Clinical Review

Advanced Stage and Relapsed/Refractory Hodgkin Lymphoma




Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.1 Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.2 Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.3


Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.4 A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.3

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.5 In the original study by Hasenclever et al,5 the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.6 This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.5,6

A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.7 This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.7

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.8 A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.9

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.10 PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.10 This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.11