Researchers have demonstrated that patients with low-grade lymphomatoid granulomatosis who were treated with the immunotherapy interferon alfa-2b may survive for a median of 20 years after diagnosis, according to a novel study published by Melani et al in The Lancet Haematology.
The findings revealed that the treatment may hold significant potential to extend survival far beyond the 2-year survival established by previous studies—and suggested that interferon alfa-2b can prevent the progression of low-grade disease to high-grade disease.
“We have shown in this rare disorder that using a novel immunotherapy-based approach for low-grade disease is effective and improves survival compared with historical treatments such as chemotherapy and corticosteroids,” explained co–lead study author Christopher J. Melani, MD, Assistant Research Physician in the Lymphoid Malignancies Branch at the National Cancer Institute’s Center for Cancer Research. “I think the results of this study represent a significant contribution to determining the standard-of-care treatment for this rare disease,” he added.
Lymphomatoid granulomatosis is a rare precancerous condition triggered by an infection from the Epstein-Barr virus. Left untreated, the disease can progress to a high-grade form—which has a poorer prognosis and can quickly develop into an aggressive and fatal B-cell lymphoma.
Lymphomatoid granulomatosis causes an overproduction of B lymphocytes. Patients typically present with lesions in the lungs, central nervous system, skin, liver, and kidneys. Symptoms can include cough, shortness of breath, fever, weight loss, and fatigue. Chemotherapy is currently the standard treatment for patients with high-grade disease, but there is no standard treatment for low-grade disease.
“Although lymphomatoid granulomatosis is uncommon, the effects of high-grade disease can be debilitating,” noted co–lead study author Jeffrey Cohen, MD, Chief of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH). “We need better ways—[such as by administering interferon alfa-2b]—to prevent the disease from progressing to this more severe state,” he emphasized.
Previous Lymphamatoid Granulomatosis Research
Though researchers had been studying lymphomatoid granulomatosis since the 1980s, it wasn’t until the early 1990s that co–lead author of the new study Wyndham Wilson, MD, PhD, a senior oncologist in the Medicine Branch at the National Cancer Institute’s Center for Cancer Research, hypothesized that low-grade disease may be the result of a defective immune response to the Epstein-Barr virus—and could therefore be treated with immunotherapy, whereas high-grade disease requires chemotherapy to curb uncontrolled cell growth.
Dr. Wilson and his colleagues treated four patients who had low-grade lymphomatoid granulomatosis with interferon alfa-2b, and after a follow-up of 5 years, 75% (n = 3) of the patients achieved complete remission. That study laid the foundation for the phase II trial of interferon alfa-2b in lymphomatoid granulomatosis, which has taken 30 years to complete due to the rarity of the disease and the challenges of recruiting enough patients for the study.
“This really illustrates the unique ability of NIH to do a study like this that nobody else could do and no one else ever has done for this particular disease,” highlighted Dr. Wilson.
Study Methods and Results
In the new phase II trial, the researchers enrolled 67 patients with lymphomatoid granulomatosis, 37 of whom had low-grade disease and 30 of whom had high-grade disease. In all cases, the patients had relapsed or refractory disease or had not yet received treatment.
During their initial treatment, most of the patients with low-grade disease underwent a regimen of interferon alfa-2b subcutaneous injections 3 times a week in increasing doses for about 1 year. Most of the patients with high-grade disease underwent six cycles of intravenous chemotherapy once every 3 weeks.
Though both groups improved, 61% ( n = 27/44) of the patients treated with interferon alfa-2b saw complete remission compared with 47% (n = 8/17) of the patients treated with chemotherapy.
After their initial treatment, some patients subsequently received crossover treatment. Patients with low-grade disease that worsened after immunotherapy were given chemotherapy, whereas patients with high-grade disease that relapsed after chemotherapy were given interferon alfa-2b. Previous research has shown that after patients with high-grade disease experience complete remission following chemotherapy, low-grade disease can reemerge.
The crossover treatments were also effective, with 50% (n = 4/8) of the patients treated with interferon alfa-2b after chemotherapy demonstrating complete remission compared to 47% (n = 7/15) of the patients treated with chemotherapy after interferon alfa-2b.
Median overall survival was 20.6 years for patients treated initially with interferon alfa-2b and 19.8 years for patients who crossed over to receive interferon alfa-2b. Further, median overall survival was 12.1 years for patients treated initially with chemotherapy and not yet reached for those who crossed over to receive chemotherapy.
The researchers noted that the most common side effect of interferon alfa-2b treatment was a low white blood cell count, and the most common side effects with chemotherapy were a low white blood cell count and infection. Serious side effects occurred in only about 25% of the patients treated with interferon alfa-2b, compared with nearly 67% of the patients treated with chemotherapy.
Many newer immunotherapies—such as nivolumab—could potentially be used to treat patients with low-grade lymphomatoid granulomatosis and other Epstein-Barr virus–associated disorders, and may have fewer side effects.
“The trial of interferon alfa-2b established that immunotherapy [may] improve survival in patients with low-grade lymphomatoid granulomatosis,” Dr. Melani underscored. “Now we can look into more novel immunotherapies that are easier to tolerate to see if they can improve on the efficacy of our current treatment,” he concluded.
Disclosure: The research in this study was funded by the intramural research programs of the National Cancer Institute and the National Institute of Allergy and Infectious Diseases. For full disclosures of the study authors, visit thelancet.com.
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