Hodgkin lymphoma represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged ≥60 years at diagnosis. Advanced-stage disease is generally classified as Ann Arbor stage III to IV, but clinical trials often incorporate patients with high-risk stage II disease, such as those with B symptoms, multiple sites, or bulky disease
Andrew M. Evens, DO, MSc
Hodgkin lymphoma represents approximately 10% of all cases of malignant lymphoma. This group of diseases most commonly affects adolescent and young adults, although approximately 20% to 25% of patients are aged ≥60 years at diagnosis. Advanced-stage disease is generally classified as Ann Arbor stage III to IV, but clinical trials often incorporate patients with high-risk stage II disease, such as those with B symptoms, multiple sites, or bulky disease. Approximately 65% to 75% of patients with advanced-stage HL will remain disease free at 5 years with conventional chemotherapy. This is in contrast with early-stage classical HL (cHL), in which the long-term cure exceeds 90%. Different prognostic indices are used for early- and advanced-stage disease. Prognosis in advanced stage is defined by the International Prognostic Index (IPS), which includes measurements of albumin and hemoglobin, sex, age >45 years, stage IV, and the presence of leukocytosis or lymphocytosis. Patients with an IPS ≥3 have inferior treatment outcomes.
The majority of clinical trials over the past 10 years in advanced-stage HL have used response-adapted designs leveraging early PET imaging to guide subsequent therapy (eg, intensification vs de-escalation for patients with cHL with positive vs negative PET2 scans, respectively).
The randomized phase III RATHL (Response-adapted therapy for advanced Hodgkin lymphoma) trial from Johnson et al1assessed a PET-adapted therapy in patients with advanced-stage disease who were treated initially with doxorubicin (Adriamycin)/bleomycin/vinblastine/ dacarbazine (ABVD). Patients had stage IIB to IV disease or stage IIA disease with adverse features such as bulky disease or at least 3 involved sites. Interim PET was performed after 2 cycles, and the investigators defined a Deauville score of 1 to 3 as negative. Patients with a negative interim scan were randomized to either continuation of ABVD (ABVD group) or omission of bleomycin (AVD group) in cycles 3 through 6. The group with PET positivity received escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone (eBEACOPP). Radiotherapy was not recommended for patients with negative findings on interim scans. Results demonstrated that the ABVD and AVD groups with PET negativity on interim scan (87%) had similar progression-free survival (PFS; 3-year PFS, 86% and 84%) and overall survival (OS; 97% and 98%) rates, respectively. The group with PET positivity had a 74% rate of negative repeat PET after BEACOPP; the 3-year PFS rate was 68.0%, and the OS rate was 87.8%. Respiratory adverse events were more severe in the bleomycin-containing group.
In addition, the S0816 US Intergroup study of response- adapted therapy in patients with stage III/IV disease by Press et al2assessed patients initially treated with ABVD. Of 60 eligible patients with PET2 positivity, 49 switched to eBEACOPP as planned, and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year OS rate was 98%, with a 2-year PFS of 64% for patients with PET2 positivity. With extended follow-up (ie, median 5.9 years) for S0816, the estimated 5-year PFS rate was 74% for all patients. The 5-year PFS rate was 76% for patients with PET2 negativity versus 66% for those with PET2 positivity. The estimated 5-year OS rate was 94%. Furthermore, 14% of patients treated with eBEACOPP had a reported second cancer versus 2% of patients treated with ABVD (P= .001).3
Brentuximab Vedotin and Chemotherapy Combinations
Investigators and clinicians have made efforts to incorporate promising new therapies into traditional chemotherapy backbones to further improve outcomes in advanced-stage cHL. Brentuximab vedotin (Adcetris) is an FDA-approved anti-CD30 antibodydrug conjugate for the treatment of relapsed/refractory HL.4ECHELON-1 was a multicenter, randomized, phase III trial of patients with stage III or IV cHL.5Patients were randomized to brentuximab vedotin/ doxorubicin/vinblastine/dacarbazine (A+AVD; n = 664) versus standard ABVD (n = 670). Two-year modified PFS rates in the A+AVD and ABVD groups were 82.1% and 77.2%, respectively, resulting in a difference of 4.9 percentage points (HR for an event of progression, death, or modified progression, 0.77;P= .03). The A+AVD group had more neutropenia, but the rate of febrile neutropenia was lower among patients who received primary prophylaxis with granulocyte colony-stimulating factor versus those who did not (11% vs 21%, respectively). Peripheral neuropathy was more common in the A+AVD group but was reversible in 67%. Grade ≥3 pulmonary toxicity was rare, reported in <1% of patients receiving A+AVD and 3% of those treated with ABVD.
