Treatment strategies for relapsed/refractory hemophagocytic lymphohistiocytosis in pediatric patients

Abstract

Hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome caused by uncontrolled activation of immune cells which leads to excessive cytokine discharge and systemic inflammation, had a mortality rate of as high as 60% when left untreated or not properly managed in the past, but the HLH-94 protocol was introduced and it brought about significant improvement in patient outcomes, however, nearly 30% of patients remain unresponsive to this initial therapy, either failing to achieve remission or relapsing after an initial response. Therefore, new chemotherapy regimens, such as those incorporating doxorubicin, PEG-asparaginase, or higher-intensity etoposide dosing, and biologically targeted therapies, including monoclonal antibodies against cytokines like interleukin-6 (IL-6) or interleukin-2 (IL-2), as well as Janus kinase (JAK) inhibitors, are being explored in relapsed or refractory patients. Nevertheless, data on their application in children remain limited. Pediatric HLH presents unique challenges due to differences in disease biology, drug metabolism, and long-term toxicity concerns. This article summarizes current treatment strategies for relapsed and refractory HLH in pediatric patients, aiming to provide evidence-based guidance for clinicians managing this complex and high-risk group.