This month, Lapo Alinari, MD, PhD, and Kristie A. Blum, MD, discuss treatment options for patients with classical Hodgkin lymphoma (cHL) whose disease has not responded to frontline chemotherapy and relapsed following autologous hematopoietic cell transplantation (AHCT).
This material was repurposed from “How I Treat Relapsed Classical Hodgkin Lymphoma After Autologous Stem Cell Transplant,” published in the January 21, 2016, edition of Blood.
- Patients with cHL who relapse after AHCT represent a population with a median OS of one to two years.
- Brentuximab vedotin should be the first choice for patients who relapse following AHCT.
- Following brentuximab vedotin, recommendations are participation in a clinical trial, checkpoint inhibitors, single-agent chemotherapy, IFRT, or observation in select cases.
- Combination chemotherapy strategies should be reserved for symptomatic patients with either a large disease burden or extranodal disease, or those who are alloHCT candidates, given the risks for toxicity and subsequent malignancies.
- Many biologic agents are under development and have shown activity in this setting, including lenalidomide, everolimus, and panobinostat.
Although cHL is highly curable with chemotherapy, up to 50% of patients have primary refractory disease, relapse after first-line chemotherapy, or relapse after high-dose therapy and AHCT. AHCT for patients with relapsed/refractory disease after frontline chemotherapy leads to five-year PFS rates of 40 to 60 percent, with a median overall survival (OS) of one to two years. Novel therapies to treat this subset of patients, as well as the availability of allogeneic HCT (alloHCT) for select patients, may help improve OS.
We advocate for a tailored therapeutic approach for patients with relapsed cHL, guided by patient-specific characteristics including age, comorbidities, sites of disease, previous chemosensitivity, and goals of treatment (long-term disease control or proceeding to alloHCT; see FIGURE).
First Choice for cHL: Brentuximab Vedotin
Brentuximab vedotin, an anti-CD30 monoclonal antibody conjugate, was approved by the U.S. Food and Drug Administration (FDA) in 2011 for cHL that has relapsed after AHCT or two prior chemotherapy regimens. In a pivotal phase II study, 75 percent of patients responded to brentuximab vedotin; of the 34 percent who achieved complete remission (CR), a subset (younger patients with relapsed, early-stage disease) experienced prolonged disease control.
Based on the exceptionally high overall response rate (ORR) with brentuximab vedotin in patients with relapsed or refractory cHL after AHCT, it is our firstline recommendation. This should be offered at the time of relapse, as patients achieving a CR may have a prolonged remission duration exceeding four years.
For patients with primary refractory disease, relapse within 12 months, or extranodal disease, treatment with brentuximab vedotin consolidation following AHCT should be offered starting one to two months post-transplant.
Treatment Following Brentuximab Vedotin
Subsequent treatment options include:
- observation for asymptomatic patients with a low disease burden
- involved-field radiation therapy (IFRT) for patients with limited disease in fields amenable to radiation
- single-agent chemotherapy or combination chemotherapy
- checkpoint inhibitors and immunomodulatory therapy
- clinical trials with novel agents
Treatment decisions for patients with cHL that relapses after AHCT and who have received brentuximab vedotin should be based on the extent and location of disease, symptoms, patient comorbidities and age, patient preference, and the long-term goals of therapy (i.e., prolonged disease control vs. achievement of best response prior to alloHCT).
In those who achieve a CR with brentuximab vedotin, particularly younger patients with low-risk early-stage disease, it is reasonable to observe them without additional consolidative therapy or alloHCT, in light of long-term response data.
Involved-Field Radiation Therapy
IFRT may lead to prolonged remissions and delay the need for palliative chemotherapy in patients with cHL who relapse after AHCT with localized disease and, in certain patients, may delay the use of chemotherapy and lead to durable remissions. In addition, it is important to note that a small number of patients with cHL who relapse after AHCT could potentially be cured with radiotherapy. The patients who appear to potentially benefit the most from this approach are those with positron emission tomography and computed tomography documented stage I or II disease at relapse, disease confined to previously unirradiated lymph nodes, and those without B symptoms.
Single-Agent and Combination Chemotherapy
There are a variety of single-agent chemotherapy regimens available for patients with relapsed cHL, including:
- liposomal doxorubicin
Many of these agents can be continued until best response or disease progression. Response rates to these therapies range from 30 to 72 percent.
For those with extranodal or organ involvement who are symptomatic or need an optimal response prior to alloHCT, many interchangeable combination regimens can be considered (see TABLE), which have been largely used as salvage treatment options in the pre-AHCT setting, leading to ORRs of 69 to 100 percent.
Limited data on the use of these combinations are available in the post-AHCT setting; however, when used post-AHCT, most of these regimens are associated with higher rates of grade 3-4 myelosuppression than observed in transplant-naïve patients.
