HLH-JAK the First Open-Label, Phase II Study Evaluating Anti-JAK1 Itacitinib, for Non Severe HLH in Adults
Authors: Bloch Coralie , Lazarro Estibaliz , Dhote Robin , Michel Marc , Terriou Louis , Lifermann Francois , Akermann Felix , Riviere Sebastien , Tudesq Jean-Jacques , Boubaya Marouane , Viallard Jean-Francois , Hermine Olivier 
Published: December 2023

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” &gt;169. Twenty-three French medical centers participated to the study. In the absence of organ failure, fibrinogen&lt;0.5 g/L, platelets&lt;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 H-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. It was planned to include 63 patients with a Simon optimal 2-stage design. The number of responses to advance to stage 2 was 9 responses out of 24 included patients. These are the results from the first fifteen patients.
Results : Fifteen patients were included between May 2022 and June 2023, 67% (10/15) were male and mean (±SD) age was 53 ± 22 y. At inclusion, 3 (20%) had relapsing and 12 (80%) de novo HLH. None but one of the patients has an associated disease known before inclusion. Associated diseases were distributed as Non Hodgkin Lymphoma (n=6), Autoinflammatory/immune disease (n=6) and unknown for 3 patients. At day 15, 10 out of 15 patients (67%) had a CR (n=6) or PR (n=4), reaching the level of efficacy (at least 9 responses) to advance to stage 2 of the protocol. Before D15, five patients stopped the treatment, with two in progression at D15 resulting in death during first months of treatment. Two patients died before D15 and one received chemotherapy for a B-cell non Hodgkin Lymphoma (NHL). Patients-related Adverse Effects (AEs) occurred in 24 of cases and fever was the most frequent AEs being detected.
Conclusions : As first line treatment, itacitinib monotherapy provided encouraging clinical activity characterized by a high RR and durable response and no safety issues were notified. The second stage of HLH JAK is ongoing. Clinical trial information: NCT NCT05063110