Hope After Salvage Therapy Fails: Novel Agents for Relapsed/Refractory Hodgkin Lymphoma

Oncology (Williston Park). 33(5):192-8.

Avyakta Kallam, MD

Julie M. Vose, MD, MBA

Table. Ongoing Clinical Trials of Novel Agents in Combination Therapies for Hodgkin Lymphoma (HL)

Hodgkin lymphoma is a highly curable malignancy, with an excellent prognosis. However, around 10% to 25% of patients will have primary refractory or relapsed disease, despite using risk-adapted strategies. The standard of care for patients with relapsed/refractory Hodgkin lymphoma has been cytoreduction using salvage chemotherapy, followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). Studies have shown that AHSCT produces a durable response rate of 50%, and that patients achieve a complete response with salvage chemotherapy. The outcomes for patients who do not respond to salvage chemotherapy or relapse after an AHSCT have been poor, with a median survival of 25 months. However, with the approval of novel agents over the last decade, the outcomes for patients with relapsed/refractory Hodgkin lymphoma have improved significantly. In this article, we present a case of a patient with relapsed Hodgkin lymphoma who responded to salvage chemotherapy incorporating brentuximab vedotin, a novel agent.

Case Presentation

A 21-year-old woman presented in 2006 with a persistent nonproductive cough and exertional shortness of breath. Further workup of her cough revealed a mediastinal and right hilar mass. A core needle biopsy of the mass was performed, which showed dense inflammatory cells with a few Reed–Sternberg cells. Immunophenotyping revealed CD15-positive, CD30-positive, CD20-negative cells with weak PAX5 staining, suggesting a diagnosis of classical Hodgkin lymphoma. Staging workup was consistent with stage II Hodgkin lymphoma. The patient was treated with a Stanford V regimen (doxorubicin, vinblastine, etoposide, vincristine, bleomycin, mechlorethamine, and prednisone) with consolidation radiation therapy. She achieved a complete remission with therapy and did well for 8 years.

In 2013, the patient presented to the clinic with prolonged upper respiratory tract infections despite antibiotic use. She also reported fatigue, night sweats, and low-grade fevers. A 7.5-cm mediastinal mass and bilateral lung lesions were found. She underwent video-assisted thoracic surgery and wedge resection of the lung lesions. Their pathology was consistent with relapsed nodular sclerosis Hodgkin lymphoma. A pretreatment PET/CT scan revealed a hypermetabolic mediastinal, hilar mass and bilateral lung lesions, with a maximum standardized uptake value of 9.0. The patient was enrolled into a clinical trial and received a combination of bendamustine and brentuximab vedotin for 2 cycles. Following 2 cycles of therapy, a PET/CT scan reported a Deauville score of 2, consistent with a complete response. Stem cell mobilization was done after 2 cycles of therapy.

Salvage chemotherapy was followed by an autologous hematopoietic stem cell transplantation (AHSCT). In July 2013, the patient underwent conditioning with BEAM (carmustine, etoposide, cytarabine, and melphalan), followed by autologous stem cell infusion. Following the AHSCT, she was placed on maintenance therapy with brentuximab vedotin. She received a total of 14 cycles, with subsequent cycles being held for peripheral neuropathy. She continues to do well and has been in complete remission for over 5 years.

Introduction

Hodgkin lymphoma is a highly curable malignancy, with an excellent prognosis.[1-4] Combination chemotherapy has been shown to cure 85% to 90% of patients with early-stage disease and 70% to 80% of patients with advanced disease.[2,3] However, around 10% to 25% of patients will have primary refractory or relapsed disease, despite using risk-adapted strategies.[5] The standard of care for patients with relapsed/refractory Hodgkin lymphoma has been cytoreduction using salvage chemotherapy, followed by high-dose chemotherapy and AHSCT.[6] Studies have shown that AHSCT produces a durable response rate of 50%, and that patients achieve complete response with salvage chemotherapy.[6,7] The outcomes for patients who do not respond to salvage chemotherapy or relapse after AHSCT have been poor, with a median survival of 25 months.[8] However, with the approval of novel agents over the last decade, the outcomes for patients with relapsed/refractory Hodgkin lymphoma have improved significantly. This article will focus on the roles of AHSCT and novel therapies in the setting of relapsed/refractory Hodgkin lymphoma.

