Clinical Advances in Hodgkin Lymphoma

ORLANDO, Fla.—According to the American Cancer Society, approximately 8,500 people will be diagnosed with Hodgkin's lymphoma in the United States during 2010. Despite the overall favorable prognosis of Hodgkin's lymphoma, efforts to improve therapy for high-risk patients and to decrease long-term toxicity for low-risk patients continue. New methods of risk stratification, including FDG-PET and molecular profiling, as well as new therapies with non-overlapping toxicity profiles, have made these goals a reality.

Presenting at the 52nd American Society of Hematology Annual Meeting and Exposition, Peter Borchmann, MD, of the University Hospital Cologne, Cologne, Germany, described the results of several key randomized trials for Hodgkin's lymphoma that have been published in the last decade. Large trials comparing standard therapies with more aggressive regimens for patients with an unfavorable prognosis and less intense treatments for patients with a favorable prognosis have shaped current approaches to Hodgkin's lymphoma.

Nancy Bartlett, MD, of the Washington University School of Medicine, in St. Louis discussed practical approaches to choosing therapy for patients with Hodgkin's lymphoma based on current available data, including how to utilize FDG-PET to guide therapy. Ongoing clinical trials aimed at optimizing therapy with the dual goal of maximal efficacy and minimal toxicity were also summarized.

Finally, Kristie Blum, MD of The Ohio State University, in Columbus, Ohio summarized the encouraging preliminary results of several phase 1, 2, and 3 clinical trials of new agents for Hodgkin's lymphoma, including the CD30 targeted antibody drug conjugate brentuximab vedotin (SGN-35), everolimus, an investigational mTOR inhibitor, and histone deacetylase (HDAC) inhibitors such as panobinostat.

SGN-35, is an antibody-drug conjugate (ADC) comprising an anti-CD30 antibody linked to a potent, synthetic drug payload, monomethyl auristatin E (MMAE). The ADC is designed to be stable in the bloodstream, but to release MMAE upon internalization into CD30-expressing tumor cells, resulting in targeted cell-killing. The CD30 antigen is an attractive target for cancer therapy because it is expressed on Hodgkin's lymphoma, but has limited expression on normal tissues.

SGN-35 has been studied in phase 1, 2, and 3 clinical trials with a safety profile ranging from fatigue, pyrexia, neutropenia, diarrhea, and nausea. The pivotal trial is a single-arm trial being conducted under a Special Protocol Assessment (SPA) to assess efficacy and safety of SGN-35 in patients with relapsed or refractory Hodgkin's lymphoma. Top-line data were reported in September 2010 and showed that 75% of the 102 patients enrolled achieved an objective response as assessed by an independent central review, the primary endpoint of the trial. The median duration of response was >6 months. SGN-35 has received fast track designation from the FDA for Hodgkin's lymphoma, as well as orphan drug designation in the United States for both Hodgkin's lymphoma and ALCL.

The histone deacetylase (HDAC) inhibitor, panobinostat is a pan–DACi and is being studied in many hematologic and solid malignancies. In preclinical studies, panobinostat has shown nanomolar activity across a range of hematologic malignancies and has shown synergy with chemotherapy, demethylators, proteasome inhibitors, and other agents. Phase 1/2 studies are ongoing in Hodgkin's lymphoma and other hematological malignancies. Phase 3 trials have started global enrollment in post–transplant HL (PATH).

Everolimus has been studied in phase 1, 2, and 3 clinical trials in Hodgkin's lymphoma. It continuously targets mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism. Everolimus has single-agent activity in relapsed/refractory HL, which has shown that targeting the mTOR pathway in HL is clinically relevant.

Efforts to incorporate these and other agents into earlier lines of therapy, either as single agents or in combination, will need to be evaluated, especially as responses in patients on these agents can be slow.

Off Label Use: SGN-35, panobinostat, and everolimus, are not FDA-approved for the treatment of Hodgkin's lymphoma.