A study of ruxolitinib response-based stratified treatment for pediatric hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder characterized by hyperinflammation. Recently, ruxolitinib (RUX), targeting key cytokines in HLH, has shown promise for HLH treatment. However, there is a lack of robust clinical trials evaluating its efficacy, especially its utility as a frontline therapy. In this study (www.chictr.org.cn, ChiCTR2000031702), we designed ruxolitinib as a first-line agent for pediatric HLH and stratified the treatment based on its early response. Fifty-two newly diagnosed patients were enrolled. The overall response rate (ORR) of ruxolitinib monotherapy (day 28) was 69.2% (36/52), with 42.3% (22/52) achieving sustained complete remission (CR). All responders achieved their first response to ruxolitinib within 3 days. The response to ruxolitinib was significantly associated with the underlying etiology at enrollment (P = .009). Epstein-Barr virus (EBV)-HLH patients were most sensitive to ruxolitinib, with an ORR of 87.5% (58.3% in CR). After ruxolitinib therapy, 57.7% (30/52) of the patients entered intensive therapy with additional chemotherapy. Among them, 53.3% (16/30) patients achieved CR, and 46.7% (14/30) patients dominated by chronic active EBV infection-associated HLH (CAEBV-HLH) developed refractory HLH by week 8. The median interval to additional treatment since the first ruxolitinib administration was 6 days (range, 3-25 days). Altogether, 73.1% (38/52) of the enrolled patients achieved CR after treatment overall. The 12-month overall survival (OS) for all patients was 86.4% (95% confidence interval [CI], 77.1% to 95.7%). Ruxolitinib had low toxicity and was well tolerated compared with intensive chemotherapy. Our study provides clinical evidence for ruxolitinib as a frontline agent for pediatric HLH. The efficacy was particularly exemplified with stratified regimens based on the early differential response to ruxolitinib. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000031702.

Zhang Q ，Zhao YZ ，Ma HH ，Wang D ，Cui L ，Li WJ ，Wei A ，Wang CJ ，Wang TY ，Li ZG ，Zhang R ... -  《-》

A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis.

Zhang Q ，Wei A ，Ma HH ，Zhang L ，Lian HY ，Wang D ，Zhao YZ ，Cui L ，Li WJ ，Yang Y ，Wang TY ，Li ZG ，Zhang R ... -  《-》

Short-term effectiveness of ruxolitinib in the treatment of recurrent or refractory hemophagocytic lymphohistiocytosis in children.

Wei A ，Ma H ，Li Z ，Zhang L ，Zhang Q ，Wang D ，Lian H ，Zhang R ，Wang T ... -  《-》

Ruxolitinib is an alternative to etoposide for patient with hemophagocytic lymphohistiocytosis complicated by acute renal injury: A case report.

Yan WL ，Yang SL ，Zhao FY ，Xu XJ ... -  《-》

Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive secretion of cytokines. Even with the recommended HLH-94/2004 regimen, over 30% of patients remain refractory to frontline therapy or relapse after an initial response, leading to poor clinical outcomes. Ruxolitinib, a JAK1/2 inhibitor targets key cytokines in HLH, has shown promising therapeutic effects. However, there has been little attention given to patients who do not respond to ruxolitinib and whether an escalating dose can provide a resolution. This study analyzed eight HLH patients who received dose-escalating ruxolitinib who had previously failed to respond to the general dose. The efficacy and safety were mainly analyzed. Overall, four out of eight (50%) patients achieved better remission after dose escalation. Two patients who only showed improvement with the general dose achieved complete remission (CR) after dose escalation, and the other two patients also achieved CR after dose escalation when they did not respond to the general dose. The median time to achieve the best overall response was 18.5 days (IQR 13.25-23.75 days). There was no correlation of treatment outcome with blood count, liver function, LDH, cytokines, ferritin levels, NK cell activity, or the time to initiation of ruxolitinib and maximum dosage. The etiology of HLH (p=0.029) and level of sCD25 (p=0.021) correlated with treatment response to dose-escalating ruxolitinib. The area of sCD25 under the ROC curve was 0.8125 (95% CI 0.5921 to 1.033, p=0.035) when using 10,000 pg/ml as the cut-off value for predicting therapeutic effects. After a median follow-up of 159 days, two patients died, and the estimated 2-month overall survival rate was 75%. Adverse effects possibly related to the dose-escalating of ruxolitinib included two cases of extremity pain and one of aminotransferase increased. No grade 3 or higher adverse events were reported. This is the first comprehensive study on the use of dose-escalating ruxolitinib in HLH. Ruxolitinib at an escalated dose represent a viable and relatively safe solution for managing refractory HLH. The levels of sCD25 (with a cut-off of 10000pg/ml) can serve as an indicator for early consideration of chemotherapy during treatment.

Song Y ，Li X ，He X ，Zhou F ，Du F ，Wang Z ，Chen S ，Wu D ... -  《Frontiers in Immunology》