OA12 JAK inhibitors, an emerging therapeutic target in haemophagocytic lymphohistiocytosis: results from a service evaluation of the UK HLH MDT

Background/Aims Despite increasing awareness of haemophagocytic lymphohistiocytosis (HLH), all-cause mortality remains unacceptably high, highlighting the urgent need for therapeutic advances. Multiple inflammatory cytokines signal via the JAK1/2-STAT pathway, supporting utility of JAK inhibitors (JAKi), although real-world data remains limited and agents are not nationally commissioned. Methods People treated with JAKi for HLH were identified via the UK HLH National Advisory Panels (NAP). The quality improvement project was registered locally. Patients received baricitinib or ruxolitinib according to local commissioning pathways. Treatment response was classified as complete response (CR), partial response (PR), or non-response (NR) based on the managing team’s assessment of clinical and/or laboratory improvement following initiation of JAKi. Results Between February 2020 and February 2025, 26 patients from 11 centres (10 UK, 1 Portugal) were included; median age was 40 (range 15-73). Triggers were rheumatic (26.9%), haematological malignancy (38.5%), unknown (11.5%), primary (11.5%), infection (7.6%), and post-partum (3.8%). Median HScore was 231 (151-319) and ferritin 19,555 µg/L (676-133,627). Patients had received a median of three prior HLH-directed therapies. 2-month overall survival (OS) was 69% and 6-month OS 50%. Reported complications from JAKi were low. (Table 1). Sixteen patients (61.5%) achieved CR, four (15.4%) achieved PR, and six (23.1%) had NR. There was no significant difference in demographics, triggers or baseline features between CR and PR/NR. 2- and 6-month OS was significantly lower among partial/non-responders (p = 0.02, p = 0.0036). Duration of therapy was significantly longer in the CR group (p = 0.03) with 31% of patients continuing therapy at their last follow up. Conclusion Current access to JAKi for patients with HLH is limited. As a result, JAKi are used in patients who have failed multiple other treatments; thus, selecting for the most complex/treatment resistant patients. In this real-life evaluation, introduction of JAKi was associated with some clinical response in 77% of patients. These findings support broader national commissioning and highlight the need for prospective studies with standardised response criteria to guide optimal use. Disclosure A.M. Holloway: Grants/research support; Supported by UCLH Charity Grant 2024 (7253). D. Gul: None. H. Alawad: None. E. Rankin: None. M. Steel: None. J. Macloed: None. D. Donaldson: None. I. Qureshi: None. C. Benham: None. R. Faria: None. R. Smith: None. D. Pietsch: None. M. Owen: None. A. Jones: None. A. Laurence: None. R. Tattersall: Grants/research support; Rachel Tattersall is part of the MRC Rare Disease Platform Node for Histiocytic Disorders [MR/Y008189/1]. J.J. Manson: Grants/research support; Supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and is part of the MRC Rare Disease Platform Node for Histiocytic Disorders [MR/Y008189/1]. S. Gohil: Grants/research support; has received honoraria, travel support and has served on an advisory board for Electra Therapeutics.