WHERE WE ARE?

Patients with advanced-stage classical Hodgkin lymphoma (cHL) have a good prognosis. In most countries, the first-line treatment has been, for at least a couple of decades, the ABVD protocol. Depending on several factors such as age, presence of bulky disease, or extranodal involvement, around 75-80% of patients are cured with this regimen1. However, there are now new treatment recommendations for advanced-stage cHL. After 6 years of follow-up, the ECHELON-1 study showed overall survival (OS) benefit for brentuximab vedotin with AVD versus the standard ABVD2. This has never happened in previous direct comparative trials. Although the BV+AVD was already approved for first-line treatment of advanced-stage cHL patients, based on the gain of progression-free survival (PFS) published a couple of years ago, a benefit in OS makes a much stronger case. Peripheral neuropathy was a special concern, with about 2 out of 3 patients treated with BV+AVD experiencing some form of symptom. Mainly it was grades I 1 and 2, and the symptoms did resolve or improved in almost 90% of cases2. But the BV-AVD reign has already been challenged. The SWOG1826 study is a randomized, multicenter, phase 3 trial, that compares the combination of nivolumab with AVD (nivo-AVD) versus BV-AVD3. This is a large trial, with almost 1000 patients, that included patients between 12 and 83 years. The 1-year PFS rate was 94% versus 86% (HR 0.48, 99%CI 0.27-0.87; p=0.0005), in favor of Nivo-AVD. OS was similar (99% vs 98%), with a short median follow-up of 12.1 months. Interesting that both arms of this study were for a limited number of 6 cycles, something different that is normally done with checkpoint inhibitors (usually until the progression of the disease, unacceptable toxicity, or up to 2 years). So, a longer follow-up will be paramount to see if this advantage for nivo-AVD will hold in time. The toxicity profile was largely as expected and no new safety signals in both arms. On the other hand, the HD21 study looked at the association between BV and a similar backbone of the escalated BEACOPP (eBEACOPP), known as BrECADD4. This new regimen was compared in a multicenter, randomized, phase 3 non-inferiority trial, with the standard eBEACOPP. Using a PET-adapted strategy, where interim PET negative patients completed 4 total cycles versus 6 total cycles in PET positive, BrECADD was non-inferior to eBEACOPP. The 3y-PFS rate was 94.9% versus 92.3%, with a median observation time of 40 months. These impressive results compare favorably with BV-AVD in the ECHELON-1 study (6y PFS of 82.3%) and with Nivo-AVD in the SWOG study (1y PFS of 94%), but with all the restrictions of comparing different trials.

WHAT TO EXPECT FOR THE FUTURE?

Clearly, in one of the lymphomas with the best overall prognosis, the treatment landscape evolved. There are now at least 3 new options for the treatment of advanced-stage cHL in the first line, with better results than ABVD, the standard for a long time. As we continue to improve efficacy, toxicity remains an important issue. Longer follow-ups will be needed to see if we can have great results without impact in our patient's quality of life.