Contemporary Therapy for Advanced- Stage Hodgkin Lymphoma

December 6, 2019

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.

Andrew M. Evens, DO, MSc


Hodgkin lymphoma (HL) 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.


PET-Adapted Strategies

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 antibody—drug 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.5 Patients 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 given sequentially as 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 vedotin sequentially as 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.

Future Directions

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.


  1. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin&rsquo;s lymphoma. N Engl J Med. 2016;374(25):2419-2429. doi: 10.1056/NEJMoa1510093.
  2. Press OW, Li H, Sch&ouml;der H, et al. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fluorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027. doi: 10.1200/JCO.2015.63.1119.
  3. Stephens DM, Li H, Sch&ouml;der H, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach for stage III/IV Hodgkin lymphoma [published online July 22, 2019]. Blood. doi: 10.1182/blood.2019000719.
  4. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin&rsquo;s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348-1356. doi: 10.1016/S1470-2045(13)70501-1.
  5. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin&rsquo;s lymphoma. N Engl J Med. 2018;378(4):331-344. doi: 10.1056/NEJMoa1708984.
  6. Evens AM, Connors JM, Younes A, et al. Older patients (pts) with previously untreated classical Hodgkin lymphoma (cHL): a detailed analysis from the phase 3 ECHELON-1 study. Blood. 2018;132(suppl 1;abstr 1618). doi: 10.1182/blood-2018-99-112178.
  7. Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015-3022. doi: 10.1200/JCO.2018.79.0139.
  8. Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients with advanced-stage Hodgkin&rsquo;s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2018;390(10114):2790-2802. doi: 10.1016/S0140-6736(17)32134-7.