While clinical trials emphasize improvement in cure rates for patients with advanced classical Hodgkin lymphoma, an important goal is reducing the potential long-term effects of treatment.— Iris Isufi, MD
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“While clinical trials emphasize improvement in cure rates for patients with advanced classical Hodgkin lymphoma, an important goal is reducing the potential long-term effects of treatment,” commented Iris Isufi, MD, of the Smilow Cancer Hospital and Yale Cancer Center, New Haven, Connecticut, and member of the National Comprehensive Cancer Network (NCCN) Guidelines Panel for Hodgkin Lymphoma. At the 2024 NCCN Annual Congress: Hematologic Malignancies, she discussed the NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®), including recommended first-line therapy options and their unique toxicities.
In the current NCCN Guidelines, four regimens are recommended for the primary treatment of stage III to IV classical Hodgkin lymphoma: ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; preferred; category 1); brentuximab vedotin plus AVD (doxorubicin, vinblastine, and dacarbazine; preferred; category 1); BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone; useful in certain circumstances; category 2A); and nivolumab plus AVD (useful in certain circumstances; category 2B).1
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
- Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
- Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
Preferred: ABVD
Dr. Isufi noted a “relatively high” cure rate of approximately 80% with ABVD, justifying its long-standing status as a “preferred” regimen for the first-line treatment of advanced classical Hodgkin lymphoma in the NCCN Guidelines.1 Despite its safety profile being deemed “acceptable,” she added that ABVD “carries a risk of bleomycin-induced pulmonary toxicity, which increases with age, decreased renal function, concomitant use of granulocyte-colony stimulating factor (G-CSF), and consolidative radiation therapy to the thorax.”
Per the NCCN Guidelines, after undergoing two cycles of ABVD and an interim fluorodeoxyglucose–positron-emission tomography/computed tomography (FDG-PET/CT) scan, patients with a Deauville score of 1 to 3 are administered four additional cycles without bleomycin. Those with a Deauville score of 4 or 5 are treated with three cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).1
This approach was established based on the response-adapted RATHL trial, according to Dr. Isufi, in which the 3-year progression-free and overall survival data showed “it is safe to omit bleomycin without compromising outcomes” in patients with advanced classical Hodgkin lymphoma who had negative findings on the interim FDG-PET/CT scan after ABVD therapy. She also pointed out that those with interim PET-positive disease experienced similar survival outcomes with escalated BEACOPP vs the time-intensive BEACOPP-14 regimen, albeit with lower rates than those seen with both AVD and continued ABVD.
Preferred: Brentuximab Vedotin Plus AVD
Continuing her discussion on the first-line therapy options for the management of advanced classical Hodgkin lymphoma, Dr. Isufi summarized the overall results from the phase III ECHELON-1 trial of brentuximab vedotin plus AVD vs ABVD: “Initially, there was a benefit in modified progression-free survival with brentuximab vedotin plus AVD. [Based on the 6-year follow-up analysis], brentuximab vedotin plus AVD [became] the first regimen to show an improvement in overall survival vs ABVD in [this patient population (93.9% vs 89.4%)].”2 Brentuximab vedotin plus AVD was also found to result in fewer disease-related deaths, second malignancies, and deaths from second malignancies, as well as more reported pregnancies and the resolution of peripheral neuropathy symptoms in approximately 86% of affected patients.
Dr. Isufi stated that these data supported treatment with six cycles of brentuximab vedotin plus AVD—a regimen that notably eliminates exposure to bleomycin and does not require interim PET/CT staging—as a “preferred” first-line option for advanced classical Hodgkin lymphoma.1 Of note, per the NCCN Guidelines, this regimen is contraindicated in patients with neuropathy.
“There was a significantly higher risk of adverse events, including grade 3 or higher adverse events, in patients [aged at least vs younger than 60 years who were treated with brentuximab vedotin plus AVD, with] more grade 3 or higher neutropenia, febrile neutropenia, and grade 3 and 4 peripheral neuropathy,” Dr. Isufi emphasized.3 “This regimen can be toxic and may require dose reductions…, [and we should] keep in mind the risk of opportunistic infections in this patient population.”
The 5-year progression-free survival rate with brentuximab vedotin plus AVD was lower in older vs younger patients (67.1% vs 84.3%). Among the older population, brentuximab vedotin plus AVD vs ABVD seemed to demonstrate similar efficacy (67.1% vs 61.6%).
Of note, baseline and prospective geriatric assessments were not performed in the ECHELON-1 study. Dr. Isufi thus advocated for the consideration of alternative strategies, including sequential brentuximab vedotin plus AVD, brentuximab vedotin combinations, and checkpoint inhibitor combinations, in elderly unfit patients with high Cumulative Illness Rating Scale–Geriatric comorbidity scores.
