An immunotherapy approach to treating advanced Hodgkin lymphoma may drastically increase patients’ chances of survival, including those as young as 12, according to a new clinical trial.
The regimen, which involves the immunotherapy drug nivolumab along with three different chemotherapies, was found to result in a two-year progression-free survival rate of 92% in a phase three trial whose results were published Wednesday in the New England Journal of Medicine.
“At two years, 92% of the patients did not relapse, did not have progression of Hodgkin lymphoma and did not die,” Dr. Jonathan Friedberg, lead study author and director of the Wilmot Cancer Institute at the University of Rochester, said in a news briefing.
“The standard endpoint in studies of Hodgkin lymphoma is progression-free survival, because we think that best predicts the future,” he said. “If you can keep people disease-free and alive for two years, generally speaking, it’s very unlikely that beyond two years you’re going to have a lot of events, and therefore we’re quite optimistic these results are going to be durable. But of course, it’s going to be important to follow these patients for a longer period of time.”
Hodgkin lymphoma is a type of cancer that originates in white blood cells called lymphocytes, affecting the lymphatic system, which is part of the body’s immune system.
The American Cancer Society estimates that more than 8,000 cases will be diagnosed in the United States this year, and about 900 people will die from the disease. Hodgkin lymphoma can develop at any age, but it’s most common in early adulthood. The average age at diagnosis is 39, and it’s the most common cancer diagnosed in adolescents ages 15 to 19.
‘An immunotherapy revolution’
The new study included nearly 1,000 people who were at least 12 years old and newly diagnosed with stage III or IV Hodgkin lymphoma that had previously been untreated.
Between July 2019 and October 2022, the patients were randomly assigned to receive one of two treatment regimens; 496 patients were assigned to receive the antibody drug brentuximab vedotin along with the chemotherapy drugs doxorubicin, vinblastine and dacarbazine, while 498 others received nivolumab along with that same trio of chemotherapies.
The patients received the treatments intravenously on the first day and then about two weeks later within a 28-day cycle. This was repeated for six cycles.
The patients were based at 256 sites across the United States and Canada. One of the sponsors of the trial was Bristol-Myers Squibb, which makes nivolumab and supplied the drug for the study.
A combination of chemotherapies has been the standard treatment for advanced-stage Hodgkin lymphoma for decades, but the researchers watched each patient closely to analyze how they responded to the drug combinations.
The researchers found that the nivolumab treatment regimen significantly improved survival compared with the brentuximab vedotin regimen. About two years after starting treatment, 92% of patients in the nivolumab group survived without relapse and without seeing the cancer progress, compared with 83% of those in the brentuximab vedotin group.
These patients who survived without cancer progression also did not need radiation therapy, which can result in significant side effects, such as the risk of additional cancers or fertility problems. In the study, only seven patients overall received radiation therapy.
The researchers noted that there were more adverse side effects in the brentuximab vedotin group compared with the nivolumab group, but a condition called neutropenia – in which the body has low levels of a type of white blood cell – was more prevalent in the nivolumab group. Neutropenia occurred in 56% of patients taking nivolumab versus 34% of those who got the brentuximab vedotin treatment.
“The one side effect that we saw that seemed higher in the nivolumab arm was neutropenia, and that’s low white blood counts that can result in an increased risk of infection,” Friedberg said.
The researchers knew that neutropenia may be a risk with brentixuimab, so more than than 90% of the patients given that treatment also received a “growth factor” medication to help evade neutropenia as a side effect. In the nivolumab group, only 50% of patients got that “growth factor” support.
“So it’s really not surprising that we’d see a slightly higher risk of neutropenia,” Friedberg said.
The researchers found that, overall, the nivolumab approach had a better side-effect profile, with fewer patients stopping treatment early, fewer deaths during treatment and a low incidence of immune-related toxic effects.
There were seven deaths from any cause in the nivolumab group, among which three were during treatment, compared with 14 in the brentuximab vedotin group, among which eight were during treatment, according to the study.
“In the context of a disease in which a high proportion of patients are cured with standard therapy and the bar to change practice is set high, the improvement in efficacy and in the risk of adverse events was clinically meaningful,” the researchers wrote.
As the study followed patients for only two years, the researchers plan to continue to monitor them and provide updates, Friedberg said. The researchers hope the US Food and Drug Administration soon will determine whether nivolumab should be added as a standard treatment for stage III or IV Hodgkin lymphoma, and they plan to start the formal process to ask the agency to expand the approval of nivolumab in the near future.
Nivolumab, sold under the brand name Opdivo, has been approved by the FDA to be included in treatment regimens for many other types of cancer, including small cell lung cancer, melanoma and urothelial carcinoma. It’s unclear how much a nivolumab treatment for Hodgkin lymphoma may cost, but an infusion of 240 milligrams – the maximum dosage given to the patients in the new trial – every two weeks has a list price of $7,635 per infusion, according to Bristol Myers Squibb’s pricing information.
“We’re in the midst of an immunotherapy revolution in the treatment of cancer,” Friedberg said.
“For decades, people tried and failed, and within the last six to 10 years, we’ve seen dramatic changes in not just Hodgkin lymphoma but many more common cancers like lung cancer and melanoma,” he said. “Unfortunately, for many of the more common cancers, although immunotherapy seems to work, it’s not a definitive cure, and a lot of the research now is looking to join immunotherapy with other standard approaches to see if that one-two punch, so to speak, may ultimately be curative.”
‘A change in the standard of care’
Many insurance companies have been approving the use of nivolumab with chemotherapies as an off-label treatment for Hodgkin lymphoma, said Dr. Ann LaCasce, director of the Dana-Farber/Mass General Brigham Fellowship in Hematology/Oncology.
“The publication of this randomized clinical trial provides high level evidence supporting the regimen’s use,” LaCasce, a lymphoma specialist who was not involved in the new study, wrote in an email.
“This is a very important study that leads to a change in the standard of care for pediatric and adult patients in the U.S. with advanced stage classic Hodgkin lymphoma,” she said. “The trial was a successful collaboration between adult and pediatric investigators and included a diverse group of patients with respect to age, race, and ethnicity. This sets the stage for future collaborative studies.”
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The traditional approach to Hodgkin lymphoma treatment has emphasized the use of chemotherapy drugs and radiation therapy to kill cancer cells, Dr. James Armitage of the University of Nebraska Medical Center and Dr. Dan Longo of Brigham and Women’s Hospital wrote in an editorial published alongside the new study.
“However, insights in the field of cancer biology identified other potential approaches to cancer treatment in general and Hodgkin’s lymphoma in particular. Two notable examples are targets of immunotherapy approaches,” Armitage and Longo said.
“The nivolumab regimen is easy to deliver, is associated with modest toxic effects, and is highly effective,” they wrote, adding that the latest trial suggests that the nivolumab approach “may become the treatment of choice” for all stages of Hodgkin’s lymphoma.