Overall, A+AVD had superior efficacy, with a 5% lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years (ie, modified PFS). The benefit seemed to be primarily for patients <60 years. Furthermore, several subgroups with higher-risk disease appeared to garner more benefit with A+AVD therapy, including those of male gender and those with stage IV disease, high IPS, and multiple extranodal sites. In addition, the absolute PFS benefit with A+AVD was 12% for patients treated in North America versus those not treated there (ie, 2-year PFS rate of 88% vs 76%, respectively).
Evens et al6also recently analyzed outcomes in older patients with previously untreated advanced-stage cHL. Overall, 186 of 1334 patients in the intention-to-treat population were ≥60 years and included in a subset analysis. With a median follow-up of ~25 months, modified PFS rates were similar between the 2 treatment arms for older patients (70% vs 71%). The treatment-related mortality rate for older patients was 4% in the A+AVD arm and 5% with ABVD (all pulmonary related). Evens et al7also reported results from a multicenter phase II clinical study (NCT01476410) examining brentuximab vedotin givensequentiallyas a single agent before and after standard AVD for patients with untreated older HL. The objective and complete response rates after the initial 2 lead-in doses of brentuximab vedotin were 82% and 36%, respectively, and 95% and 90%, respectively, after 6 cycles of AVD. By intention to treat, the 2-year PFS and overall OS rates were 84% and 93%, respectively. Furthermore, geriatric assessments (eg, activities of daily living and comorbidities) were strongly prognostic for patient survival.
In addition, a new substantially modified BEACOPP variant incorporating brentuximab has been evaluated by Borchmann et al8for the German Hodgkin Study Group (GHSG). The eBEACOPP variants met their co-primary efficacy endpoints in a phase II trial of advanced-stage cHL. In particular, the BrECADD regimen (brentuximab vedotin 1.8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5) was associated with a more favorable toxicity profile and was therefore selected to challenge standard eBEACOPP for the treatment of advanced- stage cHL in the phase III HD21 study by the GHSG (NCT02661503). Long-term follow-up will be needed from these randomized studies before clinicians can incorporate these regimens into standard practice. However, these approaches may offer an alternative strategy for improving therapy in high-risk patients with advanced-stage disease.
Based on the results of the ECHELON-1 study, the FDA approved brentuximab vedotin in combination with chemotherapy (ie, A+AVD) in March 2018 for the treatment of adult patients with previously untreated stage III or IV cHL. In my practice, I strongly consider A+AVD for patients <60 years with advanced- stage cHL and any of the aforementioned clinical risk factors (eg, high IPS, male gender, stage IV disease). For patients with lower-risk cHL and/or without access to brentuximab vedotin, therapy vis-à-vis the RATHL design is a valid option for patients <60 years. For older patients with cHL who are fit (eg, with preserved activities of daily living and low comorbidity score), I advocate giving brentuximab vedotinsequentiallyas a single agent before and after AVD chemotherapy. For unfit, older patients with cHL, therapy with single- agent brentuximab vedotin with or without dacarbazine may be considered.
The recently opened North American Intergroup phase III S1826 study randomizes patients with advanced-stage cHL to receive AVD plus brentuximab vedotin via ECHELON-1 versus AVD plus nivolumab (Opdivo; NCT03907488). Notably, this study will not alter therapy based on PET2 response, in part given the aforementioned findings from the S0816 study. Furthermore, this study was planned as a collaboration of SWOG, the Eastern Cooperative Oncology Group, Alliance for Clinical Trials in Oncology, and the Children’s Oncology Group and will enroll patients ≥12 years. Investigators are continuing to explore integration of novel targeted therapeutic agents and examination of potential predictive biologic biomarkers.