The Treatment of R/R cHL in the Era of Checkpoint Inhibitors

Dr. Catherine Diefenbach
Catherine Diefenbach, MD
Assistant Professor of Medicine
Clinical Director of Lymphoma
Department of Hematology/Oncology
NYU Langone Medical Center
New York, New York

Managing HL recently interviewed Catherine Diefenbach, MD, a renowned oncologist at NYU Langone Health, to learn more about the treatment of relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) in the era of immune checkpoint inhibitors. In this interview, Dr. Diefenbach summarizes current salvage treatment options for R/R cHL and describes the benefits and risks of various therapies that are currently available. She also discusses the expanding role of immunotherapy in R/R cHL, including recent efficacy and safety data from clinical trials.

When managing patients with R/R cHL, at what point should community oncologists begin thinking about using salvage therapy, and what are the realistic expectations for those who undergo this therapy?

Research shows that cHL is curable in 70% to 80% of patients with first-line therapy, but relapses may occur in some individuals. Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) for patients with chemotherapy-sensitive disease is the standard second-line treatment for relapsed/refractory cHL (R/R cHL). Patients who achieve a complete response prior to ASCT have better survival outcomes. Optimizing the choice of salvage therapy has become increasingly difficult in the era of novel agents because there is little direction from guidelines regarding choices for second-line regimens.1

Salvage therapy should be considered for any cHL patient who has relapsed or has primary refractory disease. Relapsed cHL patients typically have an initial response to chemotherapy but later relapse after completing chemotherapy. With primary refractory disease, patients have transient responses but ultimately experience disease progression by the time treatment with chemotherapy is finished. Regardless of category, both of these patient types will need salvage therapy.

Prior to starting salvage therapy, guidelines recommend confirming that patients truly have relapsed or refractory disease using tissue biopsy.2 This is recommended because a subset of patients will have PET-positive cHL after treatment in their initial disease site but will not have active disease. A biopsy is necessary to confirm the diagnosis before committing to second-line salvage and high-dose chemotherapy because other conditions (eg, post-treatment fibrosis) can mimic R/R cHL.

Managing expectations with salvage therapy is critical when caring for R/R cHL patients. Community oncologists should understand that about half of patients who achieve optimal disease control prior to salvage therapy can obtain a durable complete response from high-dose therapy and ASCT.1 However, those with poor disease control prior to ASCT tend to have significantly worse outcomes. For these individuals, subsequent high-dose chemotherapy is typically ineffective. Patients who relapse after ASCT have few treatment options available, but studies are exploring novel therapies that may improve outcomes.

What guideline-recommended therapies are available for salvage treatment in R/R cHL, and what is known about the efficacy and safety of these options?

Current guidelines recommend several options as second- and later-line therapies for R/R cHL (Table), and others are being explored in clinical trials.2 Recently, several additions to this list have represented important advances in the management of R/R cHL. Nivolumab and pembrolizumab, two immune checkpoint inhibitors, have been approved by the FDA for use in third- and later-line therapy in patients with R/R cHL. Brentuximab vedotin is approved as second- and later-line therapy.2 Everolimus, an mTOR inhibitor, offers another potential treatment option for salvaging patients after ASCT or for those who are multiple refractory.3

Second-line R/R cHL Options

Later-line R/R cHL Options

Brentuximab vedotin as monotherapy or in combination with other regimens listed below


DHAP (dexamethasone, high-dose cytarabine, cisplatin)

C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone)

ESHAP (etoposide, steroids, cytosine arabinoside, cisplatin)


Gemcitabine, bendamustine, vinorelbine

GCD (gemcitabine, carboplatin, dexamethasone)

GVD (gemcitabine, vinorelbine, liposomal doxorubicin)


ICE (ifosfamide, carboplatin, etoposide)

MINE (mesna, ifosfamide, mitoxantrone, etoposide)

IGEV (ifosfamide, gemcitabine, vinorelbine, prednisone)

Mini-BEAM (carmustine, etoposide, cytarabine, melphalan)




According to studies, high-dose regimens for the management of R/R cHL, such as DHAP, ESHAP, and ICE, have a complete remission (CR) rate of 30% to 35%, but these treatments can be toxic for many patients. In a pivotal trial, brentuximab vedotin induced an overall response rate (ORR) of approximately 75%, with a CR rate of about 34%, in relapsed/refractory HL patients who had relapsed after ASCT. Nivolumab and pembrolizumab also have a very high ORRs, but their CR rates are lower, ranging between 9% and 20%.4,5 Each of these treatments may play an important role in improving outcomes for this difficult-to-treat patient group.

What is the role of immunotherapy in R/R cHL, and what is known about the efficacy and safety of these agents when used in this treatment setting?