Current Standard of Care

High-dose chemotherapy and AHSCT

High-dose chemotherapy followed by AHSCT has become the standard of care in patients with relapsed/refractory disease, based on the findings of two landmark phase III clinical trials. The BNLI study compared conventional doses of chemotherapy (mini-BEAM: carmustine 60 mg/m², etoposide 300 mg/m², cytarabine 800 mg/m², and melphalan 30 mg/m² once every 3 weeks) vs higher doses of the same chemotherapy (BEAM: carmustine 300 mg/m², etoposide 800 mg/m², cytarabine 1,600 mg/m², and melphalan 140 mg/m² once every 3 weeks). Patients who received BEAM then underwent an AHSCT. This study reported superior event-free survival rates in the BEAM plus AHSCT arm compared with the mini-BEAM arm (35% vs 10%; P = .025).[9]

The HD-R1 study randomized 161 patients with relapsed Hodgkin lymphoma to high-dose chemotherapy with AHSCT or chemotherapy alone. All patients received 2 cycles of Dexa-BEAM (BEAM regimen plus dexamethasone) and were then randomized to AHSCT or 2 additional cycles of chemotherapy.[10] The 3-year survival rate in the AHSCT arm was 55% vs 34% in the chemotherapy arm. The study did not show a statistically significant benefit in overall survival; however, this was thought to be due to low patient numbers.[10]

Role of salvage chemotherapy

Response to salvage chemotherapy is a strong prognostic marker for predicting long-term outcomes with AHSCT. Studies have shown that patients with a negative PET/CT scan at the time of AHSCT have far superior outcomes compared with patients with a positive PET/CT scan following salvage chemotherapy.[7,11,12] Moskowitz et al evaluated patients treated with sequential salvage therapy and reported a 5-year event-free survival rate of 31% in patients with a positive PET scan vs 75% in patients with a negative PET scan.[7] In patients with primary refractory disease, the 10-year event-free survival rate following salvage therapy was 68% in patients with a negative PET scan vs 33% for patients with a positive PET scan.[11] A meta-analysis of 745 patients with Hodgkin lymphoma reported an overall survival rate of 17% to 77% in patients who were PET-positive at the end of salvage chemotherapy compared with 78% to 100% in PET-negative patients.[12] The varying results were due to different criteria used for determination of disease status and varying salvage chemotherapy regimens.

The optimal salvage chemotherapy regimen in patients with relapsed/refractory Hodgkin lymphoma has been debated. Several options have been proposed, such as Dexa-BEAM[10] or a combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP),[13] with comparable outcomes. In the United States, the most common regimen is ifosfamide, carboplatin, and etoposide (ICE). Studies evaluating this regimen have reported overall response rates ranging from 84% to 88%.[14,15]

Radiation therapy is often overlooked as a salvage regimen in the setting of relapsed disease. However, it can induce durable remission and should be explored as a treatment option in patients with localized relapses. Studies have shown a survival benefit with involved-field radiation therapy in patients with residual disease after salvage therapy.[16,17]

Acknowledging the importance of achieving PET negativity following salvage therapy, several regimens incorporating novel agents are under investigation to achieve a better response before proceeding with high-dose chemotherapy and AHSCT. A review of novel agents and several combinations follows.

Novel Agents Under Investigation

Brentuximab vedotin

Brentuximab vedotin is a CD30-targeted antibody-drug conjugate. The CD30 antibody is conjugated to monomethyl auristatin E (MMAE), an anti-microtubule agent.[18] Upon binding with the CD30 receptor on the Reed–Sternberg cells, the antibody-drug conjugate gets internalized. Once internalized, MMAE is released, causing apoptosis.[19]

In 2011, the US Food and Drug Administration (FDA) approved brentuximab vedotin for relapsed/refractory Hodgkin lymphoma based on the results of a pivotal phase II trial, in which the agent was given to 102 patients with relapsed/refractory disease who progressed following an AHSCT. The overall response rate was 75%, with a complete response noted in 34% of patients.[20] A subsequent 5-year follow-up study by Chen et al showed a 5-year overall survival rate of 41%. With a median 35-month follow-up, the estimated progression-free survival and overall survival were 9.3 and 40.5 months, respectively.[21] In a study by Gopal et al, it was shown that, of the patients who achieved a complete response, 47% remained in remission at a median follow-up of 53.3 months, establishing the durability of response.[22] The most common adverse reactions noted were peripheral neuropathy, neutropenia, fatigue, and diarrhea.[21] These promising results led to the exploration of brentuximab vedotin in different clinical scenarios in patients with relapsed Hodgkin lymphoma.

