In recent years, improved understanding of the biology of Hodgkin lymphoma (HL) has uncovered many potential targets for the treatment of this disease. Clarification of the B-cell origin of the Hodgkin Reed Sternberg (HRS) cell and of the complex interactions between the HRS cell and the HL microenvironment have provided new insights into the pathophysiology of HL and identified extracellular and intracellular molecules which are essential for HRS survival. New agents directed at these molecules are now in early phase clinical trials.
Ansell, S.M. , Horwitz, S.M. , Engert, A. , Khan, K.D. , Lin, T. , Strair, R. et al. (2007) Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin’s lymphoma and anaplastic large-cell lymphoma . J Clin Oncol25: 2764-2769.
2.
Blum, K.A. , Johnson, N.L. , Niedzwiecki, D. , Canellos, G.P. , Cheson, B.D. and Bartlett, N.L. ( 2007) Single agent bortezomib in the treatment of relapse and refractory Hodgkin lymphoma: cancer and leukemia group B protocol 50206 . Leuk Lymphoma48: 1313-1319.
3.
Böll, B. , Borchmann, P. , Topp, M.S. , Hanel, M. , Reiners, K.S. , Engert, A. et al. (2010) Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma . Br J Haem148: 480-482.
4.
Böll, B. , Hansen, H. , Heuck, F. , Reiners, K. , Borchmann, P. , Rothe, A. et al. (2005) The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis . Blood106: 1839-1842.
5.
Bollard, C.M. , Aguilar, L. , Straathof, K.C. , Gahn, B. , Huls, M.H. , Rousseau, A. et al. (2004) Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin’s disease . J Exp Med200: 1623-1633.
6.
Borchmann, P. , Schnell, R. , Fuss, I. , Manzke, O. , Davis, T. , Lewis, L.D. et al. (2002) Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma . Blood100: 3101-3107.
7.
Clodi, K. and Younes, A. ( 1997) Reed-Sternberg cells and the TNF family of receptors/ligands . Leuk Lymphoma27: 195-205.
8.
Di Stasi, A. , De Angelis, B. , Rooney, C.M. , Zhang, L. , Mahendravada, A. , Foster, A.E. et al. (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model . Blood113: 6392-6402.
9.
Dutton, A. , O’Neil, J.D. , Milner, A.E. , Reynolds, G.M. , Starczynski, J. , Crocker, J. et al. (2004) Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death . Proc Natl Acad Sci U S A101: 6611-6616.
10.
Ekstrand, B.C. , Lucas, J.B. , Horwitz, S.M. , Fan, Z. , Breslin, S. , Hoppe, R.T. et al. (2003) Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial . Blood101: 4285-4289.
11.
Engert, A. , Diehl, V. , Franklin, J. , Lohri, A. , Dörken, B. , Ludwig, W.D. et al. (2009) Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study . J Clin Oncol27: 4548-4554.
12.
Engert, A. , Schiller, P. , Josting, A. , Herrmann, R. , Koch, P. , Sieber, M. et al. (2003) Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group . J Clin Oncol21: 3601-3608.
13.
Fanale, M.A. , Fayad, L.E. , Pro, B. , Samaniego, F. , Zachariah, G. , Nunez, C. et al. (2008) A phase I study of bortezomib in combination with ICE (BICE) inpatients with relapsed/refractory classical Hodgkin lymphoma . Blood112: 1048 a.
14.
Forero-Torres, A. , Leonard, J.P. , Younes, A. , Rosenblatt, J.D. , Brice, P. , Bartlett, N.L. et al. (2009) A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma . Br J Haematol146: 171-179.
15.
Gallamini, A. , Hutchings, M. , Rigacci, L. , Specht, L. , Merli, F. , Hansen, M. et al. (2006) The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin’s disease . Haematologica91: 475-481.
16.
Georgakis, G.V. , Li, Y. , Humphreys, R. , Andreeff, M. , O’Brien, S. , Younes, M. et al. (2005) Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death . Br J Haematol130: 501-510.
17.
Hartmann, F. , Renner, C. , Jung, W. , da Costa, L. , Tembrink, S. , Held, G. et al. (2001) Anti-CD16/CD30 bispecific antibody treatment for Hodgkin’s disease: role of infusion schedule and costimulation with cytokines . Clin Cancer Res7: 1873-1881.
18.
Johnston, P.B. , Ansell, S.M. , Colgan, J.P. , Habermann, T.M. , Inwards, D.J. , Micallef, I.N.M. et al. (2007) mTOR inhibition for relapsed or refractory Hodgkin lymphoma: promising single agent activity with everolimus (RAD001) . Blood110: 753a .
19.
Kashkar, H. , Haefs, C. , Shin, H. , Hamilton-Dutoit, S.J. , Salvesen, G.S. , Kronke, M. et al. (2003) XIAP-mediated caspase inhibition in Hodgkin’s lymphoma-derived B cells . J Exp Med198: 341-347.
