Current and Emerging Strategies for Managing Relapsed/Refractory Hodgkin Lymphoma

Leo I. Gordon, MD

Transplant remains the cornerstone of treatment for relapsed/refractory Hodgkin lymphoma, but some new approaches are on the horizon and may also prove to be valid options, explained Leo I. Gordon, MD, Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois. Gordon outlined current approaches and suggested some future strategies in this setting at the NCCN 7th Annual Congress on Hematologic Malignancies.

Chemotherapy with ABVD (doxorubicin hydrochloride, bleomycin, vinblastine, and dacarbazine) is a preferred option for advanced Hodgkin lymphoma in the United States, Gordon said. Five-year survival with ABVD is approximately 90%. Recurrence of Hodgkin lymphoma tends to occur early in the first 5 years after treatment, and then survival curves plateau. For survivors, late effects of ABVD are the main concern, including second malignancies and cardiovascular effects.

Standard treatment for recurrence of advanced Hodgkin lymphoma is salvage chemotherapy and/or immunoconjugate therapy followed by response assessment, then autologous or allogeneic transplant. Prognostic factors in relapsed/refractory Hodgkin lymphoma include time to relapse, advanced state, and poor performance status. Patients who relapse within the first 3 months of treatment are considered primary refractory; those who relapse between 3 and 12 months after treatment are considered early relapse. Other negative prognostic factors in this setting are low albumin, anemia, age, lymphocytopenia, extra-nodal disease, disease status at transplant, and “in-field” relapse in patients treated with radiotherapy.

A number of salvage regimens have been studied. “No data suggest that one regimen is clearly better than another,” Gordon told attendees. In the United States, BEAM (carmustine, etoposide, cytarabine, and melphalan) is commonly used as a conditioning regimen prior to autologous stem cell transplant (ASCT).

Achieving complete remission on chemotherapy is a good predictor of outcome after ASCT, while chemosensitive disease has an intermediate prognosis, and resistant disease has a poor prognosis. Total lymphoid irradiation (TLI) prior to ASCT has been shown to improve outcomes for the intermediate and poor-prognosis patients based on response to chemotherapy. However, “Use of TLI after chemotherapy may be overtreating some patients,” Gordon commented.

Risk factors for poor response to ASCT include B symptoms at relapse, extra-nodal disease at relapse, remission duration of less than 1 year, and poor response to salvage therapy by FDG-PET imaging. Some patients who relapse after ASCT can extend disease-free survival if they are able to undergo reduced-intensity allogeneic transplant (RIT). “Consider use of RIT in patients predicted to have poor outcome on ASCT,” Gordon told the audience.

“Transplant remains the standard of care for relapsed/refractory Hodgkin lymphoma, but there are some newer approaches under study and results of clinical trials may change the landscape,” Gordon said.

One current approach being researched is targeting Hodgkin and Reed-Sternberg receptors, including CD30, CD40, Apo2L and receptors, IL- 13 and receptors, and CD80. The CD30 antigen is highly expressed on Hodgkin lymphoma cells and cells of other T-cell lymphoproliferative disorders, but has a restricted distribution on normal cells.

The novel compound SGN-35 is a CD30-targeted antibody conjugated to an auristatin E derivative called MMAE. MMAE is a potent anti-tubulin agent selectively delivered to CD30-positive cells. Preliminary studies show some activity of this drug in recurrent Hodgkin lymphoma, but Gordon said that the antibody drug conjugate brentuximab vedotin is a better drug. Brentuximab vedotin is approved post-ASCT and may have a role in the pretransplant setting, Gordon said.

Other small-molecule inhibitors are also being studied in relapsed/refractory Hodgkin lymphoma. These include histone deacetylase inhibitors, P13K/AKT/mTOR inhibitors, NF-kappaB inhibitors, and heat shock protein 90. Drugs that target the microenvironment may also have a role in this setting; these include rituximab, lenalidomide, and autologous LMP2 cytotoxic T cells.