Brentuximab vedotin as a first-line salvage regimen. Single-agent brentuximab vedotin was evaluated in patients with relapsed/refractory Hodgkin lymphoma as a salvage therapy, prior to proceeding with high-dose chemotherapy and AHSCT. Brentuximab vedotin was administered weekly at 1.2 mg/kg for 3 weeks. Following 2 to 3 cycles, a PET scan was completed, and patients who had achieved PET negativity underwent AHSCT. Patients who had a positive PET received ICE prior to AHSCT. The 3-year progression-free survival rate was 79%.[23] When brentuximab vedotin was administered at a standard dose of 1.8 mg/kg every 3 weeks, 35% of patients achieved a complete response after brentuximab vedotin alone, with minimal side effects.[24]

Brentuximab vedotin with bendamustine. Bendamustine is a nitrogen mustard derivative with partial cross-resistance to other alkylating agents, thus giving it the potential for use in the refractory setting. Single-agent bendamustine was evaluated in 36 patients with relapsed/refractory Hodgkin lymphoma who had progressed through multiple lines of therapy. The overall response rate was 53%, demonstrating that bendamustine is an active agent in heavily pretreated patients. Thrombocytopenia was the most common toxicity, with 20% of patients experiencing grade 3 or 4 thrombocytopenia.[25]

In another trial, bendamustine was combined with brentuximab vedotin as first salvage therapy in patients with relapsed/refractory Hodgkin lymphoma.[26] Fifty patients were enrolled and received 1.8 mg/kg brentuximab vedotin on day 1, with bendamustine 90 mg/m² given on days 1 and 2 of up to 6 total 3-week cycles. The complete response rate was 74%, with an overall response rate of 93%. Stem cell collection was successful in 93% of patients. The estimated 2-year progression-free survival rate was 70% in patients who underwent AHSCT. Infusion reactions were seen in 56% of patients, which were then mitigated by premedications.[26]

Brentuximab vedotin is also being studied in combination with standard chemotherapy combinations, such as ICE[27] and DHAP.[28] Preliminary results are promising, with complete response rates of between 69% and 90%, which are comparable to response rates seen with standard chemotherapy regimens alone.[27,28]

Brentuximab vedotin as consolidation therapy post-AHSCT. Several studies have shown that AHSCT cures 50% of patients.[29,30] Since the prognosis for patients who relapse post-AHSCT is poor, identification of patients at a high risk of relapse is important. Primary refractory disease, extranodal disease, relapse within 12 months of front-line therapy, and residual disease at the time of high-dose therapy have consistently been identified as poor prognostic factors.[14,31,32]

AETHERA was a multicenter study that randomized 320 patients with high-risk relapsed/refractory Hodgkin lymphoma who had undergone an AHSCT to receive 16 cycles of brentuximab vedotin or placebo.[32] High-risk disease was defined as patients having one of the following risk factors for progression: primary refractory disease, progression within 12 months of initial therapy, or extranodal involvement. The progression-free survival rate was superior in patients who received brentuximab vedotin vs placebo (43 months vs 24 months; hazard ratio [HR], 0.52; 95% CI, 0.37–0.71). A 5-year follow-up showed a continued benefit, with a 5-year progression-free survival rate of 59% in the brentuximab vedotin arm vs 41% in the placebo arm (HR, 0.521; 95% CI, 0.379–0.717).[33]

