a palliative, role in this disease. New treatment modalities targeting specific molecules on the surface of lymphoma cells or intracellular pathways regulating apoptosis, proliferation and cell division are intensively investigated. One such target is JAM-C, a molecule implicated in cell adhesion and in B cell migration and whose inhibition blocks B cells from reaching their supportive microenvironments in lymphoid organs. Hopefully this and other strategies will help to improve survival of B cell lymphoma patients in the future.

References

  1. Felicitas Hitz VA, Matthias Lorez, and the NICER Working Group. Survival Trends for non- Hodgkin lymphoma patients in Switzerland. Schweizer Krebsbulletin. 2015;1:61–6.
  2. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs. 2003;63(8):803–43.https://doi.org/10.2165/00003495-200363080-00005
  3. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.https://doi.org/10.1056/NEJMoa011795
  4. Raderer M, Kiesewetter B, Ferreri AJ. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CA Cancer J Clin. 2016;66(2):153–71.https://doi.org/10.3322/caac.21330
  5. Foster LH, Portell CA. The role of infectious agents, antibiotics, and antiviral therapy in the treatment of extranodal marginal zone lymphoma and other low-grade lymphomas. Curr Treat Options Oncol. 2015;16(6):28.https://doi.org/10.1007/s11864-015-0344-6
  6. Annibali O, Sabatino F, Mantelli F, Olimpieri OM, Bonini S, Avvisati G. Review article: Mucosa-associated lymphoid tissue (MALT)-type lymphoma of ocular adnexa. Biology and treatment. Crit Rev Oncol Hematol. 2016;100:37–45.https://doi.org/10.1016/j.critrevonc.2016.01.009
  7. Ferreri AJ, Govi S, Pasini E, Mappa S, Bertoni F, Zaja F, et al. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J Clin Oncol. 2012;30(24):2988–94.https://doi.org/10.1200/JCO.2011.41.4466
  8. Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am J Transplant. 2006;6(5 Pt 1):859–66.https://doi.org/10.1111/j.1600-6143.2006.01288.x
  9. Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, Fauti T, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12(10):2031–42.https://doi.org/10.1158/1535-7163.MCT-12-1182
  10. Grosicki S. Ofatumumab for the treatment of chronic lymphocytic leukemia. Expert Rev Hematol. 2015;8(3):265–72.https://doi.org/10.1586/17474086.2015.1037736
  11. Al-Sawaf O, Fischer K, Engelke A, Pflug N, Hallek M, Goede V. Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy. Drug Des Devel Ther. 2017;11:295–304.https://doi.org/10.2147/DDDT.S104869
  12. Marcus RE, Davies DA, Ando K, Klapper W, Opat S, Owen CJ, et al. Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study. Blood. 2017;128:6.
  13. Micallef IN, Maurer MJ, Wiseman GA, Nikcevich DA, Kurtin PJ, Cannon MW, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011;118(15):4053–61.https://doi.org/10.1182/blood-2011-02-336990
  14. Onuora S. Systemic lupus erythematosus: Epratuzumab not effective in phase III trials. Nat Rev Rheumatol. 2016;12(11):622. doi:.https://doi.org/10.1038/nrrheum.2016.165
  15. Repetto-Llamazares AH, Larsen RH, Patzke S, Fleten KG, Didierlaurent D, Pichard A, et al. Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma. PLoS One. 2015;10(6):e0128816.https://doi.org/10.1371/journal.pone.0128816
  16. Pereira DS, Guevara CI, Jin L, Mbong N, Verlinsky A, Hsu SJ, et al. AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML. Mol Cancer Ther. 2015;14(7):1650–60.https://doi.org/10.1158/1535-7163.MCT-15-0067
  17. Vey N, Delaunay J, Martinelli G, Fiedler W, Raffoux E, Prebet T, et al. Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia. Oncotarget. 2016;7(22):32532–42.https://doi.org/10.18632/oncotarget.8687
  18. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell. 2010;142(5):699–713.https://doi.org/10.1016/j.cell.2010.07.044
  19. Piccione EC, Juarez S, Liu J, Tseng S, Ryan CE, Narayanan C, et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs. 2015;7(5):946–56.https://doi.org/10.1080/19420862.2015.1062192
  20. Ferlin WG, Chauchet X, Buatois V, Salgado-Pires S, Shang L, Dheilly E, et al. A CD47xCD19 bispecific antibody that remodels the tumor microenvironment for improved killing and provokes a memory immune response to cancer B cells. Blood. 2016;128:44.
