Classical Hodgkin’s Lymphoma: Pathogenesis and Future Treatment Directions
Abstract
Classical Hodgkin Lymphoma is a germinal center B cell malignancy. Over the past 40 years, through greater understanding of disease pathogenesis, advancements in treatment have lead to greater than 80% long-term survival rates after standard first line therapy. Currently, first-line management of the disease varies, most commonly involving the use of a standard chemotherapy regime (i.e. ABVD or BEACOPP), with or without the use of additional chemotherapies or involved-field radiation therapy. Treatment selection is influenced by disease staging at diagnosis and the need to maintain therapeutic efficacy, whilst minimising the risk of late and potentially fatal therapy-associated side effects. Consequently, higher than acceptable drug-associated toxicities and patient relapse represent the future challenges of this disease. Novel therapies, targeting the aberrant signalling pathways and phenotypic features of the malignant cell pool, and its associated
inflammatory infiltrate, are the future direction of disease management. Currently, combination therapies targeting the PI3K/Akt/mTOR pathway and transcription modulation have shown the greatest clinical efficacy in improving survival outcomes in previously heavily treated cHL patients, with minimal side effects. Whilst these therapies do not yet achieve the clinical efficacy of first line therapies, preliminary stage I and II trials have
demonstrated a reduction in drug associated toxicities and side effects relative to existing treatments for relapse. This paper will investigate current understanding of the pathogenesis of cHL, and how this has shaped the targets of novel therapies for the disease.
References
2. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nature reviews Cancer. 2005;5(4):251-62.
3. Marri PR, Ansell SM. Progress in the initial management of Hodgkin's Lymphoma. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2013;49(1):12-8.
4. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: a cancer journal for clinicians. 2009;59(4):225-49.
5. Farrell K, Jarrett RF. The molecular pathogenesis of Hodgkin lymphoma. Histopathology. 2011;58(1):15-25.
6. Diepstra A, Niens M, Vellenga E, van Imhoff GW, Nolte IM, Schaapveld M, et al. Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma. Lancet. 2005;365(9478):2216-24.
7. Nishikori M, Uchiyama T. Molecular pathogenesis of Hodgkin lymphoma. International journal of hematology. 2006;83(5):398-403.
8. Young LS, Murray PG. Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 2003;22(33):5108-21.
9. Baumforth KR, Birgersdotter A, Reynolds GM, Wei W, Kapatai G, Flavell JR, et al. Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells. The American journal of pathology. 2008;173(1):195-204.
10. El-Galaly TC, d'Amore F, Mylam KJ, de Nully Brown P, Bogsted M, Bukh A, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(36):4508-14.
11. Kwee TC, Kwee RM, Nievelstein RA. Imaging in staging of malignant lymphoma: a systematic review. Blood. 2008;111(2):504-16.
12. Follows GA, Ardeshna KM, Barrington SF, Culligan DJ, Hoskin PJ, Linch D, et al. Guidelines for the first line management of classical Hodgkin lymphoma. British journal of haematology. 2014;166(1):34-49.
13. Eichenauer DA, Engert A. Antibodies and antibody-drug conjugates in the treatment of Hodgkin lymphoma. European journal of haematology. 2014;93(1):1-8.
14. Collins GP, Parker AN, Pocock C, Kayani I, Sureda A, Illidge T, et al. Guideline on the management of primary resistant and relapsed classical Hodgkin lymphoma. British journal of haematology. 2014;164(1):39-52.
15. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, et al. Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(18):2197-203.
16. Batlevi CL, Younes A. Novel therapy for Hodgkin lymphoma. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2013;2013:394-9.
17. Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape. The Journal of pathology. 2010;221(3):248-63.
18. Bollard CM, Aguilar L, Straathof KC, Gahn B, Huls MH, Rousseau A, et al. Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. The Journal of experimental medicine. 2004;200(12):1623-33.
19. Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(8):798-808.
20. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. American journal of hematology. 2010;85(5):320-4.
21. Oki Y, Copeland A, Younes A. Clinical development of panobinostat in classical Hodgkin's lymphoma. Expert review of hematology. 2011;4(3):245-52.
22. Oki Y, Buglio D, Zhang J, Ying Y, Zhou S, Sureda A, et al. Immune regulatory effects of panobinostat in patients with Hodgkin lymphoma through modulation of serum cytokine levels and T-cell PD1 expression. Blood cancer journal. 2014;4:e236.
23. Oki Y, Buglio D, Fanale M, Fayad L, Copeland A, Romaguera J, et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(24):6882-90.
24. Boll B, Borchmann P, Topp MS, Hanel M, Reiners KS, Engert A, et al. Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma. British journal of haematology. 2010;148(3):480-2.
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