Falciparum malaria-induced secondary hemophagocytic lymphohistiocytosis successfully treated with ruxolitinib.

JAK/STAT signaling plays a major role in the pathogenesis of secondary hemophagocytic lymphohistiocytosis. This case report on a critically ill patient with secondary hemophagocytic lymphohistiocytosis due to falciparum malaria treated successfully with ruxolitinib, demonstrates that JAK1/2 inhibition might be a promising treatment option for severe cases.

Fuchs A ，Orth HM ，Germing U ，Kondakci M ，Holtfreter M ，Feldt T ，Jensen BE ，Häussinger D ... -  《-》

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.

Hansen S ，Alduaij W ，Biggs CM ，Belga S ，Luecke K ，Merkeley H ，Chen LYC ... -  《-》

JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

Meyer LK ，Verbist KC ，Albeituni S ，Scull BP ，Bassett RC ，Stroh AN ，Tillman H ，Allen CE ，Hermiston ML ，Nichols KE ... -  《-》

Combined IL-6 and JAK/STAT inhibition therapy in COVID-19-related sHLH, potential game changer.

Portsmore S ，Tran Nguyen TN ，Beacham E ，Neelakantan P ... -  《-》

Ruxolitinib as first-line therapy in secondary hemophagocytic lymphohistiocytosis and HIV infection.

Gálvez Acosta S ，Javalera Rincón M 《-》