Background: HLH results in dysregulation of the immune system activation, characterized by excessive pro-inflammatory production, which are responsible for the main clinical and biological features of HLH syndrome. In sporadic/adult forms of HLH, treatment is challenging due to the negative effects of corticosteroids on potential infectious related HLH, and etoposide, which may mask hematological neoplasm (H)-associated hemophagocytic lymphohistiocytosis (H-HLH). Cytokines involved in HLH syndrome activate the JAK/STAT pathway in immune cells, particularly gamma- interferon through JAK1. Kinase inhibitors blocking JAK activity, particularly Ruxolitinib a JAK1/2 inhibitor, have shown some efficacy in murine genetic models of HLH. However, JAK2 inhibition may be responsible of cytopenia in contrast to JAK1, which may have an effect on Interferon-gamma signaling. HLH-JAK is the first open-label, phase II study evaluating the use of a selective and potent anti-JAK1 inhibitor, Itacitinib, alone for non-severe adult HLH (including relapsing or refractory)

Methods: Adult patients were included on criteria adapted from “HLH-2004 protocol'” and an “H Score” >169. Twenty-three French medical centers participated to the study. In the absence of organ failure, fibrinogen<0.5 g/L, platelets<20 G/l, the need for ICU transfer, or etoposide treatment, HLH patients were considered non-severe. The dose of Itacitinib treatment administered was 300 mg per day. Seven clinical and biological parameters were used as a baseline (Hemoglobin, Platelets, Polynuclear neutrophil, Fibrinogen, Ferritin, Fever, Performans Status). Patients were classified as being in complete or partial if they normalized all 7 parameters or less, respectively. The primary endpoint of the study was the rate of response (RR), complete or partial (CR or PR), at day 15 of treatment. If patients had Malignancy-HLH requiring chemotherapy or severe HLH requiring etoposide, Itacitinib treatment was stopped before day 15 and patients were considered in failure. In case of CR/PR at day 15, treatment could be followed until day 30 and increased to 400 mg (PR), which may result in delay of specific treatment of H-HLH. Patients were followed-up until D90. The study initially planned to include 63 patients with a Simon optimal 2-stage design. An overall response rate of 50% was expected, meaning that at least 25 responses out of 63 patients would be required to conclude treatment efficacy. However, the trial was prematurely discontinued due to an internal decision by the manufacturer.

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Results: Thirty-five patients were included between May 2022 and March 2025, 46% (16/35) were male and mean (±SD) age was 52 ± 18 y. At inclusion, 21 patients (60%) had a history of associated disease. Associated diseases were distributed as Non Hodgkin Lymphoma (n=18, 51%), Autoinflammatory/immune disease (n=9, 27%) and unknown for 3 (9%) patients. At day 15, 25 out of 35 patients (71%, 95 CI%: 54 to 85%) had a CR (n=15) or PR (n=10), thereby reaching the pre-specified efficacy threshold of at least 25 responses required by the protocol. The early response rate (Day 8) was 86% (95% CI: 70 to 95%), and the response rate at Day 30 was 54% (95% CI: 36 to 71%). Before D15, nine patients stopped the treatment, with three in progression at D15 resulting in death during first months of treatment. A total of six patients died, including two patients before D15, and one received chemotherapy for a B-cell non Hodgkin Lymphoma (NHL). Only six adverse effects were related to the study treatment, all of which were grade 1 or 2.

Conclusions: Itacitinib, anti-JAK1 inhibitor, demonstrated encouraging efficacy in adult patients with non-severe HLH, with a response rate at Day 15 well above the prespecified efficacy threshold, and the minimum required number of responses was met despite the premature termination of the trial. The treatment was well tolerated, with no grade ≥3 adverse events related to itacitinib. These promising preliminary results warrant further comparative studies to confirm the efficacy and safety of anti-JAK inhibitor in this setting. Clinical trial information: NCT NCT05063110.

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2025
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