  21. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6.https://doi.org/10.1200/JCO.2011.38.0402
  22. Scott LJ. Brentuximab Vedotin: A Review in CD30-Positive Hodgkin Lymphoma. Drugs. 2017;77(4):435–45.https://doi.org/10.1007/s40265-017-0705-5
  23. Kreitman RJ, Stetler-Stevenson M, Margulies I, Noel P, Fitzgerald DJ, Wilson WH, et al. Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol. 2009;27(18):2983–90.https://doi.org/10.1200/JCO.2008.20.2630
  24. Jain P, Polliack A, Ravandi F. Novel therapeutic options for relapsed hairy cell leukemia. Leuk Lymphoma. 2015;56(8):2264–72.https://doi.org/10.3109/10428194.2014.1001988
  25. Wick W, Hertenstein A, Platten M. Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol. 2016;17(12):e529–41.https://doi.org/10.1016/S1470-2045(16)30571-X
  26. Riches JC, Gribben JG. Mechanistic and Clinical Aspects of Lenalidomide Treatment for Chronic Lymphocytic Leukemia. Curr Cancer Drug Targets. 2016;16(8):689–700.https://doi.org/10.2174/1568009616666160408145741
  27. Maffei R, Fiorcari S, Bulgarelli J, Rizzotto L, Martinelli S, Rigolin GM, et al. Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia. Exp Hematol. 2014;42(2):126–36.e1.https://doi.org/10.1016/j.exphem.2013.10.007
  28. Arora M, Gowda S, Tuscano J. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. Ther Adv Hematol. 2016;7(4):209–21.https://doi.org/10.1177/2040620716652861
  29. Arkwright R, Pham TM, Zonder JA, Dou QP. The preclinical discovery and development of bortezomib for the treatment of mantle cell lymphoma. Expert Opin Drug Discov. 2017;12(2):225–35.https://doi.org/10.1080/17460441.2017.1268596
  30. Gu JJ, Kaufman GP, Mavis C, Czuczman MS, Hernandez-Ilizaliturri FJ. Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells. Oncotarget. 2017;8(8):12741–53. doi:.https://doi.org/10.18632/oncotarget.14405
  31. Vallumsetla N, Paludo J, Kapoor P. Bortezomib in mantle cell lymphoma: comparative therapeutic outcomes. Ther Clin Risk Manag. 2015;11:1663–74. doi:.https://doi.org/10.2147/TCRM.S72943
  32. Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, et al.; LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372(10):944–53.https://doi.org/10.1056/NEJMoa1412096
  33. Olzscha H, Sheikh S, La Thangue NB. Deacetylation of chromatin and gene expression regulation: a new target for epigenetic therapy. Crit Rev Oncog. 2015;20(1-2):1–17.https://doi.org/10.1615/CritRevOncog.2014012463
  34. Broccoli A, Zinzani PL. Peripheral T-cell lymphoma, not otherwise specified. Blood. 2017;129(9):1103–12.https://doi.org/10.1182/blood-2016-08-692566
  35. Holkova B, Yazbeck V, Kmieciak M, Bose P, Ma S, Kimball A, et al. A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma. Leuk Lymphoma. 2017;58(6):1349–57.https://doi.org/10.1080/10428194.2016.1276287
  36. Roskoski R, Jr. Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms. Pharmacol Res. 2016;113(Pt A):395–408.https://doi.org/10.1016/j.phrs.2016.09.011
  37. Deeks ED. Ibrutinib: A Review in Chronic Lymphocytic Leukaemia. Drugs. 2017;77(2):225–36.https://doi.org/10.1007/s40265-017-0695-3
  38. Gertz MA. Waldenström macroglobulinemia: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 2017;92(2):209–17.https://doi.org/10.1002/ajh.24557
