Hodgkin Lymphoma (HL)

Hodgkin lymphoma (HL) is a subtype of lymphoma resulting from change in the DNA of a type of white blood cell known as a lymphocyte and is characterized by the presence of a cell known as the Reed-Sternberg cell.  HL is a highly treatable and there are numerous treatments approved, including a few novel, targeted agents. However, for the 20 to 30 percent of HL patients who relapse, new treatment options are still needed, and LLS continues to support research to pursue new avenues of therapy for these cases.

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Current Treatment

Currently, there are numerous treatments for HL, including a few FDA approved novel, targeted agents. The gold standard in the United States was ABVD (a combination of four chemotherapy drugs: doxorubicin, bleomycin, vinblastine, and dacarbazine) as it was the most effective and least toxic regimen available to date for early-stage, low-risk HL (Stage I and II) with survival rates of over 90% at 10 years.  As few as two cycles of ABVD therapy in low-risk patients can be just as effective as longer regimens to help aid in reducing potential toxicity and long-term side effects. Another chemotherapy regimen more commonly used in Europe is called BEACOPP (a combination of seven chemotherapy drugs: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). The cure rate with BEACOPP is as good as ABVD, but more toxic. Nevertheless, BEACOPP can be an option for higher-risk or advanced stage HL that requires a more intensive chemotherapy regimen. For those advanced HL patients with bulky Stage II or Stage III/IV, the disease is still potentially curable but typically more cycles of therapy are used.

Recently, frontline therapy for advanced stage HL patients has begun to shift towards including a novel, targeted agent in combination with standard ABVD and to eliminate the B (bleomycin) from ABVD since it can cause cardiac toxicity. Brentuximab vedotin (BV), a monoclonal antibody-drug combination targeting CD30 expressing cells, had been approved by the FDA for treatment of relapsed/refractory HL and as of March 2018 has been FDA approved for first line patients. The approval was based on compelling data comparing ABVD vs. BV+AVD in newly diagnosed HL patients. In this Phase III study, BV+AVD  produced a significant improvement in progression-free survival (PFS) compared to standard ABVD, all secondary endpoints trended in favor of BV+AVD, and less pulmonary toxicity (associated with the use of bleomycin) was found. This new regimen will likely end the use of ABVD for advanced stage HL patients. In frontline HL, any new agent will need to out-compete the current standard of BV +AVD or combine with it.

When frontline regimens fail for HL patients, which is estimated to occur in 20-30% of patients, there are a variety of combination regimens available in the relapsed setting. The regimens for relapsed HL patients can potentially cure 50% of the patients.

Within the past two years, the PD-1 checkpoint inhibitors, nivolumab and pembrolizumab, were approved by the FDA for use in HL in the relapsed setting after multiple prior lines of therapy have been exhausted. Each was approved from separate studies testing the therapy given alone following bone marrow transplant (ASCT) failure. Both studies resulted in ORRs of ~70% with durable CR rates around 20%. Currently, these inhibitors are being tested as salvage regimens prior to ASCT and have been tested in combination with BV for a chemotherapy free approach or with chemotherapy for a BV free approach. These checkpoint combinations studies have resulted in high ORRs over 80% with CR rates greater than 60%. LLS has funded work in checkpoint inhibitor studies but not directly in HL.

Future Directions

Treatment for HL has improved significantly since the ABVD chemotherapeutic combination was introduced many years ago and for most patients the new regimens lead to cures of the disease.  Clinicians are moving towards a more personalized risk-adapted approach to treatment. This approach aims to maintain high response rates and delivering lower toxicity while staying with aggressive with regimens for higher-risk patients. For the minority of patients who fail frontline therapy, novel agents such as BV and the PD-1 checkpoint blockers, nivolumab and pembrolizumab, have produced high response rates and durability of response. To continue progress, we will need to conduct trials in patients who have failed BV or conduct trials combining with or competing with BV. Further research is needed to better understand and determine how these novel agents can make life better for patients with HL and for survivors.

LLS currently has 4 active grants and one Therapy Acceleration Program (TAP) project that have a major focus on HL. LLS has many additional grants also focused on other lymphomas that are likely to have some relevance to HL (e.g. JAK/STAT signaling and new immunotherapies).

Some key areas of HL research that are being addressed by researchers and clinicians around the world including some by the active grants and TAP portfolio projects funded by LLS include biomarkers of disease and genetic causes, using clinical imaging to guide therapy decisions (Davide Rossi, M.D. at the Foundation for the Institute of Oncology Research in Switzerland), developing better therapies for relapsed/refractory disease (Alex Herrera, M.D. at the Beckman Research Institute of the City of Hope) and development of immunotherapies and checkpoint blockers (Hema Dave, M.D., M.P.H. at Children's Research Institute and Helen E Heslop, M.D., D.Sc., Baylor College of Medicine). Since HL has a high cure rate, one area of interest is understanding and mitigating the long term effects of the drug therapies.

The LLS funded TAP project focusing on HL is in conjunction with Affimed, a company focused on immunotherapies.  Affimed’s proprietary, next-generation bispecific antibodies, termed TandAbs®, have the ability to bring NK-cells or T-cells into proximity and trigger a signal cascade that leads to the destruction of cancer cells. AFM13 is a TandAb® that binds both CD30-positive HL cells and NK (natural killer) cells, which leads to activation of NK cells. AFM13 is being developed as a monotherapy in Phase II and in combination with pembrolizumab in Phase 3.

Photograph by Nephron, distributed under a CC BY-SA 3.0 license