EBV-Associated T/NK-LPD Manifesting As HLH Cured By Nivolumab and Emapalumab, Avoiding the Need for Allogeneic HCT

Abstract

Introduction

EBV-associated NK- and T-cell lymphoproliferative disorders (LPDs) manifest variably as EBV-HLH, T-cell lymphoma, or chronic-active EBV. HLH-directed therapy and cytoreductive chemotherapy lead to short-lived remissions, and inevitably lead to recurrences. Allogeneic HCT is usually the only curative therapy. Notably, people of East Asian, and Central/South American ethnicity are most affected, and finding a suitable donor is often a challenge. Nivolumab, the anti-PD-1checkpoint inhibitor increases effector T-cell activity and has shown promise in treating many cancers. Emapalumab, the anti-interferon-gamma antibody controls HLH without affecting T-cell viability.

Methods

We report eight patients with EBV T/NK-LPDs treated with nivolumab, often with emapalumab. The diagnosis of EBV-LPD was ascertained by high viremia and quantitative EBV PCR on sorted lymphocytes.

Results

Five female and three male patients, ages 14 months to 20 years, all presented with a hyper-inflammatory HLH-like syndrome, with transient response to HLH-directed cytotoxic therapy. Six patients had T-cell LPD while two had NK-LPD. Seven patients received etoposide, with three also receiving additional rounds of multi-agent chemotherapy. No HLH-causing mutations were detected. All patients were treated with Nivolumab 3mg/kg every 3 weeks. Six patients with ongoing active HLH also received Emapalumab as steroid- and etoposide-sparing therapy. Seven patients achieved complete clinical remissions that have been sustained. Five patients are off therapy, having received a median of 6 doses of nivolumab (range 2 to 9). All remain well with a median follow-up of 14 months since completion of therapy. Two recently diagnosed patients continue to receive treatment with clinical remissions and declining EBV viremia. One patient who had experienced severe chemotherapy toxicity had a response but developed myocarditis after nivolumab. Therapy was discontinued and he remains well after undergoing HCT.

Conclusion

Nivolumab, combined with emapalumab led to sustained remission of EBV T/NK-LPDs in this cohort, largely avoiding the need for HCT.