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

Abstract

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.

The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders

“…Eight out of 12 patients (66.7%) achieved complete response by day 28. With a median follow‐up of 8.2 months, five of 12 patients had an event, leading to an estimated 6‐month event‐free survival of 58.3% 65 . Finally, Meyer and coauthors showed that ruxolitinib treatment sensitizes CD8+ T cells to dexamethasone‐induced apoptosis 66 ; they found that IL‐2 and IL‐12 induce resistance to dexamethasone in this cell subset, via STAT5, by altering cellular apoptotic potential and that this can be reverted by the administration of ruxolitinib.…”

Progress in Biological Therapies for Adult-Onset Still’s Disease

“…Indeed, a pilot study in 12 children with secondary HLH showed a good clinical response after 28 days of oral treatment. 90 Partial response was also reported for two Still’s patients with the concurrent use of steroids. 85 …”

The Pathogenic Role of Interferons in the Hyperinflammatory Response on Adult-Onset Still’s Disease and Macrophage Activation Syndrome: Paving the Way towards New Therapeutic Targets

“…Since they were concomitantly affecting different proinflammatory pathways, these drugs could simultaneously target IFN-γ and other pathogenic mechanisms of MAS during AOSD, possibly allowing for better management of cytokine storm syndrome in these patients [ 61 ]. On these bases, recent evidence has shown ruxolitinib may be considered for patients with secondary HLH with contraindications to glucocorticoids, with a good clinical response [ 62 , 63 , 64 ].…”