FOR MANY YEARS, chemotherapy coupled with radiation was the standard of care for many people with advanced-stage Hodgkin lymphoma. Then, in 2018, the Food and Drug Administration approved Adcetris (brentuximab vedotin) based on research showing that the antibody-drug conjugate, which delivers chemotherapy to a target on cancer cells, could be just as effective in treating cancer as the standard of care.

Now, results from a phase III clinical trial suggest that immunotherapy could improve outcomes with fewer side effects compared with treatment with Adcetris. The study, published Oct. 16, 2024, in the New England Journal of Medicine, included 970 patients with newly diagnosed stage III or IV Hodgkin lymphoma who received either the immunotherapy drug Opdivo (nivolumab) or Adcetris—along with standard chemotherapy of doxorubicin, vinblastine and dacarbazine. After two years of follow-up, 92% of patients who received Opdivo and chemotherapy were alive without cancer growth—compared with 83% for the group treated with Adcetris and chemotherapy.

“Since more patients are alive and free of Hodgkin lymphoma two years after initiation of therapy [with Opdivo], we expect the vast majority of these patients to be cured,” says Jonathan Friedberg, a hematologist-oncologist and director of the University of Rochester Wilmot Cancer Institute in New York and the study’s corresponding author. “The two-year time point is a customary one for studies in Hodgkin lymphoma [as a surrogate for survival outcomes], so we anticipate these favorable outcomes seen with nivolumab [in this study] will be durable.”

Those in the Opdivo group experienced fewer side effects, such as infections, sepsis and neuropathy, than those who took Adcetris. “We were able to demonstrate that this new treatment was less toxic and more effective,” Friedberg says.

One of the study’s strengths, Friedberg notes, is that it enrolled adolescents between ages 12 and 17 along with older adults over 60. The study also pooled data from 256 clinical sites in the U.S. and Canada and enrolled patients from academic and community sites, which helped to ensure a diversity of participants, including Black and Hispanic patients, Friedberg says.

Hodgkin lymphoma is most frequently diagnosed in people between 20 and 30 years of age. It is one of the most common cancers in adolescents between 15 and 19. Older adults over 55 can be diagnosed with the disease as well.

Only seven patients in the study received radiation after completing treatment. In the past, most children with advanced-stage Hodgkin lymphoma have had radiation as part of their treatment plan, which can cause side effects years into the future, Friedberg says. “In our study, less than 1% of patients received radiation, yet we still achieved outstanding outcomes,” he says. “We know from extensive previous literature that radiation contributes to heart disease, lung disease and second cancers, particularly breast cancer in women. So we expect that the incidence of second cancers will be dramatically less without radiation as a component of therapy.”

Friedberg and his colleagues plan to continue to follow people in the study for several more years to understand whether there are any unanticipated toxicities associated with the treatments they received.

Gwen Nichols, who is the chief medical officer of the Leukemia & Lymphoma Society and was not involved in the study, welcomes efforts to explore treatments that minimize long-term side effects. Five-year relative survival rates for stage III and IV Hodgkin lymphoma are 87% and 81%, respectively, which means even those diagnosed with advanced disease can live a long time after diagnosis.

“In young people in particular, our success rate in curing patients is extremely high, so we have the luxury now of trying, in the appropriate patients, to decrease the long-term side effects by altering the therapies that we use,” Nichols says, citing the risks of heart disease and breast cancer in people who receive chest radiation. However, “we have to be certain that any changes we make in the therapy don’t impact the cure rate negatively,” she says.

The study only looked at people with advanced disease, although patients with early-stage Hodgkin lymphoma can ask their oncologist about treatment with immunotherapy as part of a clinical trial, says Akil Merchant, a hematologist-oncologist at Cedars-Sinai Medical Cancer in Los Angeles who was not involved in the study. He notes that immunotherapy is a relatively new treatment, but research does suggest the treatment is generally safe for patients in the long term. “The side effects for radiation, on the other hand, are well known and put patients at risk for decades,” he says.

Friedberg notes that insurance coverage for Opdivo will vary since the immunotherapy is not yet approved as a first-line treatment for advanced-stage Hodgkin lymphoma. It is approved for use in later-line treatment of advanced-stage Hodgkin lymphoma after other treatments have not worked. However, Friedberg says that the National Comprehensive Cancer Network updated its guidelines for stages III and IV Hodgkin lymphoma to include first-line Opdivo treatment with chemotherapy in certain circumstances. He adds that he expects health insurance coverage to follow.