Checkpoint inhibitors

Hodgkin lymphoma is histologically characterized by Reed–Sternberg cells, which are surrounded by inflammatory T-cell infiltration. Alterations in chromosome 9p24.1 within Hodgkin lymphoma cells lead to upregulation of programmed death ligand 1 (PD-L1) and 2 (PD-L2) on the surface of the Reed–Sternberg cells, thus making checkpoint inhibitors a potential therapy.[34] Anti–PD-1 antibodies, such as nivolumab and pembrolizumab, have been evaluated in patients with relapsed/refractory disease in two pivotal studies, with promising results.[35,36]

In the first such study, nivolumab was evaluated in patients who had progressed following AHSCT and brentuximab vedotin, a group associated with poor prognosis.[35] A total of 80 patients were enrolled, and nivolumab was administered every 2 weeks until disease progression occurred. The overall response rate was 66%, with a median duration of response of 7.8 months. The promising results of this study led to the FDA approval of nivolumab in this setting in 2016. The second pivotal study, KEYNOTE-087, was a single-arm phase II study of pembrolizumab in patients with chemo-refractory disease or those who had progressed following an AHSCT. The overall response rate was 69%, with a complete response rate of 22%.[36] The median progression-free survival exceeded 1 year, which led to the FDA approval of pembrolizumab in this setting in 2017.

Both nivolumab and pembrolizumab are well tolerated; immune-related adverse events include: hypothyroidism/hyperthyroidism (12% to 16%), rash (6% to 9%), hepatitis (5%), and pneumonitis (3%). Grade 3/4 adverse events are rare, including gastrointestinal toxicities and neutropenia (both < 5%).[35,36]

Avelumab, an anti–PD-L1 monoclonal antibody, has also shown promising activity in Hodgkin lymphoma. A phase I study of avelumab in 31 patients with relapsed/refractory Hodgkin lymphoma showed a 42% overall response rate and a 16% complete response rate.[37] Further studies involving PD-L1 antibodies are ongoing.

Across the board, a remarkable feature of checkpoint inhibitors is the continued clinical benefit seen with treatment that extends beyond disease progression.[38] In a phase II study, 70 patients who experienced disease progression on nivolumab were continued on the therapy for a median of 5.2 months.[39] Of the 51 evaluable patients, 60% had a decreased or stable tumor burden. The median time to the next systemic therapy was 8.8 months, with a 1-year overall survival rate of 84%.[39]

Brentuximab vedotin and nivolumab

Combination therapy with brentuximab vedotin and nivolumab is being evaluated as an initial salvage therapy in patients with relapsed/refractory Hodgkin lymphoma.[1] In a clinical trial, 62 patients were enrolled and administered up to 4 cycles of combination therapy. The complete response rate was 61%, with an objective response rate of 82%. This therapy did not impact stem cell collection and was fairly well tolerated, with grade 3 or higher immune events noted in 13% of patients. A phase III study evaluating the efficacy of this regimen in patients who are ineligible for AHSCT is ongoing (ClinicalTrials.gov identifier: NCT03138499).

Other checkpoint inhibitors are being evaluated in combination therapies, particularly with additional checkpoint blockade with cytotoxic T-lymphocyte–associated antigen 4 inhibitors or cytotoxic chemotherapy, in both the front-line and refractory settings.[40] Additionally, studies that combine different novel agents for the treatment of relapsed Hodgkin lymphoma are being designed (Table).

Histone deacetylase inhibitors

Panobinostat and mocetinostat target histone deacetylase, which plays a role in cell cycle progression, angiogenesis, and cell survival. In a clinical trial of 129 patients with relapsed/refractory Hodgkin lymphoma, patients received 40 mg of oral panobinostat 3 times a week.[41] A decrease in tumor size was seen in 74% of patients, with an overall response rate of 27%. The median duration of response and progression-free survival were 6.9 months and 6.1 months, respectively, thus making it an effective therapy for Hodgkin lymphoma. Panobinostat was reasonably well tolerated, with the most common side effects being grade 1/2 nausea and fatigue. The most common grade 3/4 side effect was thrombocytopenia, which was easily regulated.[41]

