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In a study spanning almost three decades, the use of interferon alfa-2b led to durable remission for patients with low-grade lymphomatoid granulomatosis and increased overall survival compared with historical data by reducing progression to high-grade disease, a single-center showed.

Among 67 patients with the rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder, those with low-grade disease initially treated with interferon alfa-2b had an overall response rate (ORR) of 64%, with 61% having a complete response, reported Wyndham H. Wilson, MD, PhD, of the National Cancer Institute (NCI) in Bethesda, Maryland, and colleagues.

In the patients with high-grade disease who were initially treated with DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin, and rituximab [Rituxan]), the ORR was 76%, with 47% having a complete response, they noted in .

Median overall survival reached 20.6 years in the low-grade disease group and 12.1 years in the high-grade disease group, substantially higher than historical survival figures of reported in a large historical retrospective study, and in a single-center retrospective study.

"I think the results of this study represent a significant contribution to determining the standard-of-care treatment for this rare disease," said co-author Christopher J. Melani, MD, of NCI's Center for Cancer Research, in a .

Among the patients with residual or progressive disease after initial therapy who crossed over to the alternative therapy, the ORR was 63% (50% complete response) with interferon alfa-2b, and 67% (47% complete response) with DA-EPOCH-R.

Median overall survival was 19.8 years and not reached for these two groups, respectively.

"We observed no difference in survival rates of patients depending on when they started treatment, indicating that the overall survival observed in our study reflects the effect of interferon alfa-2b treatment during the enrollment period and not the effect of newer therapies developed over time," Wilson and colleagues wrote.

The 5-year progression-free survival rate was 48.5% after initial treatment with interferon alfa-2b, 50.0% after crossover treatment with interferon alfa-2b, 25.4% after initial treatment with DA-EPOCH-R, and 62.5% after crossover treatment with DA-EPOCH-R.

"Previous studies suggest no specific therapy is optimal, with up to two-thirds of patients dying, many within 1-2 years of diagnosis from uncontrolled high-grade lymphomatoid granulomatosis or evolution to malignant lymphoma," the authors pointed out.

According to co-author Jeffrey Cohen, MD, of the the National Institute of Allergy and Infectious Diseases, lymphomatoid granulomatosis is uncommon, but "the effects of high-grade disease can be debilitating. We need better ways to prevent the disease from progressing to this more severe state, such as interferon alfa-2b."

The authors hypothesized that low-grade lymphomatoid granulomatosis is immune-dependent and would be responsive to immunotherapy, whereas high-grade disease is immune-independent and requires chemotherapy.

The study "is a major advancement in elucidating the natural history of lymphomatoid granulomatosis, and in establishing a standard approach for the condition," wrote Anthea Peters, MD, and Minakshi Taparia, MD, both of the University of Alberta in Edmonton, Canada, in an .

However, they noted that in the decades since the study was launched, Merck has stopped manufacturing interferon alfa-2b, and it is uncertain whether the pegylated version -- peginterferon -- has the same efficacy in patients with lymphomatoid granulomatosis.

"Although the study ... represents a victory for clinicians faced with the challenge of treating patients with this rare disorder, we are now left with the conundrum of no or limited access to a drug with proven benefit," they added.

For this open-label study, 67 patients with untreated, or relapsed or refractory lymphomatoid granulomatosis at the NCI were enrolled from January 1991 to September 2019. Median age was 46 years, and 63% were men. At enrollment, 27% of patients had histological grade 1 lymphomatoid granulomatosis, 28% had grade 2, and 45% had grade 3.

The most common grade 3 or higher adverse events (AEs) in patients treated with interferon alfa-2b included neutropenia (53%), lymphopenia (47%), and leukopenia (47%), while the most common grade 3 or higher AEs in patients treated with DA-EPOCH-R included neutropenia (88%), leukopenia (85%), infection (55%), and lymphopenia (52%).

Serious AEs occurred in 25% of patients receiving interferon alfa-2b and 64% of patients receiving DA-EPOCH-R, with five treatment-related deaths -- one thromboembolic, one infection, and one hemophagocytic syndrome with interferon alfa-2b, and one infection and one hemophagocytic syndrome with DA-EPOCH-R.

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