Lucas, K.G. , Salzman, D. , Garcia, A. and Sun, Q. ( 2004) Adoptive immunotherapy with allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent, EBV-positive Hodgkin disease . Cancer100: 1892-1901.
22.
Marshall, N.A. , Christie, L.E. , Munro, L.R. , Culligan, D.J. , Johnston, P.W. , Barker, R.N. et al. (2004) Immunosuppressive regulatory T-cells are abundant in the reactive lymphocytes of Hodgkin lymphoma . Blood103: 1755-1762.
23.
Mathas, S. , Lietz, A. , Anagnostopoulos, I. , Hummel, F. , Wiesner, B. , Janz, M. et al. (2004) c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis . J Exp Med199: 1041-1052.
24.
Meyer, R.M. , Gospodarowicz, M.K. , Connors, J.M. , Pearcey, R.G. , Bezjak, A. , Wells, W.A. et al. (2005) Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin’s lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group . J Clin Oncol23: 4634-4642.
25.
Moskowitz, C.H. , Nimer, S.D. , Zelenetz, A.D. , Trippett, T. , Hedrick, E.E. , Filippa, D.A. et al. (2001) A 2-step comprehensive high-dose chemoradiotherapy second line program for relapsed and refractory Hodgkin’s disease: analysis by intent to treat and development of a prognostic model . Blood97: 616-623.
26.
Noordijk, E.M. , Carde, P. , Dupouy, N. , Hagenbeek, A. , Krol, A.D. , Kluin-Nelemans, J.C. et al. (2006) Combined-modality therapy for clinical stage I or II Hodgkin’s lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials . J Clin Oncol24: 3128-3135.
27.
Re, D. , Hofmann, A. , Wolf, J. , Diehl, V. and Staratschek-Jox, A. ( 2000) Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95 . Exp Hematol28: 348 .
28.
Re, D. , Thomas, R.K. , Behringer, K. and Diehl, V. ( 2005) From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential . Blood105: 4553-4560.
29.
Rodig, S.J. , Savage, K.J. , Nguyen, V. , Pinkus, G.S. , Shipp, M.A. , Aster, J.C. et al. (2005) TRAF-1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas . Am J Surg Pathol29: 196-203.
30.
Rosato, R.R. , Almenara, J.A. and Grant, S. ( 2003) The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1 . Cancer Res63: 3637-3645.
31.
Schnell, R. , Staak, O. , Borchmann, P. , Schwartz, C. , Matthey, B. , Hansen, H. et al. (2002) A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin’s and non-Hodgkin’s lymphoma . Clin Cancer Res8: 1779-1786.
32.
Schulz, H. , Rehwald, U. , Morschhauser, F. , Elter, T. , Driessen, C. , Rüdiger, T. et al. (2008) Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG) . Blood111: 109-111.
33.
Swerdlow, S.H. , Campo, E. , Harris, N.L. , Jaffe, E.S. , Pileri, S.A. , Stein, H. et al. (2008) WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues, IARC: Lyon .
34.
van den Berg, A. , Visser, L. and Poppema, S. ( 1999) High expression of the CC chemokine TARC in Reed-Sternberg cells: a possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma . Am J Path154: 1685-1691.
35.
Younes, A. , Forero-Torres, A. , Bartlett, N.L. , Leonard, J.P. , Lynch, C. , Kennedy, D.A. et al. (2008) Multiple complete responses in a phase I dose-escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or refractory CD-30-positive lymphomas . Blood112: 370a .
36.
Younes, A. , McLaughlin, P. , Fayad, L.E. , Goy, A. , Romaguera, J.E. , Pro, B. et al. (2005) Six weekly doses of rituximab plus ABVD fore newly diagnosed patients with advanced stage classical Hodgkin lymphoma: depletion of reactive B-cells from the microenvironment by rituximab . Blood106: 431a .
37.
Younes, A. , Pro, B. , Fanale, M. , McLaughlin, P. , Neelapu, S. , Fayad, L. et al. (2007) Isotype-selective HDAC inhibitor MGCD0103 decreases serum TARC concentrations and produces clinical responses in heavily pretreated patients with relapsed classical Hodgkin Lymphoma (HL) . Blood110: 756 a.
38.
Younes, A. , Pro, B. and Fayad, L. ( 2006) Experience with bortezomib for the treatment of patients with relapsed classical Hodgkin lymphoma . Blood107: 1731-1732.
39.
Younes, A. , Romaguera, J. , Hagemeister, F. , McLaughlin, P. , Rodriguez, M.A. , Fiumara, P. et al. (2003) A pilot study of rituximab in patients with recurrent, classic Hodgkin disease . Cancer98: 310-314.
40.
Zheng, B. , Fiumara, P. , Li, Y.V. , Georgakis, G. , Snell, V. , Younes, M. et al. (2003) MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival . Blood102: 1019-1027.
