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Frontline Therapy for Advanced HL
How Recent Data Have Influenced How I Treat Advanced Hodgkin Lymphoma

Released: September 13, 2018

Expiration: September 12, 2019

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The standard treatment in the United States for patients with newly diagnosed advanced (stage III-IV) Hodgkin lymphoma (HL) has been 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). However, the standard of care for these patients has recently shifted based on data from 2 clinical trials: RATHL, which assessed initial ABVD followed by response-adapted therapy, and ECHELON-1, which compared brentuximab vedotin plus AVD vs standard ABVD. In this commentary, I discuss key findings from these trials and how I now treat newly diagnosed patients with advanced HL.

ABVD Adapted Based on Initial Response
In the phase III RATHL study, patients with newly diagnosed advanced HL were treated with 2 cycles of ABVD, after which an interim PET scan was conducted; PET-negative patients were randomized to another 4 cycles of either ABVD or AVD (ie, ABVD without bleomycin). It was hypothesized that de-escalating therapy for responders by removing bleomycin after 2 cycles could produce fewer adverse events without affecting PFS (compared with ABVD). PET-positive patients received BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone)-14 or escalated BEACOPP, according to treating center preference.

Similar 3-year PFS and OS results were demonstrated for PET-negative patients receiving AVD and ABVD, suggesting that removing bleomycin from the ABVD regimen after a positive initial response is a viable option. In addition, BEACOPP yielded promising 3-year PFS results in patients who were PET positive at the interim scan. Although findings from RATHL have changed practice for both PET-negative and PET-positive patients, the real impact of this trial is for PET-negative patients, for whom most clinicians would now consider dose de-escalation. For those patients who are PET-positive after 2 cycles of ABVD, most clinicians would recommend continued ABVD, as many patients have difficulty tolerating escalated BEACOPP.

Brentuximab Vedotin Plus AVD
The ECHELON-1 trial evaluated a new frontline option for advanced HL: brentuximab vedotin, a CD30-targeted antibody–drug conjugate. In this phase III study, patients with newly diagnosed advanced disease were randomized to 6 cycles of either ABVD or AVD plus brentuximab vedotin. When the trial was first reported at ASH 2017, the modified 2-year PFS benefit with AVD plus brentuximab vedotin was 4.9%. However, this benefit was accompanied by increased peripheral neuropathy and neutropenic fever, along with decreased pulmonary complications. Based on the ECHELON-1 findings, in March 2018, the FDA expanded the indications of brentuximab vedotin to include treatment (in combination with chemotherapy) of all patients with previously untreated stage III/IV HL.

It should be noted that when results of the trial were published, subgroup analysis showed that patients in higher-risk International Prognostic Score categories derived the greatest PFS benefit from treatment with brentuximab vedotin plus AVD (vs treatment with ABVD). Based on these data, not all clinicians chose to use this regimen as frontline therapy at that time. Since then, additional data from ECHELON-1 were presented at the ASCO and EHA meetings, showing that patients in North America experienced substantial benefit from this regimen—a modified PFS benefit of approximately 10.0%, which is much higher than the 4.9% originally reported for all patients (including those in Europe and Asia). In addition, a post hoc analysis showed that PET2-positive patients who were treated with brentuximab vedotin plus AVD had a 2-year modified PFS rate of approximately 57%, which was improved vs those treated with ABVD (42%).

How I Treat Patients With Newly Diagnosed Advanced HL
Based on these data, I am more inclined to recommend brentuximab vedotin plus AVD instead of ABVD for all patients with stage III/IV HL. Upfront treatment with brentuximab vedotin plus AVD removes the need for interim PET scanning to determine whether a change in therapy is warranted; even for PET-positive patients, there is no need to modify therapy to escalated BEACOPP, which some clinicians prefer to avoid if possible.

Your Thoughts
Have recent clinical trial findings changed how you treat newly diagnosed patients with advanced HL? I encourage you to join the conversation in the comments section or by answering the polling question on your screen.

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Which regimen do you most frequently recommend for treatment of patients with newly diagnosed stage III/IV HL?
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