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Hodgkin Lymphoma FAQ
Experts Answer Frequently Asked Questions on the Management of Hodgkin Lymphoma

Released: February 07, 2019

Expiration: February 06, 2020

Robert W. Chen
Robert W. Chen, MD
Joseph M. Connors
Joseph M. Connors, MD, FRCPC
Andrew M. Evens
Andrew M. Evens, DO, MSc, FACP
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This ClinicalThought features a selection of questions asked by participants during an ASH 2018 satellite symposium focused on the optimal management of patients with Hodgkin lymphoma, with responses provided by members of the program faculty.

Frontline Treatment

What are key considerations in choosing frontline treatment for elderly patients with advanced Hodgkin lymphoma?
The treatment of older patients (older than 60 years of age) can be challenging. Elderly patients are more likely to be intolerant of standard dosing with contemporary treatment regimens; for example, older patients are at higher risk of bleomycin toxicity (ie, pulmonary toxicity) as this drug is renally excreted and many older patients have diminished renal function. Older patients can also have a different disease biology vs younger patients (eg, more mixed cellularity disease and/or more underlying Epstein-Barr virus infection).

In looking at treatment concerns with older patients in a recent study of frontline treatment for patients with advanced disease, the phase III ECHELON-1 study (overall N = 1334)—which evaluated brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line treatment for advanced Hodgkin lymphoma—included 186 patients older than 60 years of age. Results showed that older patients treated with BV plus AVD may have had less benefit (HR: 1.00) than patients younger than 60 years of age (HR: 0.73) and had higher rates of febrile neutropenia (37% vs 17%, respectively). However, such subgroup analyses must be interpreted cautiously.

There are numerous studies assessing treatment strategies in older patients. In a recently published phase II study, the use of BV sequentially before and after AVD was assessed for untreated patients older than 60 years of age (N = 48). In this study, outcomes were promising, with ORRs and CR rates of 95% and 90%, respectively, after BV plus 6 cycles of AVD. This is a population with difficult-to-treat disease, but it is the hope that use of novel agents such as BV and immune checkpoint inhibitors can improve outcomes.

Transplantation-Eligible Patients

What are the optimal salvage treatment regimens for younger patients who have relapsed within 12 months of receiving frontline ABVD or BV plus AVD?
For most patients in this situation, a clinical trial is the best answer. With the caveat that this is an off-label use for this agent, for patients who received upfront ABVD without BV or who received AVD plus BV and relapsed more than 6 months after completing treatment, BV might be considered as salvage therapy. If the patient achieves a CR, an autologous stem cell transplantation could then be considered. If the patient does not achieve a CR, the combination of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy could be considered as salvage therapy. For patients relapsing after less than 6 months after treatment with AVD plus BV, ICE could be considered as the first salvage therapy regimen.

What are some of the key regimens being studied as salvage therapy for patients experiencing a first relapse?
Several phase II trials have demonstrated the effectiveness of brentuximab vedotin plus chemotherapy (ICE, bendamustine, ESHAP, and others) after first relapse (typically following treatment with ABVD). Another study demonstrated the efficacy of bendamustine, gemcitabine, and vinorelbine in this setting. The chemotherapy-free combination of BV and nivolumab has been assessed in a phase I/II trial, with very promising results in terms of response and PFS.

There are currently many opinions as to the most effective salvage combination but few randomized studies to guide choices. Clinicians should select salvage therapy based on current clinical data and institutional/personal preferences and generally should employ regimens with which they have gained considerable experience, including management of potential toxicities.

Progression After High-Dose Therapy and Autologous SCT

Is a long-term cure possible with immune checkpoint inhibitors or BV in patients who progress after high-dose therapy and autologous SCT?
There is no question that immune checkpoint inhibitors and BV are active following progression after high-dose therapy and autologous SCT; however, it is premature to estimate how many patients may experience long-term remission or even cure with these agents as the clinical data are not yet available. With the immune checkpoint inhibitors nivolumab and pembrolizumab, 2-year findings are just now beginning to be published. With nivolumab, the phase II CheckMate 205 study had median follow-up of 18 months and showed a median PFS of 14.7 months after autologous SCT failure. Two-year results from the phase II KEYNOTE-087 study of pembrolizumab are expected in 2019.

With BV, there are some longer-term data with patients who were not cured with ABVD-like frontline treatment followed by intensified chemotherapy plus autologous SCT for relapse. In a follow-up study of the phase II trial of BV for patients with relapsed/refractory Hodgkin lymphoma after ASCT, approximately 50% of patients who achieved a CR with BV remained free of any evidence of progressive disease after 5-6 years. Although it is challenging to definitively state that these patients have been cured, their probability of relapse after this length of time is very, very low. In both the phase II trial of BV and in the phase III AETHERA study, the PFS curves flatten out before the 5- to 6-year mark, providing ample evidence that a small number of patients with disease resistant to both ABVD and intensified chemotherapy can be cured by this agent. It is as-yet unknown whether a similar statement will be able to be made about the immune checkpoint inhibitors in this setting.

Which patients with Hodgkin lymphoma are candidates for allogeneic SCT?
The challenge to using allogeneic SCT—at any point in the treatment of a patient with Hodgkin lymphoma—is the associated high-grade toxicity. Transplantation-related mortality can be > 20% for allogeneic SCT, and more than 30% of patients will develop graft-vs-host disease. In practical terms, this means patients should know their chance of either dying or being miserable after an allogeneic SCT is at least 50%—and, not only miserable, but persistently miserable for a long time after the transplant.

Now that newer agents like BV and immune checkpoint inhibitors are available, we are sending fewer patients with Hodgkin lymphoma to allogeneic SCT. Allogeneic SCT should be recommended for only those few patients with a) resistance to BV and PD-1 inhibition, b) very long intervals between their relapses, and c) who are young, fit, and have a good transplant match. Those with a good haplotype match and who receive posttransplant cyclophosphamide have a lower risk of graft-vs-host disease.

Your Thoughts
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