Nivolumab treatment of relapsed/refractory Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis in adults

Abstract

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1–positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

Immune responses during COVID-19 infection

“…Stressing the relevance of possibly exhausted CD8 + T cell functions in the uncontrolled monocyte activation and cytokine release syndrome, Liu et al ., recently described how systemic PD-1 blockade could mitigate the hemophagocytic lymphohistiocytosis (HLH) syndrome in patients suffering from EBV-induced HLH. 197 In EBV-induced HLH, single-cell RNA-sequencing analysis revealed that HLH syndrome was associated with hyperactive monocytes/macrophages (expressing high levels of CD163, IL-1β, IL-6) and ineffective CD8 + T cell response characterized by a defective activation program (apoptosis, reduced TCR signaling, lower IFNγ/GrzB/Ki67 and higher PD-1/LAG3 exhaustion markers). 197 SARS-CoV2 -induced secondary HLH could be observed in severe cases of COVID-19.…”

“… 197 In EBV-induced HLH, single-cell RNA-sequencing analysis revealed that HLH syndrome was associated with hyperactive monocytes/macrophages (expressing high levels of CD163, IL-1β, IL-6) and ineffective CD8 + T cell response characterized by a defective activation program (apoptosis, reduced TCR signaling, lower IFNγ/GrzB/Ki67 and higher PD-1/LAG3 exhaustion markers). 197 SARS-CoV2 -induced secondary HLH could be observed in severe cases of COVID-19. 32 , 198 , 199 …”

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

“…The clinical role of ICIs in EBV-positive DLBCL and EBV-related PTLDs is unknown. Case reports/studies of ICIs in EBV-related PTLD post allogeneic stem cell transplantation and other B-cell EBV lymphoproliferations, such as lymphomatoid granulomatosis and hemophagocytic lymphohistiocytosis [ 97 – 100 ], suggest a potential role of ICIs in the treatment of such EBV-related diseases. An interesting ongoing clinical trial is evaluating the role of nivolumab monotherapy or in combination with agents or cellular therapies in EBV-positive lymphomas ( Table 3 ).…”

Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

“…19,20 Several studies have reported that the single-agent anti-PD-1 antibody could provide an ORR of 57.1-100% in r/r NKTL, with a 1-year OS rate of 82.1%. [21][22][23][24][25] Further, those encouraging results on anti-PD-1 antibody in NKTL have started to challenge the current treatment paradigms of NKTL and have provided the rationale for evaluating PD-1 blockade as a firstline therapy of patients with advanced NKTL.…”