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

Background Lymphomatoid granulomatosis is a rare Epstein-Barr virus- associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. In this study, we hypothesised that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immuneindependent. On the basis of this hypothesis, we investigated the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. Methods In this open-label, single-centre, phase 2 trial, we enrolled patients aged 12 years or older with untreated, or relapsed or refractory lymphomatoid granulomatosis at the National Cancer Institute (National Institutes of Health, Bethesda, MD, USA). Patients with low-grade disease received dose-escalated interferon alfa-2b, starting at 7 center dot 5 million international units subcutaneously three times per week for up to 1 year past best response, and patients with high- grade disease received six cycles every 3 weeks of intravenous, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). Starting doses were 50 mg/m(2) per day as a continuous intravenous infusion from day 1 to day 4 ( 96 h) for etoposide; 60 mg/ m (2) twice daily by mouth from day 1 to day 5 for prednisone; 0 center dot 4 mg/m(2) per day as a continuous intravenous infusion from day 1 to day 4 ( 96 h) for vincristine; 750 mg/m(2) intravenous on day 5 for cyclophosphamide; 10 mg/m(2) per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for doxorubicin; and 375 mg/m(2) intravenous on day 1 for rituximab. The doses of doxorubicin, etoposide, and cyclophosphamide were adjusted up or down on the basis of neutrophil and platelet nadirs. Patients with residual or progressive disease after initial therapy crossed over to alternative therapy. The primary endpoint was the proportion of patients who had an overall response and the 5-year progression-free survival after initial or cross-over treatment. Analysis of response included all participants who underwent restaging imaging; safety analysis included all patients who received any dose of study drugs. The trial is open for enrolment and is registered at ClinicalTrials.gov, NCT00001379. Findings 67 patients were enrolled between Jan 10, 1991, and Sept 5, 2019 (42 [ 63%] were male). 45 patients received initial treatment with interferon alfa-2b (16 of whom crossed over to DA-EPOCH-R) and 18 received initial treatment with DA-EPOCH-R (eight of whom crossed over to interferon alfa-2b); four underwent surveillance only. After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% ( 27 of 44) having a complete response, whereas, after cross- over treatment with interferon alfa-2b, the overall response was 63% ( five of eight evaluable patients) with 50% ( four of eight) having a complete response. After initial treatment with DA- EPOCH-R, the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response, whereas, after cross-over treatment with DA-EPOCH-R, the overall response was 67% (ten of 15 evaluable patients) with 47% ( seven of 15) having a complete response. 5-year progression-free survival was 48 center dot 5% (95% CI 33 center dot 2- 62 center dot 1) after initial treatment with interferon alfa-2b, 50 center dot 0% (15 center dot 2-77 center dot 5) after cross-over treatment with interferon alfa-2b, 25 center dot 4% (8 center dot 2-47 center dot 2) after initial treatment with DAEPOCH-R, and 62 center dot 5% (34 center dot 9-81 center dot 1) after cross-over treatment with DA-EPOCH-R. The most common grade 3 or worse adverse events in patients treated with interferon alfa- 2b included neutropenia (27 [53%] of 51 patients), lymphopenia ( 24 [47%]), and leukopenia (24 [47%]). The four most common grade 3 or worse adverse events in patients treated with DA-EPOCH-R included neutropenia (29 [88%] of 33 patients), leukopenia (28 [ 85%]), infection (18 [ 55%]), and lymphopenia (17 [52%]). Serious adverse events occurred in 13 (25%) of 51 patients receiving treatment with interferon alfa-2b and 21 (64%) of 33 patients receiving DA-EPOCH-R, with five treatment-related deaths: one thromboembolic, one infection, and one haemophagocytic syndrome with interferon alfa-2b, and one infection and one haemophagocytic syndrome with DA-EPOCH-R. Interpretation Interferon alfa-2b is efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy. Uncontrolled immune regulation of Epstein-Barr virus is hypothesised to result in the emergence of low-grade disease after chemotherapy, for which treatment with interferon alfa-2b is efficacious.