Advances in the treatment of relapsed or refractory Hodgkin's lymphoma

Abstract

Hodgkin's lymphoma (HL) is diagnosed in 20,000 men and women annually in North America and Europe. Despite treatment advancements for HL resulting in an overall survival rate of 80%, patients with advanced stage disease continue to have suboptimal outcomes, with relapse rates of 30%-40%. An additional 10%-15% of patients present with primary refractory disease. For patients who relapse after initial treatment, salvage chemotherapy followed by autologous stem cell transplant in those with chemotherapy-sensitive disease is the standard of care. Patients who relapse after second-line therapy have a median survival time in the range of 6-36 months, and the optimal management of these patients remains unclear. Unfortunately, there have been no new agents approved for relapsed HL treatment since the 1970s. Consequently, clinical decision making in this population is difficult. Recently however, several agents have emerged that have shown clinical promise in this poor-risk population. This review discusses the management of these patients and also discusses several newer agents showing clinical promise in the treatment of HL.

Figure 1.

Targeted inhibition of HRS cells. Diagram depicts multiple biologically active aberrant pathways in HL, including mTOR, HIF-1α, deacetylation, and CD30. Included are many of the postulated sites of activity for the discussed agents. Of importance is the redundancy of the pathways. Novel therapeutic agents affect tumor pathways directly but also influence the microenvironment, DNA transcription and translation of antiapoptotic and antiangiogenic factors, and immune modulation of tumor cells. Abbreviations: HL, Hodgkin's lymphoma; HIF, hypoxia-inducible factor; HRS, Hodgkin Reed–Sternberg; IκB, inhibitor of NF-κB; IKK, IκB kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; RANK, receptor activator of NF-κB.

Figure 2.

Constitutive activation of the NF-κB pathway in HRS cells. Two distinct pathways of NF-κB activation have been identified in HRS cells. In the canonical pathway (left), stimulation of the B-cell receptor or TNF receptor superfamily members (such as CD30 or CD40) results in proteasomal degradation of IκB. The lack of IκB inhibition results in increased NF-κB nuclear transport and ultimately results in increased transcription of a number of target genes. In HL, these targets include a variety of proinflammatory cytokines and antiapoptotic factors. In the alternative pathway (right), ligand-mediated stimulation of a number of receptors, including BAFF-R, TAC1, CD30, CD40, and RANK, induces the proteasomal processing of the NF-κB precursor protein p100 into its active form, p52. This event permits heterodimers composed of p52 and another member of the NF-κB family, RelB, to move to the nucleus where they upregulate transcription of several target genes. Abbreviations: cIAP2, cellular inhibitor of apoptosis 2; DACI, deacetylase inhibitor; FLIP, FLICE inhibitory protein; GPCR, G-protein-coupled receptor; HL, Hodgkin's lymphoma; HIF, hypoxia-inducible factor; HRS, Hodgkin Reed–Sternberg; IκB, inhibitor of NF-κB; IL, interleukin; IKK, IκB kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; PI3K, phosphatidylinositol-3-kinase; RANK, receptor activator of NF-κB; RANTES, regulated upon activation, normal T-cell expressed and presumably secreted; RTK, receptor tyrosine kinase; TAC1, transmembrane cyclophilin ligand interactor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.