Immunotherapy significantly improves the longevity of persons with lymphomatoid granulomatosis, according to a new study.

Researchers at the National Institutes of Health (NIH) have found that patients with low-grade lymphomatoid granulomatosis who receive the immunotherapy interferon alfa-2b can live for decades after being diagnosed. Epstein-Barr virus infection is a rare precancerous condition known as lymphomatoid granulomatosis. If the condition is not treated, it can develop into a high-grade form that has a worse prognosis and quickly transform into an aggressive and fatal B-cell lymphoma.

Patients receiving interferon alfa-2b lived for a median of about 20 years in the phase 2 trial, which was directed by researchers at the National Cancer Institute (NCI), a division of the NIH. In contrast, previous research found that people with lymphomatoid granulomatosis had a median survival of less than two years.

The results imply that immunotherapy can stop the development of low-grade diseases into high-grade diseases. The findings were revealed in a Lancet Haematology article.

“We have demonstrated in this uncommon ailment that utilizing a new immunotherapy-based strategy for low-grade disease is beneficial and improves survival when compared to previous therapies such as chemotherapy and corticosteroids,”

Christopher J. Melani, M.D., of NCI’s Center for Cancer Research,

“We have shown in this rare disorder that using a novel immunotherapy-based approach for low-grade disease is effective and improves survival compared to historical treatments like chemotherapy and corticosteroids,” said Christopher J. Dr. Melani co-led the study along with Dr. of the NCI’s Center for Cancer Research. “In my opinion, the findings of this study significantly advance our understanding of how to treat this rare disease.”.

B-lymphocyte overproduction is a symptom of lymphomatoid granulomatosis. Patients frequently have lesions in their skin, liver, kidneys, central nervous system, lungs, and skin. Cough, breathlessness, fever, fatigue, and weight loss are just a few symptoms that can appear. For people with high-grade diseases, chemotherapy is currently the norm; however, there is no norm for low-grade diseases.

Although lymphomatoid granulomatosis is not common, its symptoms can be extremely crippling, according to Jeffrey Cohen, M.D., co-leader of the study and director of the infectious diseases laboratory at the National Institute of Allergy and Infectious Diseases. We require more effective treatments, like interferon alfa-2b, to stop the disease from progressing to this more serious stage.”.

Since the 1980s, NIH scientists have been researching lymphomatoid granulomatosis. Wyndham Wilson, M.D., began working in the early 1990s. He posited that high-grade disease necessitates chemotherapy to control uncontrolled cell growth, while low-grade disease is caused by a compromised immune response to the Epstein-Barr virus and can therefore be treated with immunotherapy.

Over the course of five years, he and his colleagues administered interferon alfa-2b to four patients with low-grade lymphomatoid granulomatosis, and in three of them, the therapy resulted in a complete remission—the absence of all disease-related symptoms. Because lymphomatoid granulomatosis is a rare condition and it was difficult to enroll enough patients for the study, it took 30 years to complete the phase 2 interferon alfa-2b trial. This study served as the basis for that trial.

Dr. Dot Wilson, who co-led the study, said that it “really illustrates the unique ability of NIH to do a study like this that nobody else could do and no one else has ever done for this particular disease.”

67 lymphomatoid granulomatosis patients, 30 with high-grade disease and 37 with low-grade disease, were enrolled in the trial. In every case, the participants had not yet received treatment for their illness, or the illness had not improved after other treatments or had come back.

Most of the patients with low-grade disease initially received interferon alfa-2b injections subcutaneously three times per week in increasing doses for about a year. Six cycles of intravenous chemotherapy were administered every three weeks to the majority of patients with high-grade disease.

The disease disappeared in 27 of 44 patients (61%) receiving interferon alfa-2b treatment and 8 of 17 patients (47%) receiving chemotherapy in both groups.

Some patients received the alternate therapy, known as crossover treatment, after their initial treatment. Chemotherapy was administered to patients with low-grade disease that got worse after immunotherapy, whereas interferon alfa-2b was administered to patients with high-grade disease that returned after chemotherapy. According to earlier research, low-grade disease can reappear after high-grade disease is treated with chemotherapy.

The crossover therapies were also successful, with 4 of 8 patients (50%) who received interferon alfa-2b after chemotherapy and 7 of 15 patients (47%) who received chemotherapy after interferon alfa-2b experiencing a complete remission of their disease.

Patients receiving interferon alfa-2b for the first time had a median overall survival of 20 pts over 6 years, whereas patients switching to interferon alfa-2b had a median overall survival of 19 pts over 8 years. For patients who received chemotherapy as their initial treatment, the median overall survival was 12.1 years, but it was not achieved for patients who switched to chemotherapy.

Low white blood cell count was the most frequent side effect of interferon alfa-2b therapy, and infection and low white blood cell count were the most frequent side effects of chemotherapy. Only a quarter of patients receiving interferon alfa-2b experienced serious side effects, as opposed to nearly two-thirds of patients receiving chemotherapy.

Numerous more recent immunotherapies, such as nivolumab, may be used to treat low-grade lymphomatoid granulomatosis and other diseases linked to the Epstein-Barr virus, and they may be less harmful than older immunotherapies.

“The interferon alfa-2b trial established that immunotherapy improves survival in patients with low-grade lymphomatoid granulomatosis,” Dr. Melani said. Now that novel immunotherapies are more tolerable, we can examine them to see if they can boost the effectiveness of our present therapy.”.

More information: Christopher Melani et al, Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial, The Lancet Haematology (2023). DOI: 10.1016/S2352-3026(23)00029-7

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