  39. Patel V, Balakrishnan K, Bibikova E, Ayres M, Keating MJ, Wierda WG, et al. Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells. Clin Cancer Res. 2017;23(14):3734–43.https://doi.org/10.1158/1078-0432.CCR-16-1446
  40. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):323–32.https://doi.org/10.1056/NEJMoa1509981
  41. Barrientos JC. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2016;12(18):2077–94.https://doi.org/10.2217/fon-2016-0003
  42. Barrientos JC. Sequencing of chronic lymphocytic leukemia therapies. Hematology (Am Soc Hematol Educ Program). 2016;2016(1):128–36.https://doi.org/10.1182/asheducation-2016.1.128
  43. Nair KS, Cheson B. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia. Ther Adv Hematol. 2016;7(2):69–84.https://doi.org/10.1177/2040620715625966
  44. Calimeri T, Ferreri AJM. m-TOR inhibitors and their potential role in haematological malignancies. Br J Haematol. 2017;177(5):684–702.https://doi.org/10.1111/bjh.14529
  45. Lampson BL, Davids MS. The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia. Curr Hematol Malig Rep. 2017;12(1):11–9.https://doi.org/10.1007/s11899-017-0359-0
  46. Roberts AW, Stilgenbauer S, Seymour JF, Huang DCS. Venetoclax in patients with previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(16):4527–33.https://doi.org/10.1158/1078-0432.CCR-16-0955
  47. Galanina N, Kline J, Bishop MR. Emerging role of checkpoint blockade therapy in lymphoma. Ther Adv Hematol. 2017;8(2):81–90.https://doi.org/10.1177/2040620716673787
  48. Hude I, Sasse S, Engert A, Bröckelmann PJ. The emerging role of immune checkpoint inhibition in malignant lymphoma. Haematologica. 2017;102(1):30–42.https://doi.org/10.3324/haematol.2016.150656
  49. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.https://doi.org/10.1056/NEJMoa1411087
  50. Kuruvilla J. The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma. Blood. 2016;127(17):2093–100.https://doi.org/10.1182/blood-2015-11-624320
  51. Stiff P. What is the role of autologous transplant for lymphoma in the current era? Hematology (Am Soc Hematol Educ Program). 2015;2015(1):74–81.https://doi.org/10.1182/asheducation-2015.1.74
  52. Merryman RW, Kim HT, Zinzani PL, Carlo-Stella C, Ansell SM, Perales MA, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017;129(10):1380–8.https://doi.org/10.1182/blood-2016-09-738385
  53. Hong S, Le-Rademacher J, Artz A, McCarthy PL, Logan BR, Pasquini MC. Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders. Bone Marrow Transplant. 2015;50(3):367–74.https://doi.org/10.1038/bmt.2014.269
  54. Allegra A, Russo S, Gerace D, Calabrò L, Maisano V, Innao V, et al. Vaccination strategies in lymphoproliferative disorders: Failures and successes. Leuk Res. 2015;39(10):1006–19.https://doi.org/10.1016/j.leukres.2015.08.001
  55. Iribarren K, Bloy N, Buqué A, Cremer I, Eggermont A, Fridman WH, et al. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy. OncoImmunology. 2015;5(3):e1088631.https://doi.org/10.1080/2162402X.2015.1088631
  56. Lee ST, Jiang YF, Park KU, Woo AF, Neelapu SS. BiovaxID: a personalized therapeutic cancer vaccine for non-Hodgkin’s lymphoma. Expert Opin Biol Ther. 2007;7(1):113–22.https://doi.org/10.1517/14712598.7.1.113
