With the vast majority of patients cured with primary therapy, classical Hodgkin lymphoma is largely a success story. For the 10% to 20% of patients who either relapse or are refractory to front-line therapy, the disease can still be fatal. At the National Comprehensive Cancer Network® (NCCN®) 12th Annual Congress: Hematologic Malignancies™, Ranjana H. Advani, MD, of the Stanford Cancer Institute, outlined standard treatment options for patients with relapsed or refractory Hodgkin lymphoma and identified novel immunomodulatory agents to manage this population.1
Maintenance brentuximab is a reasonable approach in brentuximab-naive patients following ASCT in selected high-risk patients.— Ranjana H. Advani, MD
As Dr. Advani reported, the standard of care for relapsed or refractory Hodgkin lymphoma is salvage therapy followed by autologous stem cell transplant (ASCT); with this approach, approximately half of patients achieve a long-term remission. However, for patients who relapse within 3 to 6 months of ASCT, outcomes are “dismal,” revealed Dr. Advani, with a median overall survival of approximately 8 months.2 Recent advances in the understanding of the biology of Hodgkin lymphoma, however, have led to a surge in drug development.
Brentuximab vedotin (Adcetris), an antibody-drug conjugate, has been approved by the U.S. Food and Drug Administration (FDA) for Hodgkin lymphoma after failure of ASCT or after failure of at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates and for treatments of patients at high risk of relapse or disease progression post-ASCT consolidation. In a phase II pivotal trial in relapsed Hodgkin lymphoma (after ASCT failure), 13 of 34 patients (38%) who achieved complete remission with brentuximab have remained in remission for at least 5 years and may be cured. Moreover, 9 of these 13 patients have remained in long-term remission without a consolidative allogeneic transplant.3
For those with high-risk disease, providers might also consider maintenance therapy with brentuximab. In the AETHERA trial, consolidation with brentuximab after ASCT improved progression-free survival in Hodgkin lymphoma patients.4 The rate of 2-year progression-free survival was 65% with brentuximab vs 45% with placebo.
“Maintenance brentuximab is a reasonable approach in brentuximab-naive patients following ASCT, in selected high-risk patients,” said Dr. Advani, who noted that the role of brentuximab maintenance in patients with prior brentuximab treatment remains unclear.
Novel Combinations as Salvage Therapy
According to Dr. Advani, an ideal salvage regimen should achieve high rates of complete response, enable peripheral blood stem cell mobilization, and have minimal toxicity. Current chemotherapy-based salvage therapies are usually inpatient regimens often associated with significant hematologic toxicity. The metabolic complete remission rates are typically 50% to 60%.5 Given its favorable toxicity profile and high efficacy in the posttransplant setting, brentuximab is an appealing candidate for consideration in first-line salvage therapy.
In addition, said Dr. Advani, a number of studies have combined brentuximab with different salvage chemotherapy backbones to see whether complete remission rates can be improved beyond brentuximab or chemotherapy alone. For example, brentuximab has been evaluated in combination with bendamustine, ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), and ICE (ifosfamide, carboplatin, etoposide) chemotherapy regimens, with high response rates. Whether these responses will translate to improved long-term survival will require evaluation in a randomized trial.
Investigators are also exploring the effectiveness of checkpoint inhibitors in the treatment of lymphoma. Two recently FDA-approved agents, anti–programmed cell death protein 1 (anti–PD-1) nivolumab (Opdivo) and pembrolizumab (Keytruda), have had similar response rates and toxicity profiles. A phase II trial in Hodgkin lymphoma after failure of both ASCT and brentuximab showed a median duration of response of 7.8 months and 6-month progression-free survival of 76.9% with nivolu-mab.6 Similar findings were seen in cohorts with (a) prior ASCT and brentuximab, (b) ASCT-ineligible patients who failed to respond to salvage therapy and brentuximab, and (c) brentuximab-naive patients with prior ASCT. Pembrolizumab demonstrated an overall response rate of 69.0% across all cohorts.7
Given high response rates in relapsed or refractory Hodgkin lymphoma with checkpoint inhibitors, the next logical step is to combine these agents with chemotherapy or brentuximab to improve the quality and durability of responses and potentially long-term outcomes. As Dr. Advani reported, preliminary results from a phase I/II study of brentuximab in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma showed a “remarkable” overall response rate of 90% and a complete metabolic response rate of 62%, which is double that seen with either used as a single agent.8 A separate study combining nivolumab and ipilimumab (Yervoy), a cyotoxic T-lymphocyte–-associated protein 4 (CTLA-4) checkpoint inhibitor, demonstrated an overall response rate of 74%, but complete response appears to be similar to nivolumab alone.9
“Numerous ongoing trials are combining checkpoint inhibition with every chemotherapy backbone you can think of,” said Dr. Advani, who also noted that these therapies are moving into the front-line setting. “These approaches are still experimental, but as these agents move to the front-line setting, their efficacy in the relapsed setting will need to be reevaluated.”
Finally, patient selection will continue to play an expanded role in Hodgkin lymphoma in the future. Recently, a gene-expression signature was shown to predict post-ASCT outcomes. “If you can identify poor-performing patients based on gene-expression profiling, perhaps we can design trials specifically for that subset,” Dr. Advani concluded.
Andrew D. Zelenetz, MD, PhD, Medical Director of Quality Informatics at Memorial Sloan Kettering Cancer Center, underscored the challenges of treating a disease where the expected outcome is cure and reiterated the importance of patient selection.
We have a lot of new agents in Hodgkin lymphoma, but we need biomarkers to identify the 20% to 25% of patients who are going to do poorly for an intervention.— Andrew D. Zelenetz, MD, PhD
“We will hear the results of the Eschelon 1 trial at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition, but based on the press release, I would actually consider it a negative study,” said Dr. Zelenetz. “There’s no overall survival advantage, and the magnitude of the benefit was really quite small. I want to see more data, of course, to find out which subsets had benefits, but when we’re talking about new therapies, if we’re going to add a quarter of a million dollars to the cost of care, it has to be an astoundingly real result, and a few percentage points in progression-free survival is not enough for me.”
“We have a lot of new agents in Hodgkin lymphoma, but if we’re really going to make advances in the front-line setting, we need biomarkers to identify the 20% to 25% of patients who are going to do poorly for an intervention,” Dr. Zelenetz concluded. “That’s the major challenge we have today.” ■
DISCLOSURE: Drs. Advani and Zelenetz reported no conflicts of interest.
2. Arai S, Fanale M, DeVos S, et al: Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma 54:2531-2533, 2013.
3. Chen R, Gopal AK, Smith SE, et al: Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128:1562-1566, 2016.
4. Moskowitz CH, Nademanee A, Masszi T, et al: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385:1853-1862, 2015.
5. Moskowitz AJ, Yahalom J, Kewalramani T, et al: Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood 116:4934-4937, 2010.
6. Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-1294, 2016.
7. Chen R, Zinzani PL, Fanale MA, et al: Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35:2125-2132, 2017.
8. Herrera AF, Bartlett NL, Ramchandren R, et al: Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. 2016 ASH Annual Meeting & Exposition. Abstract 1105.
9. Ansell S, Gutiereez ME, Shipp MA, et al: A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). 2016 ASH Annual Meeting & Exposition. Abstract 183.