Interferon-gamma (IFN-gamma) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-gamma inhibition has been documented; emapalumab, an anti-IFN-gamma monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-gamma inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-gamma and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-gamma neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.
The role of interferon-gamma and its signaling pathway in pediatric hematological disorders
Merli, Pietro;
2021-01-01
Abstract
Interferon-gamma (IFN-gamma) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-gamma inhibition has been documented; emapalumab, an anti-IFN-gamma monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-gamma inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-gamma and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-gamma neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
