Phase 2 Study of Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-Hodgkin Lymphomas
Authors: Yilmaz Elif , Lakhotia Rahul , Pittaluga Stefania , Muppidi Jagan R. , Phelan James D. , Evans Sarah , Pradhan Amynah , Hillsman Amy , Steinberg Seth M. , Jaffe Elaine S. , Wilson Wyndham H. , Roschewski Mark , Melani Christopher 
Published: November 2021

Introduction: Immune tolerance and evasion plays a significant role in the pathogenesis of EBV+ lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL). Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. PD-L1 expression is a marker of poor prognosis in aggressive lymphomas and most EBV+ LPDs demonstrate high levels of PD-L1 expression. Chronic viral infections, such as EBV, also result in T-cell exhaustion that can be reversed by PD-1 blockade. Nivolumab is a fully human IgG4 monoclonal anti-PD-1 antibody which has demonstrated activity and favorable safety in lymphoid malignancies. We hypothesized that PD-1 blockade may reverse the inactivation of tumor-specific effector T-cells and result in anti-tumor responses in EBV+ LPD and NHL.

Methods: Relapsed/refractory (R/R) EBV+ LPD and B-cell NHL pts age ≥ 12y with adequate organ function are eligible. Untreated pts are eligible if EBV+ LPD. Exclusions include prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, prior solid organ transplant and HIV. Pts with immunodeficiency or autoimmune illness are eligible if not requiring steroids or immunosuppression. CNS involvement is permitted if no seizure activity within 4 weeks of study. Nivolumab 480mg IV is given every four weeks for up to 2y. Pts who achieve CR discontinue nivolumab after 1y of treatment. Baseline evaluation includes CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy along with optional tumor biopsy. CT scans are performed after cycles 3, 6, 13 and 19 and end of treatment (EoT). PET is performed after cycles 1, 3 and EoT. Surveillance CT scans are performed q3m for 1y, q6m for yrs 2-5, and annually thereafter.

Results: 9 pts, 7 (78%) R/R and 2 (22%) untreated, enrolled between April 2018 and May 2021; 5 (56%) with EBV+ LPD [4 G1-2 lymphomatoid granulomatosis (LYG) and 1 chronic active EBV disease (CAEBV)] and 4 (44%) with EBV+ NHL (all DLBCL, NOS). Median age was 48y (range 30-63) and all pts (100%) had stage III/IV disease. Four pts (44%) had elevated LDH (all DLBCL). Median baseline CD4 and CD8 count (cells/mcL) was 378 (range 99-984) and 86 (range 22-1237), respectively, for LPD and 190 (range 133-255) and 90 (range 9-630), respectively, for NHL. Median EBV VL at baseline (Log10 IU/mL) was 2.55 (range 0-6.78) and 2.53 (range 0-5.33) for LPD and NHL, respectively. Eight (89%) pts had extranodal disease with pulmonary involvement most common in 6 (67%). Median prior therapies were 1 (range 0-1) and 2 (range 1-4) for LPD and NHL pts, respectively. Three (43%) R/R pts were refractory (i.e., &lt;PR) to last therapy.

Of 9 pts enrolled, 7 were evaluable for response (1 NHL pt died prior to restaging and 1 NHL pt has not yet been restaged). In 6 measurable pts, tumor reduction was observed in 67% (Fig 1A). ORR and CR rate was 57% (4/7) and 43% (3/7), respectively; 60% (3/5) and 40% (2/5) in LPD and 50% (1/2) and 50% (1/2) in NHL. Median TTR was 3.0m with 3 (75%) of 4 responses ongoing from 6.9m to 35.2m after first response (Fig 1B).

Most common adverse events (AEs) (% pts) included maculopapular rash (38%), ALT elevation (25%), AST elevation (25%), CPK elevation (25%) and fatigue (25%). One pt discontinued therapy due to G2 immune-mediated myositis that required prolonged steroid therapy. &gt;G3 AEs included AST elevation in 1 (13%) pt with no G4/G5 or serious adverse events.

With a median potential follow up of 12.6m, 12-month PFS and OS was 50.8% (95% CI: 15.7-78.1) and 75.0% (95% CI: 31.5-93.1). In LPD pts, 12-month PFS and OS was 80% (95% CI: 20.4-96.9) and 100%. Three (75%) NHL pts progressed and 2 (50%) died of disease progression. One NHL pt stopped therapy due to apparent disease progression after 2 cycles but later developed CR without further therapy and remains in remission 35.2m after stopping therapy.

Conclusion: Nivolumab appears safe in pts with EBV+ LPD and NHL without unexpected toxicities. Preliminary clinical activity, including CRs, is noted in pts with EBV+ LPD and NHL. Additional pts are needed for a better assessment of true activity in these rare entities and correlates of response including PD-1/PD-L1 expression and/or 9p24.1 alterations are ongoing and will be presented at the meeting.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.

OffLabel Disclosure:

Nivolumab for EBV+ LPD and EBV+ NHL.