Studies evaluating combination therapies with lenalidomide as a potential salvage therapy are ongoing. The results of one phase I study testing panobinostat and lenalidomide in heavily pretreated patients with Hodgkin lymphoma were promising, with an overall response rate of 30%.[42] A phase Ib/IIa study evaluated panobinostat in combination with ICE (P-ICE) vs ICE in patients with relapsed/refractory Hodgkin lymphoma. A complete response was seen in 82% and 67% of patients who received P-ICE and ICE, respectively. However, in the ICE group, grade 4 thrombocytopenia was seen in 100% of patients, and grade 4 neutropenia occurred in 55% of patients.[43] Further studies investigating a combination of panobinostat with less myelosuppressive agents are ongoing.

mTOR inhibitors

The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been found to be active in Hodgkin lymphoma, and is therefore a potential target for novel agents.[44]

Everolimus is one such oral agent that targets the mTOR complex 1. A phase II study was conducted in 19 patients with heavily pretreated relapsed/refractory Hodgkin lymphoma.[45] These patients had received a median of 6 prior treatments, and 84% had undergone a prior AHSCT. The overall response rate was 45%, while 6% achieved a complete response and 39% achieved a partial response. The median progression-free survival and overall survival were 9 months and 36 months, respectively, thus making everolimus a potential agent for use in relapsed Hodgkin lymphoma.[45] The combination of everolimus with agents that specifically target other signal transduction pathways-such as the JAK/STAT pathway and the NF-kappa B pathway-may potentially prolong the duration of response.

Lenalidomide

Lenalidomide is an immunomodulatory agent that has additional anti-angiogenesis properties. In a phase II study, the efficacy of lenalidomide was evaluated among 38 patients with heavily pretreated Hodgkin lymphoma who had received a median of 4 prior therapies before enrollment.[46] Patients received 25 mg/day of lenalidomide on days 1 to 21 of a 28-day cycle. The overall response rate was 19%; 1 patient achieved a complete response, 6 achieved a partial response, and 5 patients had stable disease. The drug was fairly well tolerated, thus confirming the moderate efficacy of lenalidomide in treating patients with Hodgkin lymphoma.[46]

JAK inhibitors

JAK is a family of tyrosine kinases that are involved in signal transduction from cell surface receptors. Phosphorylation of JAK results in recruitment of STAT proteins, which are involved in cell proliferation and survival.[47] The JAK/STAT pathway has been found to be activated in Hodgkin lymphoma, thus making it a potential target for therapy. Pacritinib is a JAK2 inhibitor that has been tested in clinical trials of patients with relapsed/refractory Hodgkin lymphoma. A total of 34 patients were enrolled, and an overall response rate of 14% was noted.[48] In light of this poor single-agent response, subsequent studies have looked at combination therapies. One such clinical trial evaluated the combination of an oral PI3K-delta inhibitor (INCB040093) and itacitinib, an oral JAK2 selective inhibitor.[49] Seventeen patients with relapsed/refractory Hodgkin lymphoma were enrolled. All patients were heavily pretreated, and 82% had undergone a previous AHSCT. The overall response rate was 67%, including 2 complete responses. The treatment was well tolerated, and further studies using this combination are ongoing.[49]

ADCT-301

ADCT-301 is an antibody-drug conjugate, with a CD25 antibody conjugated to a pyrrolobenzodiazepine toxin. CD25 is expressed on the surface of Hodgkin lymphoma cells, thus making it a potential therapy target.[50] Phase I studies have shown activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma. In one such study of 22 patients, the progression-free survival rate was 64% and the complete response rate was 27%. The most common adverse events reported were fatigue, rash, nausea, and mucositis.[50] Further studies are ongoing based on the results from the early-phase studies.

Chimeric antigen receptor (CAR) T-cell therapy

Since success has been seen with CAR T-cell therapy in treating patients with relapsed/refractory non-Hodgkin lymphomas and leukemias, the use of CAR T cells that target the CD30 receptor on Reed–Sternberg Hodgkin lymphoma cells is being explored.[51] One phase I trial of CD30-specific CAR T cells enrolled 18 patients with relapsed/refractory Hodgkin lymphoma. The overall response rate was 39%, with 7 of 18 patients achieving a partial response.[52] Additional studies evaluating anti-CD30 CAR T cells in relapsed Hodgkin lymphoma are ongoing (ClinicalTrials.gov identifiers: NCT02690545, NCT02917083).