Useful in Certain Circumstances: BrECADD
Based on the results of the phase III HD21 trial of PET-guided BrECADD vs escalated BEACOPP for advanced classical Hodgkin lymphoma, treatment with two cycles of the former regimen was deemed “useful in certain circumstances” in the NCCN Guidelines.1 Patients treated with BrECADD vs BEACOPP seemed to experience a significantly lower rate of treatment-related morbidity (42% vs 59%); of note, peripheral sensory neuropathy was documented in 39% and 49% of the arms, -respectively.4 Dose reductions and transfusion support were also found to be less frequent with BrECADD.
The 4-year rate of progression-free survival with BrECADD (vs BEACOPP: 94.3% vs 90.9%) was “one of the highest that has been shown in randomized controlled trials [in newly diagnosed patients with advanced classical Hodgkin lymphoma],” according to Dr. Isufi. She noted that, at the current follow-up, the rates of overall survival did not appear to significantly differ between the arms (98.6% vs 98.2%).
“It is important to keep in mind that this was designed as a noninferiority open-label study,” Dr. Isufi remarked. “At the present time, we do not have any randomized controlled data of BrECADD with brentuximab vedotin plus AVD or nivolumab plus AVD.”
Looking Ahead: Perhaps New Preferred Treatment
The classification of six cycles of nivolumab plus AVD as “useful in certain circumstances” for the treatment of advanced classical Hodgkin lymphoma in the NCCN Guidelines1 is backed by data from the SWOG S1826 trial. In this study, the regimen (G-CSF optional) was compared with brentuximab vedotin plus AVD (G-CSF required) in patients aged 12 or older.
The most frequently reported adverse event with nivolumab plus AVD was neutropenia (vs brentuximab vedotin plus AVD: 55% vs 32%); of note, G-CSF–induced bone pain was commonly seen with brentuximab vedotin plus AVD (vs nivolumab plus AVD: 20% vs 8%).5 The rates of other adverse events of interest, such as infectious toxicities (febrile neutropenia: 5% vs 7%; sepsis: 2% vs 3%; infections/infestations: 5% vs 8%) and peripheral sensory neuropathy (29% vs 55%), were lower with nivolumab vs brentuximab vedotin plus AVD. According to Dr. Isufi, it is important to note that nivolumab plus AVD conferred low rates of immune-related adverse events and a very low rate of requiring radiation therapy to the chest.
Patients treated with nivolumab plus AVD vs brentuximab vedotin plus AVD demonstrated higher rates of progression-free (94% vs 86%) and event-free (91% vs 84%) survival at 1 year. Although the overall survival rates did not appear to differ between the arms, more events were reported with brentuximab vedotin plus AVD (11 vs 4).
Nivolumab vs brentuximab vedotin plus AVD was also better tolerated in patients over 60 years, according to Dr. Isufi, with low rates of immune-related adverse events.6 Improved 1-year progression-free (93% vs 64%) and event-free (93% vs 57%) survival rates were also seen with the former regimen.
“Follow-up is ongoing…, but the study made significant progress in recruiting diverse populations and toward harmonizing pediatric and adult therapy for classical Hodgkin lymphoma,” Dr. Isufi remarked. “[Nivolumab plus AVD] is well positioned to become a standard therapy for [patients with] advanced Hodgkin lymphoma, including for older patients who are still considered fit for anthracycline-based combination therapy.”
Dr. Isufi concluded: “The results of studies like ECHELON-1, HD21, and SWOG S1826 will inform future studies regarding de-escalation of therapy and giving less chemotherapy. [When using the currently available data to] decide what I am going to treat a patient with, I pay particular attention to their level of fitness, comorbidities, and ability to perform activities of daily living. At this time, it is great to have all of these available options.”
DISCLOSURE: Dr. Isufi has received consulting fees from Bristol Myers Squibb, Caribou, Incyte Corporation, and Janssen; and has served on a product or speakers bureau for Kite.
REFERENCES
1. Hoppe RT, Advani RH, Ambinder RF, et al: NCCN Clinical Practice Guidelines in Oncology: Hodgkin Lymphoma. Version 3.2024. Available at www.nccn.org. Accessed October 2, 2024.
2. Ansell SM, Radford J, Connors JM, et al: Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med 387:310-320, 2022.
3. Evens AM, Connors JM, Younes A, et al: Older patients (aged ≥ 60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: A detailed analysis from the phase III ECHELON-1 study. Haematologica 107:1086-1094, 2022.
4. Borchmann P, Ferdinandus J, Schneider G, et al: Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): A randomised, multicentre, parallel, open-label, phase 3 trial. Lancet 404:341-352, 2024.
5. Herrera AF, LeBlanc ML, Castellino SM, et al: SWOG S1826, a randomized study of nivolumab-AVD versus brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. 2023 ASCO Annual Meeting. Abstract LBA4. Presented June 4, 2023.
6. Rutherford SC, Li H, Herrera AF, et al: Nivolumab-AVD is better tolerated and improves progression-free survival compared to Bv-AVD in older patients (aged ≥ 60 years) with advanced stage Hodgkin lymphoma enrolled on SWOG S1826. Blood 142(suppl):181, 2023.
