Hemophagocytic lymphohistiocytosis (HLH) is a lethal disorder characterized by hyperinflammation. Recently, ruxolitinib, 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 front-line 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=0.009). 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 Epstein Barr virus infection-associated HLH (CAEBV-HLH) developed refractory HLH by week-8. The median interval to additional treatment since first ruxolitinib administration was 6-days (range, 3-25). Altogether, 73.1% (38/52) of the enrolled patients achieved CR after treatment overall. The 12-month overall survival for all patients was 86.4% (95%CI, 77.1%-95.7%). Ruxolitinib had low toxicity and was well tolerated compared to intensive chemotherapy. Our study provides clinical evidence for ruxolitinib as a front-line agent for pediatric HLH. The efficacy was particularly exemplified with stratified regiment 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.
Hemophagocytic lymphohistiocytosis (HLH) is an immune-regulatory disorder characterized by excessive production of inflammatory cytokines. The treatment recommendations of the HLH-1994 and HLH-2004 protocols have long been used in HLH therapy, but some patients still do not respond well to or have unacceptable side effects from conventional therapies. It is believed that cytokine-targeted strategies that directly target disease-driving pathways will be promising options for HLH. This prospective study aimed to investigate the efficacy and safety of ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, as a front-line therapy in children with secondary HLH. Twelve newly diagnosed patients without previous treatment were enrolled in this study with a median follow-up of 8.2 (7.1-12.0) months, including 8 cases of Epstein-Barr virus associated HLH (EBV-HLH), 2 cases of autoinflammatory disorder (AID)-associated HLH, and 2 cases of unknown etiology. Patients received oral ruxolitinib dosed on 2.5 mg, 5 mg or 10 mg twice daily depending on the body weight for 28 consecutive days. The overall response rate at the end of treatment (day 28) was 83.3% (10/12), with 66.7% (8/12) in complete response (CR), 8.3% (1/12) in partial response (PR), and 8.3% (1/12) in HLH improvement. Among the patients achieving CR, 87.5% (7/8) maintained CR condition for6 months, and one patient with EBV-HLH relapsed following CR. For the EBV-HLH subgroup, all 8 patients responded to ruxolitinib, with a CR rate of 75% and a PR rate of 25%. Two patients with AID-associated HLH had quite different responses, with one showing reversal of the HLH abnormalities soon and the other showing no improvement, as did the two cases of unknown etiology. Patients who had no response or discontinued ruxolitinib all responded well to the subsequent HLH-1994 regimen. The expected 6-month event-free survival (EFS) rate was 58.3%±10.2%. No serious adverse effects were reported. Our study provides further support for the possibility of ruxolitinib targeted therapy for secondary HLH in children. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000029977.
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