Incorporating Novel Agents Into Classical Hodgkin Lymphoma Treatment

The advent of novel treatment options for classical Hodgkin lymphoma (cHL) has revolutionized the cHL therapeutic landscape. The CD30-targeting antibody-drug conjugate brentuximab vedotin (BV) and the programmed death-1 (PD-1)–blocking antibodies nivolumab and pembrolizumab have all been approved by the U.S. Food and Drug Administration for the treatment of relapsed/refractory (R/R) cHL.

These immunotherapies targeting specific biologic features of cHL have expanded the therapeutic armamentarium for patients with multiply R/R cHL and have now been studied in various settings throughout a patient’s disease course, from initial therapy to posttransplant consolidation. With the abundance of studies, often nonrandomized and controlled, that have evaluated BV and PD-1 blockade as part of cHL therapy, the dilemma of how to optimally integrate these drugs into clinical practice has arisen. Here, we offer practical guidance on how to incorporate these agents into the management of cHL.

Novel Agent–Naïve Multiply R/R cHL

Although both BV and PD-1 inhibitors are effective in multiply R/R cHL, there is no consensus on the optimal timing and sequencing of these drugs.

The phase III randomized KEYNOTE-204 study showed that pembrolizumab was associated with significantly longer progression-free survival (PFS) compared with BV, a benefit noted across subgroups. Pembrolizumab and BV were associated with a similar incidence of grade ≥3 adverse events (AEs), but pembrolizumab was associated with a higher incidence of infusion-related AEs whereas BV was associated with more nausea and peripheral neuropathy.

Based on available evidence, there is no clear difference in the efficacy or toxicity between pembrolizumab and nivolumab. They are administered on different schedules (every 2 or 4 weeks for nivolumab, every 3 or 6 weeks for pembrolizumab).

We typically use a personalized approach to antibody and schedule selection, tailored to the patient’s wishes, clinical status, and depth of response. For patients who need closer monitoring, we choose a schedule of nivolumab every two weeks or pembrolizumab every three weeks.

In patients who achieve complete remission (CR), we treat until progression, with consideration of discontinuation after six months (at the earliest) and usually discontinue after two years. For patients with partial response or stable disease in response to PD-1 blockade, we usually treat until progression. Based on results from the CM205 trial of nivolumab in patients with relapsed/refractory cHL after unsuccessful autologous hematopoietic cell transplantation (AHCT), we continue treatment beyond progression if the patient is clinically well and the disease burden is not high.

Follow-up imaging is critical to distinguish between “pseudoprogression” and true progressive disease. In patients with multiply R/R cHL who have progressed on anti-PD-1 therapy, we recommend BV for up to 16 cycles, depending on tolerance of AEs (e.g., peripheral neuropathy).

For patients who have multiply R/R cHL or relapse after AHCT with prior BV or anti-PD-1 exposure, we recommend selecting the agent that has not been used previously. Although the overall response rate to BV or anti-PD-1 monotherapy is high, the complete response rate and ultimate curative potential with either type of agent is relatively low. To improve the depth and duration of response, combination strategies are currently being evaluated in clinical trials with promising results thus far, although these approaches are not standard and are not recommended in routine practice at this time.

Novel Agent–Based Salvage Therapy for R/R cHL

There are no randomized, controlled data to guide decisions about first salvage therapy for patients with R/R cHL. Regimens are selected based on physician or patient preference (e.g., desire to avoid chemotherapy or inpatient hospitalization). Salvage combination chemotherapy remains the standard approach; however, we would also consider use of BV plus nivolumab based on the high likelihood of achieving CR and excellent PFS, outpatient administration, and its favorable toxicity profile. This use of BV or nivolumab has not been approved, but is supported by guidelines.

Primary refractory, novel agent–naïve cHL

Some salvage regimens are associated with lower CR rates in patients with primary refractory cHL compared with relapsed cHL, including some chemotherapy regimens, BV plus chemotherapy regimens, and BV plus nivolumab. At present, chemotherapy-based salvage remains the standard for these patients, although novel salvage approaches remain satisfactory options supported by guidelines.

R/R cHL with prior exposure to novel agents

Some patients will have received novel agents as part of frontline therapy. In these patients, we would use a standard chemotherapy-based salvage regimen at the present time. However, with promising early data on anti-PD-1–based salvage independent of BV, anti-PD-1–based salvage may be a future option for patients with frontline BV failure. Priorities regarding therapy duration and toxicities should be considered when selecting a salvage regimen.

