Ruxolitinib in malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH): A systematic literature review

Abstract

Abstract Introduction: HLH (Hemophagocytic lymphohistiocytosis) is a critical hyperinflammatory syndrome caused activation of cytotoxic T-cells and macrophages, resulting in a cytokine storm and multi-organ failure. Malignancy-associated HLH (M-HLH), commonly associated with hematological malignancies like lymphomas and having poor outcomes with 28-days mortality of more than 50%. Standard therapies (e.g. HLH-94/2004 protocols) are usually not effective in M-HLH due to drug resistance and toxicity. Ruxolitinib (JAK1/2 inhibitor), gives a specific alternative by disrupting the JAK-STAT pathway involved in proinflammatory cytokine signalling. This is the first systematic review primarily focused on ruxolitinib-based regimens in M-HLH, seeking to assess its efficacy, safety, and likely role in improving outcomes in this high-risk population. Methods: PRISMA 2020 guidelines were used for conducting this systematic review. PubMed, Embase, MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched thoroughly in June 2025. A combination of MeSH terms and keywords such as “ruxolitinib,” “hemophagocytic lymphohistiocytosis,” “HLH,” and “malignancy” were used. Included studies involved adult patients diagnosed with malignancy-associated HLH (M-HLH) and treated with ruxolitinib. Studies reporting at least one clinical outcome such as complete response(CR), partial response(PR), overall response rate(ORR), overall survival(OS), adverse events(AEs) and minimum sample size of 5 were included. We excluded case reports, case series, review articles, or studies that do not report M-HLH-specific data . Literature reviews were performed independently by two authors. Disagreement was resolved through consensus and opinion of a third reviewer. Data were pooled on variables like study design, type of malignancy, ruxolitinib regimen, and clinical outcomes. All included studies scored≥6 on Newcastle-Ottawa Scale, indicating moderate-high methodological quality. Results: Out of 68 identified articles, 59 were screened after removing duplicates. 43 studies were not relevant to present review, 11 were excluded due to case reports, case series, not having M-HLH data, or inaccessible full texts. So, five studies were included. Meta-analysis was not undertaken due to clinical and methodological variations. Zhou et al (2020) studied 70 adult patients with lymphoma-associated HLH(LAHS). Comparison of R-DED regimen (Ruxolitinib 0.3 mg/kg/day(Day1–14) + doxorubicin(20mg Day1–2) + etoposide(100mg Day1, 50mg Day2–5) + dexamethasone(10mg BID Day1–5, then 10mg OD Day6–14) with HLH-94 therapy achieved an ORR of 89%(CR:50%, PR:39%), with a median OS of 5.4 months as compared to 1.5 months in the control group. Neutropenia(61%), febrile neutropenia(33%), and transaminitis(19%) were common toxicities. Stalder et al. (2023) evaluated 6 adults with AML-associated HLH who were treated with a dose-adjusted RED regimen Dose-adjusted ruxolitinib (5–20mg BID) + etoposide 50–150mg/m² twice weekly +dexa 10mg/day achieved ORR of 100%(CR:83%, PR:17%). Despite one-third 60-day mortality (due to AML progression), the adRED regimen showed grade reduction of ≥3 infections and lower cumulative steroid/etoposide use compared to historical controls. Infections (33%) and cytopenias were toxicities reported. Zhou et al (2022) in phase-II trialusedruxolitinib plus dexamethasone(Ru-D) (ruxolitinib 15mg BID 8weeks; dexamethasone 10mg/day) in 15 adults with HLH [8 with LAHS]. ORR 86.7%, LAHS specific 2-month OS of 62.5% and mortality of 37.5% due to lymphoma progression, not HLH. LAHS specific response rates were not separately mentioned but all responders proceeded to chemotherapy. Regimen was well tolerated with no treatment-related deaths or discontinuations, suggesting Ru-D is effective as initial treatment before starting chemotherapy in LAHS. Two ongoing Phase-II trials namely HLHRUXO trial (NCT04551131) and a trial in China (NCT04999878) are investigating ruxolitinib-based regimens in M-HLH cases. Conclusion: Ruxolitinib shows promise as a targeted therapy for malignancy-associated HLH, achieving response rates up to 100% with manageable toxicity in early-phase studies. Early and timely incorporation of ruxolitinib with rapid bridge to definitive therapy needs to be studied due to very high 28 day mortality in LAHS. Larger prospective trials are urgently needed to validate efficacy, optimize dosing strategies, and define its role within current HLH treatment paradigms.