Eculizumab for hyperhemolysis syndrome in sickle cell disease: A systematic review and meta-analysis

Abstract Background Hyperhemolysis syndrome (HHS) is a rare, potentially fatal transfusion complication seen in patients with sickle cell disease (SCD), characterized by the destruction of both donor and recipient red blood cells, leading to a paradoxical drop in hemoglobin. Eculizumab, a monoclonal antibody targeting the terminal complement protein C5, has shown promise in controlling complement-mediated hemolysis. We aim to investigate outcomes with Eculizumab in patients with HHS. Methods Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, Google Scholar, and ClinicalTrials.gov, and 11 original studies reporting outcomes in HHS patients treated with Eculizumab were included for analysis and review. Pooled proportions with 95% confidence intervals were calculated using the DerSimonian–Laird estimator and analyzed with the ‘meta’ package in R (version 4.16-2). Demographic, clinical, genetic, and treatment-related data were extracted and analyzed descriptively. Results A total of 11 reports reporting outcomes in 14 patients were included for analysis. The median age was 25 years (range, 9-42), and 71% (n = 10) were female. Most patients had an SS genotype (n = 10/14, 71%). HHS was acute in 50% (n = 7) of the cases. Reported triggers included transfusions (n = 10, 71%), infections (n = 3, 14%), and surgery (n = 1, 7%). Common pre-treatments included steroids (n = 9/14, 64%), intravenous immunoglobulins (IVIG) (n = 9/14, 64%), and Rituximab (n = 5/14, 36%). The median hemoglobin (Hb) level before treatment with Eculizumab was 4.2 g/dL (range, 2.4-9.0 g/dL). The dose of Eculizumab ranged from 600 mg to 1200 mg; patients required from 1 to 8 infusions. The pooled rates for patients who required admission to the intensive care unit (ICU) and mechanical ventilation were 27% (95% CI: 0.0-0.73, I2 = 30.2, p = 0.1676) and13% (95%CI: 0.00-0.49, I2 = 0.0%, p = 0.7527), respectively. The pooled rate of HHS resolution was 93% (95% CI: 0.62-1.00, I2 = 0.00%, p = 0.947). The pooled rates for HHS recurrence and mortality were 0% (95% CI: 0.00-0.25, I2 = 0.00%, p = 1.00) and 7% (95% CI: 0.00-0.38, I2 = 0.00%, p = 0.947), respectively. The pooled rate for overall survival (OS) at the last follow- up was 93% (95%CI: 0.59-1.00, I2 = 0.0%, p = 0.9149). The pooled rates of fever, hypotension, and thrombosis were 14% (95% CI: 0.00-0.48, I2 = 0.0%, p = 0.9348), 7% (95% CI: 0.00-0.38, I2 = 0.0%, p = 0.9471), and 0% (95% CI: 0.00-0.18, I2 = 0.0%, p = 1.00) respectively, whereas the pooled rate for anaphylaxis was 0% (95% CI: 0.00-0.18, I2 = 0.0%, p = 1.00). Conclusion Eculizumab was associated with the complete resolution of HHS in the majority of cases, with a low recurrence rate and an excellent survival rate at follow-up. However, there is a lack of high-quality data and larger, prospective registries and clinical trials are urgently needed to validate these findings, define optimal patient selection, timing, and dosing.