Novel Agents as Post–AHCT Consolidation Therapy

BV consolidation after AHCT is approved for use in high-risk patients with cHL with primary refractory disease, relapse within 12 months of frontline therapy completion, or extranodal relapse. The benefit of BV consolidation is unclear in patients with prior BV exposure and we do not recommend BV consolidation in patients who have demonstrated BV resistance before AHCT. In high-risk patients who remain BV sensitive after a short course of BV before AHCT (e.g., CR to BV-based salvage), we consider BV consolidation, although there are no data to support its use. We recommend counting salvage BV cycles toward the maximum 16 cycles of consolidation (e.g., maximum 12 consolidation cycles after 4 cycles of salvage BV). Although results are promising thus far, because limited data are available, we do not currently recommend post–AHCT consolidation with PD-1 blockade.

Novel Agents for Patients with Newly Diagnosed cHL

Combination chemotherapy, with or without radiotherapy, is the standard treatment of newly diagnosed cHL. Positron emission tomography (PET)-adapted approaches allow for de-escalation of therapy in patients with a negative interim PET and therapy intensification in patients with early evidence of chemoresistance. In early-stage cHL, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with radiotherapy or PET-adapted chemotherapy yields cure rates of 85% to 90%, depending on disease bulk and other risk factors. In patients with advanced-stage cHL, PET-adapted approaches starting with ABVD or escalated-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), are associated with 75% to 90% long-term PFS.

Young, fit patients

In young, fit patients with early-stage cHL, we do not recommend incorporation of BV or PD-1 blockade because of the dearth of randomized, controlled data with sufficient long-term follow-up at this time.

In patients with newly diagnosed advanced-stage cHL, treatment selection requires consideration of the risks and benefits of the various options available in discussion with the patient. ABVD has been the standard in North America and bleomycin can be safely discontinued after two cycles in patients with a negative interim PET scan. However, patients with a positive interim PET scan have dismal outcomes with ABVD continuation, and the alternative is escalation to BEACOPP, a regimen associated with increased toxicity compared with ABVD.

Although BV+AVD was compared with ABVD without PET adaptation and the primary endpoint of the ECHELON-1 study was the unfamiliar modified PFS (mPFS), both the mPFS and traditionally defined PFS were higher than those in the control arm. Major drawbacks of BV+AVD include increased toxicity compared with ABVD (e.g., peripheral neuropathy, neutropenia, and infections), the requirement for granulocyte colony-stimulating factor use, and high cost. However, in secondary analyses of the ECHELON-1 study, younger patients with higher-risk disease appeared to benefit the most from BV+AVD.

We do not recommend the use of PD-1 blockade as part of initial frontline therapy for young, fit patients with advanced-stage cHL based on lack of supporting data.

Elderly patients

In patients who are elderly or frail, or those with comorbidities, we base decision making on whether the patient can tolerate combination chemotherapy. If yes, for early-stage favorable elderly/unfit patients, two cycles of ABVD followed by radiation therapy is relatively well tolerated and associated with excellent outcomes. For patients with non-bulky, early-stage disease, PET-adapted ABVD (3-4 cycles as per RAPID or CALGB 50604) can be considered, but four cycles of bleomycin is associated with increased toxicity and the risks versus benefits of using bleomycin in elderly patients or in the presence of comorbidities must be weighed.

For advanced-stage patients or those who can tolerate chemotherapy but not bleomycin, we use the sequential BV+AVD regimen because of its curative potential as a full systemic course of therapy compared with BV monotherapy or doublets. If the patient cannot tolerate combination chemotherapy, we recommend BV-based therapy, preferably BV plus dacarbazine, because it is associated with a longer duration of response or BV monotherapy for patients who are very elderly or unfit. If the patient’s performance status improves after treatment with BV monotherapy, it is reasonable to transition to sequential BV+AVD.

The FIGURE illustrates an algorithm for incorporating novel agents into the management of cHL.

Future Directions

Dilemmas regarding how to integrate novel therapies into the treatment of cHL remain because the field is evolving so rapidly. A patient with cHL encountered in the clinic may have multiply R/R cHL with no prior exposure to novel agents or may have received a novel agent as frontline or salvage treatment. This variety of presentations prevents uniform recommendations for all patients at a particular time point.

There is also a lack of randomized controlled data to guide decisions, although studies such as KEYNOTE-204 are aiming to bridge the gap. A critical question for the future of cHL management is the optimal timing for the use of BV and PD-1 blockade and what the best combination partners are.

More experience with treating patients with these drugs earlier in the disease course means patients with R/R cHL will increasingly have BV- or anti-PD-1–resistant cHL and approaches to overcoming resistance will be necessary. We must also accept that many patients have cHL that is not cured by the current novel agents and that newer targeted therapies for cHL are needed.