March 11, 2020
2 min read

Anakinra effective in pediatric secondary hemophagocytic lymphohistiocytosis

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Randy Q. Cron

Anakinra was effective in pediatric patients with non–malignancy-associated secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome, particularly when administered early and in those with underlying rheumatic disease, according to data published in Arthritis & Rheumatology.

“In terms of its pathologic origins, secondary HLH/MAS develops as part of a ‘cytokine storm,’” Randy Q. Cron, MD, PhD, of the Children's Hospital of Alabama and the University of Alabama at Birmingham, and colleagues wrote. “The proinflammatory cytokines that have been associated with secondary HLH/MAS include interferon, interleukin1 (IL1), IL6, IL12, IL18, and tumor necrosis factor. Anakinra is a recombinant human IL1 receptor antagonist that blocks IL1 function.”

“While the safety and benefits of IL1 blockade in the inflammatory process have been demonstrated in many diseases, including in the treatment of systemic juvenile idiopathic arthritis (JIA) and systemic JIA–related MAS, its role in treating non–systemic JIA–related MAS has not been widely explored,” they added. “Nevertheless, anakinra has been reported to improve survival in several cases of MAS associated with non–systemic JIA rheumatic disorders, including systemic lupus erythematosus (SLE).”

To analyze the benefit of anakinra (Kineret, SOBI) in children with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions, Cron and colleagues conducted a retrospective chart review of all such patients treated with the drug at Children's of Alabama. Focusing on the period from Jan. 2008 through Dec. 2016, the researchers identified 44 patients aged older than 1 year who were treated with anakinra, with diagnoses of HLH/MAS based on ICD-9 and ICD-10 codes in the electronic medical record.

Anakinra was effective in pediatric patients with non–malignancy-associated secondary HLH/MAS, particularly when administered early and in those with underlying rheumatic disease, according to data.
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The researchers assessed demographic, clinical, laboratory and genetic characteristics, outcomes data and information on concurrent treatments, all collected from electronic records. Analyses were performed using appropriate univariate statistical approaches to characterize changes following treatment and associations between patient variables and outcomes.

According to the researchers, the overall mortality rate was 27%. However, earlier initiation of anakinra — within 5 days of hospitalization — was associated with reduced mortality (P = .046), whereas thrombocytopenia (P = .008) and STXBP2 mutations (P = .012) were linked with increased mortality. Patients with systemic juvenile idiopathic arthritis demonstrated the lowest mortality rate, with no deaths among the 13 cases included in the study (P = .006). However, all three patients with an underlying hematologic malignancy died.

“This is the largest reported retrospective cohort of IL-1 blockade for treating secondary HLH,” Cron told Healio Rheumatology. “The use of anakinra to treat pediatric secondary HLH resulted in only 27% mortality, which is favorable compared with etoposide-based protocols. Anakinra was particularly effective at treating secondary HLH associated with systemic juvenile idiopathic arthritis, with 100% survival. Thrombocytopenia at any point was statistically associated with increased mortality. Lack of significant reduction in serum ferritin values at 2 weeks was also predictive of poor outcome.”

“Approximately one-third of tested secondary HLH patients possessed heterozygous mutations in known familial HLH associated genes involved in perforin-mediated cytolytic activity used by natural killer cells and CD8 T lymphocytes,” he added. “Having a heterozygous mutation in the familial HLH gene, STXBP2, was associated with increased mortality; an earlier start of anakinra treatment resulted in decreased mortality. Early introduction of anakinra in patients with non-malignancy associated secondary HLH is a safe and promising treatment for this otherwise frequently fatal condition.” – by Jason Laday

Disclosure: Cron and co-author Timothy Beukelman, MD, MSCE, also of the University of Alabama at Birmingham, report consulting and speaking fees, as well as honoraria, from SOBI.