  57. Brody J, Levy R. Lymphoma immunotherapy: vaccines, adoptive cell transfer and immunotransplant. Immunotherapy. 2009;1(5):809–24.https://doi.org/10.2217/imt.09.50
  58. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.https://doi.org/10.1200/JCO.2014.56.2025
  59. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol Ther. 2017;25(1):285–95.https://doi.org/10.1016/j.ymthe.2016.10.020
  60. Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53.https://doi.org/10.1186/s13045-017-0423-1
  61. Crassini K, Shen Y, Mulligan S, Giles Best O. Modeling the chronic lymphocytic leukemia microenvironment in vitro. Leuk Lymphoma. 2017;58(2):266–79.https://doi.org/10.1080/10428194.2016.1204654
  62. Fowler NH, Cheah CY, Gascoyne RD, Gribben J, Neelapu SS, Ghia P, et al. Role of the tumor microenvironment in mature B-cell lymphoid malignancies. Haematologica. 2016;101(5):531–40.https://doi.org/10.3324/haematol.2015.139493
  63. Luissint AC, Nusrat A, Parkos CA. JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol. 2014;36(2):211–26.https://doi.org/10.1007/s00281-014-0421-0
  64. Arrate MP, Rodriguez JM, Tran TM, Brock TA, Cunningham SA. Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem. 2001;276(49):45826–32.https://doi.org/10.1074/jbc.M105972200
  65. Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem. 2002;277(31):27589–92.https://doi.org/10.1074/jbc.C200331200
  66. Liang TW, Chiu HH, Gurney A, Sidle A, Tumas DB, Schow P, et al. Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3. J Immunol. 2002;168(4):1618–26.https://doi.org/10.4049/jimmunol.168.4.1618
  67. Woodfin A, Voisin MB, Beyrau M, Colom B, Caille D, Diapouli FM, et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol. 2011;12(8):761–9.https://doi.org/10.1038/ni.2062
  68. Bradfield PF, Scheiermann C, Nourshargh S, Ody C, Luscinskas FW, Rainger GE, et al. JAM-C regulates unidirectional monocyte transendothelial migration in inflammation. Blood. 2007;110(7):2545–55.https://doi.org/10.1182/blood-2007-03-078733
  69. Lamagna C, Hodivala-Dilke KM, Imhof BA, Aurrand-Lions M. Antibody against junctional adhesion molecule-C inhibits angiogenesis and tumor growth. Cancer Res. 2005;65(13):5703–10.https://doi.org/10.1158/0008-5472.CAN-04-4012
  70. Ody C, Jungblut-Ruault S, Cossali D, Barnet M, Aurrand-Lions M, Imhof BA, et al. Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies. Leukemia. 2007;21(6):1285–93.https://doi.org/10.1038/sj.leu.2404689
  71. Doñate C, Ody C, McKee T, Ruault-Jungblut S, Fischer N, Ropraz P, et al. Homing of human B cells to lymphoid organs and B-cell lymphoma engraftment are controlled by cell adhesion molecule JAM-C. Cancer Res. 2013;73(2):640–51.https://doi.org/10.1158/0008-5472.CAN-12-1756
  72. Doñate C, Vijaya Kumar A, Imhof BA, Matthes T. Anti-JAM-C therapy eliminates tumor engraftment in a xenograft model of mantle cell lymphoma. J Leukoc Biol. 2016;100(5):843–53.https://doi.org/10.1189/jlb.1HI1114-549RR
  73. Karpova D, Bonig H. Concise Review: CXCR4/CXCL12 Signaling in Immature Hematopoiesis--Lessons From Pharmacological and Genetic Models. Stem Cells. 2015;33(8):2391–9.https://doi.org/10.1002/stem.2054
  74. Rashidi A, Uy GL. Targeting the microenvironment in acute myeloid leukemia. Curr Hematol Malig Rep. 2015;10(2):126–31.https://doi.org/10.1007/s11899-015-0255-4