Conclusion

The outcomes of patients with relapsed and refractory Hodgkin lymphoma have improved significantly with the advent of antibody-based therapies (eg, brentuximab vedotin) and immunotherapies. With several targeted therapies and CAR T cells showing promising results in early-phase trials, the future is bright for patients with Hodgkin lymphoma. Integrating these novel agents into existing treatment guidelines and developing safe and effective combination therapies are the next steps in optimizing the clinical outcomes in this disease.

Financial Disclosure:Dr. Vose receives research grant support from Acerta Pharma, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Incyte Corporation, Kite Pharma, Merck, Novartis, and Seattle Genetics. She also receives consulting/honoraria fees from AbbVie, Acerta/Astra-Zeneca, BeiGene, Epizyme, Janssen/Pharmacyclics, Karyopharm, Kite Pharma, Legend Biotech, Nordic Nanovector, Novartis, Roche, Sandoz, Vaniam Group, and Verastem Oncology. Dr. Kallam has no significant financial interest in the manufacturer of any product or provider of any service mentioned in this article.

PERSPECTIVE

Moving Closer to Chemotherapy-Free Regimens in Hodgkin Lymphoma

John W. Sweetenham, MD, FRCP

In recent years, the development of front-line treatment strategies for Hodgkin lymphoma has been based on two main-and to some extent-competing principles: improving disease control and reducing the potential for long-term toxicity. The latter is incredibly important in this predominantly young patient population. The emergence of early “interim” functional imaging has allowed for the development of protocols aimed at maintaining efficacy while de-escalating treatment in those with favorable-risk disease to reduce the potential for late toxicity. For those with poor-risk disease, identified by persistently positive interim imaging, various strategies are under investigation, some of which involve the use of more intensive chemotherapy regimens, and others that introduce novel agents early in the course of treatment.

As Dr. Kallam and Dr. Vose describe in the accompanying article, agents now being evaluated as part of front-line therapy for Hodgkin lymphoma have emerged from studies of patients with relapsed and refractory disease. Until recently, treatment options for patients with relapsed and refractory Hodgkin lymphoma were very limited. Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) has been the standard of care for more than 20 years (and still is), resulting in long-term disease-free survival for about 50% of patients.

With an improved understanding of the biology of Reed–Sternberg cells and of the unique tumor microenvironment in Hodgkin lymphoma, many new targeted therapies have been shown to have clinical activity. For some agents, such as brentuximab vedotin, this has led to new US Food and Drug Administration–approved indications, such as maintenance therapy after ASCT for high-risk patients. This treatment, as well as other new treatments, are being investigated as components of front-line therapy based on promising phase II trial results, and the prospect of chemotherapy-free regimens for Hodgkin lymphoma is now closer to becoming a clinical reality.

The outcome for patients with relapsed disease is improving. The use of brentuximab vedotin as maintenance therapy for high-risk patients undergoing high-dose therapy has resulted in improvements in progression-free survival for certain patients, although the effect on overall survival has not yet been reported. It also remains unclear whether this approach is beneficial to patients who are PET-negative immediately prior to transplant. The remarkable activity of checkpoint inhibitors and the promise of several other agents have allowed some patients to avoid or delay the necessity for ASCT.

The phase III ECHELON-1 study[1] recently evaluated the combination of brentuximab vedotin and chemotherapy for stage III or IV Hodgkin lymphoma. As the results showed, it’s difficult to demonstrate a major impact in a disease for which outcomes are already excellent. Although the study met its primary endpoint, it has not dramatically changed US practice, largely because the standard arm of the study has less relevance now. We probably have several years to go before chemotherapy-free regimens become a standard first-line approach in Hodgkin lymphoma. Future studies will need to be very carefully designed to ensure that signals of inferiority are picked up very early, and that late toxicities are detected as soon as possible.

Financial Disclosure:Dr. Sweetenham receives consulting fees from Seattle Genetics.

REFERENCE

1. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378:331-44.

Dr. Sweetenham is the Senior Director for Clinical Affairs and Physician in Chief at Huntsman Cancer Institute, and a Professor of Medicine in the Department of Hematology, at the University of Utah, Salt Lake City, Utah. He is also a member of ONCOLOGY’s Editorial Board (Leukemia/Lymphoma).

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