New Research, Discoveries in Hodgkin Lymphoma

Treating Hodgkin lymphoma (HL) represents one of the first successes in medical oncology. The story begins in the trenches of World War I, when troops exposed to nitrogen mustard gas developed marrow and lymphatic suppression. In the mid-1940s, when researchers were concerned that mustard gas might again be used, this effect was studied further. Pharmacological pioneers Louis Goodman, MD, and Alfred Gilman, PhD, were among the first to conduct phase 1 and 2 trials in cancer, focusing on lymphatic cancers, such as Hodgkin lymphoma.

Around the same time, radiation therapy was being increasingly used (rather indiscriminately in some cases) with impressive results in HL. These initial attempts produced only transient remissions. But by the mid-1960s, collaborations among investigators led to the development of the Rye staging system and the establishment of clinical trials with combination chemotherapy regimens. The combination of MOPP (Mustargen [nitrogen mustard], Oncovin [vincristine], procarbazine and prednisone) upped the complete remission rate from about 20 percent to around 80 percent.

The introduction of Adriamycin (doxorubicin)—containing regimens and large-scale randomized trials in the early 1970s set the stage for today’s modern treatments, which have not changed significantly during the past couple of decades—essentially combination chemotherapy and selective use of radiation therapy. In part, this has been due to relatively high survival rates, even after relapse. After all, it is difficult to show improvements in 80 to 90 percent cure rates with randomized trials.

However, not all patients do well, and those who recur and do not respond have had limited options. The feature article on HL puts into perspective the downside of having a “good” cancer.

After a long hiatus, a new therapy is now available for relapsed or refractory HL. Progress had been hindered in part by the confusing histology of Hodgkin tumors—a mixture of cells, which until very recently engendered significant controversy as to exactly which cell was driving the malignancy. The Reed-Sternberg cell, initially described in 1898, is now accepted by most as the malignant cell, usually derived from B-cell lymphocytes (a subset of white cells), although the vast majority of the tumor is composed of inflammatory and other immune cells. By targeting proteins expressed on Reed-Sternberg cells, newer approaches are being developed, as outlined in the feature article, "Great Expectations." Advances in cellular and molecular biology are identifying more targets on Reed-Sternberg cells—many of these overlap with more common cancer types and are being tested in the clinic. It is possible that some of these may soon be integrated into standard initial therapy, although very large trials will be needed to show a benefit. Also, toxicities of any new drug will need to be rather low since most patients will be cured with standard treatment.

The story of HL reminds us that even “curable” cancers need the attention of the research community since some of those affected are left behind. In fact, some variants of HL have a low cure rate from the very beginning and clearly need further study. It is encouraging to know that the new drug pipeline for this disease is relatively healthy. We must remain vigilant that the “orphan” disease status of HL (defined as fewer than 200,000 total individuals affected) and the low number of relapses will not discourage a commitment to research and new discoveries.

Debu Tripathy, MD

Editor-in-Chief

Professor of Medicine, University of Southern California

Co-Leader, Women’s Cancer Program at the USC/Norris Comprehensive Cancer Center

The story of HL reminds us that even “curable” cancers need the attention of the research community since some of those affected are left behind.