  75. Barbieri F, Bajetto A, Thellung S, Würth R, Florio T. Drug design strategies focusing on the CXCR4/CXCR7/CXCL12 pathway in leukemia and lymphoma. Expert Opin Drug Discov. 2016;11(11):1093–109.https://doi.org/10.1080/17460441.2016.1233176
  76. Shaughnessy P, Uberti J, Devine S, Maziarz RT, Vose J, Micallef I, et al. Plerixafor and G-CSF for autologous stem cell mobilization in patients with NHL, Hodgkin’s lymphoma and multiple myeloma: results from the expanded access program. Bone Marrow Transplant. 2013;48(6):777–81.https://doi.org/10.1038/bmt.2012.219
  77. Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012;119(17):3917–24.https://doi.org/10.1182/blood-2011-10-383406
  78. Kashyap MK, Kumar D, Jones H, Amaya-Chanaga CI, Choi MY, Melo-Cardenas J, et al. Ulocuplumab (BMS-936564 / MDX1338): a fully human anti-CXCR4 antibody induces cell death in chronic lymphocytic leukemia mediated through a reactive oxygen species-dependent pathway. Oncotarget. 2016;7(3):2809–22.https://doi.org/10.18632/oncotarget.6465
  79. Herishanu Y, Gibellini F, Njuguna N, Hazan-Halevy I, Farooqui M, Bern S, et al. Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. Leuk Lymphoma. 2011;52(9):1758–69.https://doi.org/10.3109/10428194.2011.569962
  80. Finlayson M. Modulation of CD44 Activity by A6-Peptide. Front Immunol. 2015;6:135.https://doi.org/10.3389/fimmu.2015.00135
  81. Lai H. S. Z., Christina Wu, Liguang Chen, Grace Liu, RongRong Wu, Fitzgerlad Lao, Jian Yu, Laura Rassenti, Michael Choi, Stephen Howell, Malcolm Finlayson, Thomas Kipps. in Proceedings of the 105th Annual Meeting of the American Association for Cancer Research Vol. 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; (2014).
  82. Zhang S, Lai H, Liu G, Rassenti L, Choi MY, Howell SB, et al. A6 peptide is selectively cytotoxic for chronic lymphocytic leukemia cells. Blood. 2013;122(21):5303.
  83. Gayko U, Fung M, Clow F, Sun S, Faust E, Price S, et al. Development of the Bruton’s tyrosine kinase inhibitor ibrutinib for B cell malignancies. Ann N Y Acad Sci. 2015;1358(1):82–94.https://doi.org/10.1111/nyas.12878
  84. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26(1):93–104.https://doi.org/10.1016/j.immuni.2006.11.012
  85. Chang BY, Francesco M, De Rooij MF, Magadala P, Steggerda SM, Huang MM, 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):2412–24.https://doi.org/10.1182/blood-2013-02-482125
  86. Okada T, Ngo VN, Ekland EH, Förster R, Lipp M, Littman DR, et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196(1):65–75.https://doi.org/10.1084/jem.20020201
  87. Wong S, Fulcher D. Chemokine receptor expression in B-cell lymphoproliferative disorders. Leuk Lymphoma. 2004;45(12):2491–6.https://doi.org/10.1080/10428190410001723449
  88. Rehm A, Mensen A, Schradi K, Gerlach K, Wittstock S, Winter S, et al. Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs. Blood. 2011;118(4):1020–33.https://doi.org/10.1182/blood-2010-11-321265
  89. Somovilla-Crespo B, Alfonso-Pérez M, Cuesta-Mateos C, Carballo-de Dios C, Beltrán AE, Terrón F, et al. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma. J Hematol Oncol. 2013;6(1):89.https://doi.org/10.1186/1756-8722-6-89