Background: Lymphomatoid granulomatosis (LYG) is a rare EBV-driven B-cell lymphoproliferative disorder characterized by a reactive T-cell infiltrate that is angioinvasive and angiodestructive. Dysregulated immune surveillance of EBV is thought to contribute to the pathogenesis of LYG and grading of disease is based on the density and number of EBV+ large atypical B-cells. Grade I-II (low-grade) disease is typically polyclonal/oligoclonal and immune-dependent whereas grade III (high-grade) disease is typically monoclonal and immune-independent. Herein, we report additional and extended results from an on-going prospective study at the National Cancer Institute on the treatment of patients with low and high-grade LYG using Interferon-α (INF-α) and/or DA-EPOCH+/-R, respectively.

Methods: Pts with histologically confirmed LYG by the Laboratory of Pathology, NCI, were eligible. LYG of any grade or stage was included as were pts with untreated or previously treated disease. Baseline tests included laboratory studies, body CT and FDG-PET, CT or MRI brain, echocardiogram, LP with flow cytometry/cytopathology, and bone marrow aspiration/biopsy. Grade 1-2 LYG pts received primary therapy with INF-α initially at 7.5 MIU TIW which was dose-escalated every 1-2 wks. as tolerated until best response and then continued for 1 yr. Pts with grade 3 LYG received combination chemotherapy with DA-EPOCH+/-R for up to 6 cycles. Pts with progression after primary INF-α therapy and those who progressed after or failed to achieve CR after DA-EPOCH+/-R could cross over to the other treatment. Restaging CT was performed every 4 wks. until stable dose of INF-α and then every 3 mos. and after cycles 4 and 6 of DA-EPOCH+/-R. Surveillance CT was performed every 3, 4, 6 and 12 mos. for post-treatment yrs. 1, 2, 3, and 4-5, respectively, and then as clinically indicated.

Results: 70 LYG pts were enrolled between Jan. 1991 and Feb. 2018. Characteristics included; male sex in 45 (64%) pts, median (range) age of 46.2 yrs. (14.9-67) and histologic grade I in 19 (27%), II in 24 (34%), and III in 27 (39%) pts. Twenty-three (33%) pts were untreated, and 32 (46%) and 21 (30%), respectively, had received steroids and/or chemotherapy+/-R. The most common disease sites included lung (100%), CNS (37%), skin (33%), kidney (17%), and liver (17%). Peripheral blood at baseline showed median (range) CD4, CD8 and NK-cell counts of 510 (80-1864; Normal: 359-1565), 138 (8-1245; Normal: 178-853), and 96 (25-1567; Normal: 126-729) cells/uL, respectively, and a median (range) EBV viral load of 100 (1-13,950) copies/mL and 3.48 (0-4.48) Log 10 IU/mL. With a median potential follow-up of 12.9 yrs., 5-yr. PFS and OS for all 67 treated pts was 41% and 70.8%, respectively (Fig.1). There was no significant difference in PFS or OS associated with baseline histologic grade (p=0.47 and p=0.23, respectively) or CNS involvement (p=0.67 and p=0.98, respectively). Of 49 INF-α treated pts, 47 were evaluable for response with an ORR of 60% (CR 55%) and a median (range) TTR of 6.7 mo. (1.4-40) and 5-yr. DOR of 66.6% (95% CI: 45.4-81.1%). ORR was similar [60% (CR 55%)] in the 20 INF-α treated pts with baseline CNS involvement. Overall, in 49 INF-α treated pts, 5-yr. PFS and OS were 46.2% and 72.5%, respectively (Fig.1). Median (range) dose and duration of INF-α was 20 MIU (7.5-40) and 7.9 mo. (0.5-48.6), respectively. Nineteen pts received secondary therapy with DA-EPOCH+/-R for progression during/after INF-α with an ORR of 72% (CR/CRu 56%) in 18 evaluable pts. In 13 evaluable pts refractory to INF-α, ORR was 92% (CR/CRu 69%) with DA-EPOCH+/-R. Of 18 DA-EPOCH+/-R treated pts, 17 were evaluable for response with an ORR of 76% (CR/CRu 41%) and a median (range) TTR of 4.1 mo. (2.6-7.4) and median DOR of 1.5 yrs. (95% CI: 0.3-9.2). Overall, in 18 DA-EPOCH+/-R treated pts, 5-yr. PFS and OS were 27.8% and 66.2%, respectively (Fig.1). Eight pts received secondary INF-α therapy for progression during/after or failure to achieve CR after DA-EPOCH+/-R with an ORR of 75% (CR/CRu 63%).

Conclusion: INF-α and DA-EPOCH+/-R result in prolonged remissions in a significant subset of pts with low and high-grade LYG, respectively. Progression to high-grade disease and relapse with low-grade disease following INF-α and DA-EPOCH+/-R treatment, respectively, occurs frequently due to the continued immune dysregulation of EBV and can be successfully treated through cross over to the alternative treatment modality.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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