Nivolumab, pembrolizumab, and brentuximab vedotin are considered real game changers in the management of R/R cHL because data suggest that most patients will respond to these therapies. The ORRs for each of these agents is high and the durability of responses appear to be significant over time.6-9 Many R/R cHL patients will achieve a partial response with traditional treatments, but these individuals are at higher risk for relapses than those who achieve a CR. For this patient group, allogeneic stem cell transplant may be their only potential curative treatment. Immunotherapy has the potential to improve CR rates, which in turn could cure some patients or may serve as a bridge to transplant.10

Clinicians should be aware that immunotherapies are no less toxic than standard chemotherapy, but their toxicity spectrum is different. The typical toxicities seen with high-dose chemotherapy regimens, such as hair loss, fatigue, and nausea/vomiting, are not as common with immunotherapy. Instead, the side-effect profile of immunotherapy often includes rashes, diarrhea, pneumonitis, and elevated hepatic enzyme levels.10 These toxicities must be monitored closely and managed early when using immunotherapy in R/R cHL because their effects can be quite severe.

What factors should be considered when determining if a patient with R/R cHL is a good or poor candidate for treatment with immunotherapy?

Unlike many treatments for R/R cHL, there is no biomarker that is suggestive of who may be a good or poor candidate for immunotherapy. This is because Hodgkin Reed-Sternberg cells express a high amount of PD-L1 and peritumoral T cells express a high amount of PD-1. PD-L1 expression is typically ubiquitous on the surface of Hodgkin Reed-Sternberg cells, which are primary tumor cells in cHL.11 Although there is no effective way to stratify how well or poorly R/R cHL patients will do with immunotherapy, investigators are trying to determine if different aspects of lymphoma biology and immune profiles affect responses to these treatments. It is hoped this research will eventually improve our capabilities to differentiate responders and non-responders to immunotherapy and determine which patients are likely to have long-term, transient, or partial benefits.

Several factors are important to consider when determining candidacy for immunotherapy. Most patients with R/R cHL can be considered potential candidates for immunotherapy, including those with well-controlled HIV. However, poorer candidates for immunotherapy include those with pre-existing autoimmune diseases (eg, lupus, pulmonary fibrosis, sarcoidosis) or HIV that has not been well managed or controlled.

Are there any ongoing clinical trials further investigating combination treatments involving immunotherapies for R/R cHL?

Several clinical trials are currently exploring various combinations of immunotherapies for R/R cHL. For example, an ongoing ECOG-ACRIN sponsored study is assessing different combinations involving brentuximab vedotin, nivolumab, and/or ipilimumab in heavily pretreated patients with R/R HL. Early results from this study showed that combining nivolumab with brentuximab vedotin led to durable long-term CRs and was well tolerated. Of note, 20% of patients had prior treatment with brentuximab vedotin and 60% previously received ASCT. The ORR in this trial was 95% and the CR rate was more than 60%, suggesting a deepening of response when compared with either therapy alone.12

In an effort to optimize this combination strategy, the ongoing study is comparing doublet therapy with brentuximab plus nivolumab to triplet therapy consisting of brentuximab vedotin plus nivolumab and ipilimumab.13,14 Other trials are exploring different immunotherapies in the treatment of R/R cHL, including pembrolizumab. Any site that participates in the Clinical Trials Network can access this study and other trials, and community oncologists can learn more about these and other industry-sponsored trials by collaborating with larger, hospital-connected groups.

What are the major take-home points regarding salvage therapy in the era of immunotherapy when managing patients with R/R cHL?

Considering the high cure rate associated with most cHL cases, it is likely that many community oncologists will see very few patients with relapsed or refractory disease. As such, it may be helpful for community oncologists to consult with specialized centers so that these patients are steered to salvage combination treatments or immunotherapies that may not be readily accessible outside the setting of an experienced academic medical center.15 Experts at these centers may also offer guidance on optimal approaches to sequencing therapy or assist with enrolling patients into a clinical trial.

Although patients with R/R cHL are often insensitive to chemotherapy, the emergence of immune checkpoint inhibitors have revolutionized treatment because they offer a therapeutic modality that may result in long-term disease control.16 Clinicians must be aware of the different types of toxicities that can occur with immunotherapy and discuss these risks with patients. Clinical trials are continuing to evaluate the long-term durability of these agents and seek to determine which patients are most likely to benefit from them. Partnering with specialized academic centers helps continue the development of groundbreaking therapies. Community oncologists should reassure patients that they will work with them to develop treatment plans that maximize their potential for achieving a cure.


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  12. Diefenbach CS, Hong F, David KA, et al. A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412 Arms D and E). Blood. 2016;128:1106. Available at: Accessed November 2, 2018.
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  14. A phase I study with an expansion cohort/randomized phase II study of the combinations of ipilimumab, nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma. NLM Identifier: NCT01896999. October 4, 2018. Available at: Accessed November 2, 2018.
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