Efficacy of Ruxolitinib in Patients with Hemophagocytic Lymphohistiocytosis: A Systematic Review

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation. Standard treatments include steroids, chemotherapy, and immunosuppressants, but new therapies are needed to improve outcomes. Ruxolitinib, a Janus kinase (JAK) inhibitor, has shown potential in treating HLH.

Methods: We conducted a systematic review following PRISMA Statement 2020 guidelines. Our population consisted of patients diagnosed with HLH, with the intervention being Ruxolitinib treatment. Key outcomes included overall survival, relapse rates and adverse effects. Inclusion criteria encompassed primary clinical studies published in the last 20 years in English and non-English languages. Databases searched included Clinicaltrials.gov, Cochrane CENTRAL, Embase, Medline, and PubMed, yielding 433 studies after removing duplicates.

Results: Seventeen studies met the inclusion criteria, involving 75 patients with a median age of 41.65 years (IQR: 21.25). The gender distribution was nearly equal, with 50.7% males and 49.3% females. Types of HLH included primary (8%) and secondary (92%). Standard treatments administered to patients included steroids (88.3%), etoposide (13.3%), IVIg (11.7%), chemotherapy and HLH-specific protocols (6.7%), antibiotics and antifungal treatments (5.0%), and other immunosuppressive treatments (1.7%). Patients also received a median Ruxolitinib dose of 10 mg twice daily (interquartile range: 5-20 mg). The overall response rate was 70.7%, with 41.3% achieving complete response and 21.3% partial response. The relapse rate was 16%. The survival rate was 76.0%, with 57 out of 75 patients surviving. Adverse events were noted in 90.5% of patients. No adverse events or severe side effects were reported in 9.5% of patients. Hematologic adverse events included leukopenia (Grade III/IV) in 3.2% and thrombocytopenia (Grade III/IV) in 6.3%. Liver-related adverse events included elevated transaminases (Grade III/IV) in 9.5%, elevated bilirubin (Grade III/IV) in 4.8%, and hypertriglyceridemia (Grade III/IV) in 1.6%. Infections reported were pulmonary infections in 4.8%, urinary infection in 1.6%, CSKP infection in 1.6%, lung infection (CMV+fungi) in 1.6%, and febrile neutropenia in 1.6%. Gastrointestinal and metabolic adverse events included CMV gastritis in 1.6% and mild nausea in 7.9%. Other adverse events included pain in extremities (Grade 1 & 2) in 3.2%, maculopapular rash (Grade 1) in 1.6%, intermittent candidiasis (Grade 1) in 1.6%, a major bleeding event in 1.6%, xerophthalmia in 1.6%, and DIC in 1.6%. The mortality rate was 24% with 18 out of 75 patients dying during the study period.

Conclusion: Ruxolitinib appears to have superior survival and reduced HLH symptoms compared to standard treatments alone, with an acceptable safety profile. These findings support further investigation and potential inclusion of Ruxolitinib in HLH treatment protocols to enhance patient outcomes and quality of life. Future studies should focus on long-term effects and optimal dosing strategies.

Shune:BMS: Membership on an entity's Board of Directors or advisory committees; Norvatis: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. McGuirk:Caribou bio: Consultancy; CRISPR therapeutics: Consultancy; Autolus: Consultancy; BMS: Consultancy; Kite: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Novartis: Consultancy; Sana technologies: Consultancy; NEKTAR therapeutics: Consultancy; Legend biotech: Consultancy. Mushtaq:Iovance Biotherapeutics: Research Funding.