The prospect of high-dose vitamin c in improving early survival in patients with hemophagocytic lymphohistiocytosis

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is a severe disease incited by an inflammatory cytokine storm. Current standard regimen relies on steroids and cytotoxic drugs. Etiologic identification of HLH is crucial in therapeutics, whereas the agents employed often interfere with the differential diagnosis and may even delay the therapy initiation for the underlying causes. Over the past decades, the efficacy of high-dose vitamin C (VC) has been widely studied at the bench and beside, particularly in critical care settings with hyper-inflammatory characteristics such as sepsis and severe acute pancreatitis, with its safety repeatedly validated. However, the efficacy of VC in HLH still remains unanswered. Herein, we present the first clinical data for the application of VC in HLH. Methods In this real-world study, patients (pts) diagnosed with HLH in our center received high-dose VC: 200 mg/kg for 4 consecutive days plus standard HLH regimens providing the HLH diagnosis has been made. We observed and documented the survival rate, overall response rate and adverse events involved. Results From November 2024 through May 2025, our center received 24 pts diagnosed with HLH aged from 15 to 76 years. All pts were enrolled in the study and survived the first week. 23 pts (95.8%) survived the first 28 days and had response. With a median follow-up duration of 5 months, 20 pts survived until July 2025 (83.3%). The median overall survival time was not reached. The 3-month survival rate was 91.7%. With respect to etiology, 5 patients had EBV infection, 15 patients had lymphoma, and other causes including other virus infection (4 pts) and autoimmune diseases (4 pts). No patients were diagnosed with primary HLH. Eight patients had multiple factors contributing to HLH. The 28-day survival rate of EBV-associated HLH patients was 100%, and the 28-day survival rate for lymphoma-associated HLH patients receiving VC therapy was 93.3%, respectively. As for other patients, the 28-day survival rate was 100%. Two pts with central nervous system disease at onset both survived at 28 days. Throughout the treatment, none of the patients experienced severe high-dose VC-related fluctuations in blood glucose test. At the end of follow-up, no patient developed urinary tract lithiasis or relative VC deficiency. Overall, high-dose VC is safe in the treatment of HLH. Conclusion In our study, the safety of high-dose vitamin C in the treatment of HLH was confirmed. Patients' early mortality rate is relatively lower than that in prior reports. We postulate that further randomized controlled trials will confirm the impact of vitamin C on early mortality in HLH.