In addition to risks of myelosuppression, combination chemotherapy regimens also increase the risk of secondary malignancy in cHL long-term survivors. Myelodysplastic syndromes (MDS) or therapy-related acute myeloid leukemia (AML) typically occur in a dose-dependent manner, two to eight years after initial treatment of HL with alkylating agents and topoisomerase inhibitors. Salvage chemotherapy and conditioning regimens for AHCT also contribute to the increased risk of AML/MDS in these patients.
For this reason, we favor use of combination therapies for a limited duration (maximum 4-6 cycles) and only in specific circumstances in which a rapid and significant response is necessary; that is, in patients with organ involvement, symptoms, or to achieve best response prior to alloHCT. Furthermore, cumulative anthracycline dose must be limited, and pretreatment ejection fraction assessed if anthracycline-containing regimens are used in the relapsed setting.
Checkpoint Inhibitors and Immunomodulatory Therapy
Over the last few years, there has been a growing interest in modulating the extensive, but ineffective, inflammatory and immune cell infiltrate surrounding Reed-Sternberg (RS) cells. RS cells express high levels of programmed death receptor-1 ligands (PD-L1), and by engaging PD-1–positive immune effector cells, tumors can evade the immune response.
In May 2016, the FDA approved the PD-1 inhibitor nivolumab for the treatment of patients with cHL who have relapsed or progressed after AHCT and post-transplant brentuximab vedotin. The drug carries a warning for patients who have undergone alloHCT, based on reports of transplant-related deaths and hyper-acute and severe-acute graft-versus-host disease (GVHD) following nivolumab treatment. The FDA also required that the drug’s manufacturers conduct a post-marketing study to assess the safety of nivolumab in these patients.
In March 2017, pembrolizumab became the second PD-1 inhibitor approved for cHL, for a slightly different population: adults and children whose disease is refractory to treatment or has relapsed after receiving three or more prior lines of therapy. In a phase II study evaluating the safety and efficacy of pembrolizumab, response rates ranged from 70 to 74 percent in patients who had undergone AHCT, with or without subsequent brentuximab vedotin.
Confirmatory studies are under way with checkpoint inhibitors in cHL. If the promising response rates in multicenter studies of these agents hold up, this approach should probably be offered after brentuximab.
Novel Agents in Clinical Trials
Several biologic agents are under development and have shown activity in this setting, including lenalidomide, everolimus, panobinostat, and the immune checkpoint inhibitors nivolumab and pembrolizumab.
Response rates with everolimus and histone deacetylase inhibitors rival those observed with lenalidomide in patients with relapsed cHL. Given the associated risks of grade 3/4 toxicities and pulmonary toxicity, we recommend exercising caution if considering the use of everolimus in patients with pulmonary manifestations of cHL or in patients with preexisting pulmonary complications from bleomycin, AHCT, IFRT, or gemcitabine.
We favor clinical trial participation for all patients with relapsed cHL when available; however, in patients for whom this may not be an option and who have previously received brentuximab vedotin, we recommend a checkpoint inhibitor as the next line of therapy, given the impressive ORR with these agents.
Results from ongoing studies will better direct our use of these agents in the future in patients with relapsed cHL. Following therapy with a checkpoint inhibitor, patients will likely receive a variety of single agents or combination therapies, depending on their disease burden and severity of symptoms over the course of their disease. In asymptomatic patients, therapy should be minimized, and observation or limited IFRT is acceptable.
Role of Second AHCT and AlloHCT in Relapsed cHL
A second autograft is an option for cHL patients who relapse after first AHCT; however, the data supporting this approach in cHL are limited. A second AHCT could be beneficial for those patients who relapse more than 12 months after initial AHCT. Time to relapse after first AHCT is the strongest predictor of improved outcome, and patients who were refractory to the first AHCT would not benefit from a second one.
AlloHCT may also represent a treatment option for select cHL patients who relapse after AHCT. Outcomes vary according to the conditioning regimen prior to alloHCT. In a retrospective trial by the European Group for Blood and Marrow Transplantation, treatment-related mortality was significantly higher in patients undergoing alloHCT with a myeloablative approach than with reduced-intensity conditioning, but there was no significant difference in survival between the groups.
Although we do not routinely recommend a second AHCT for patients with recurrent cHL, it is reasonable to consider this for those with late relapses who may not have an available donor for alloHCT. However, this may increase the risks of therapy-related MDS and secondary AML.
AlloHCT may offer prolonged disease control to select patients with a suitable human leukocyte antigen-matched donor, particularly younger patients with an available donor and a low comorbidity index. Many other factors play a role in the decision to proceed with alloHCT, including chemosensitivity, patient compliance, and the risks of transplant-related mortality and long-term GVHD.
Multiple pathways are dysregulated in cHL, including nuclear factor-κB, phosphatidylinositol kinase/AKT, mammalian target of rapamycin, and cell-surface receptors signaling through CD30 and CD40, as well as an ineffective immune cell infiltrate leading to malignant RS cell escape.
Some biologic agents in clinical development have shown significant activity in this setting (including lenalidomide, everolimus, and panobinostat). Novel approaches, including the use of chimeric antigen receptor T-cells targeting CD30 are also under investigation for patients with cHL, which may offer exciting new treatment options.