Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice

Joly, Josée-Anne; Vallée, Alexis; Bourdin, Benoîte; Bourbonnais, Sara; Patey, Natalie; Gaboury, Louis; Théôret, Yves; Decaluwe, Hélène

doi:10.1016/j.jaci.2022.07.026

Cited by 17 publications

(9 citation statements)

References 83 publications

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“…Our findings differ from those of Joly et al., who reported that combination therapy with ruxolitinib and aIFNg was more effective than treatment with ruxolitinib alone ( 11 ). However, the dose of ruxolitinib used in the study by Joly was much lower than the one used in our study (4 mg/kg vs. 90 mg/kg, respectively).…”

Section: Discussioncontrasting

confidence: 99%

“…In this regard, a recent study combining treatment with “high” doses of ruxolitinib (90 mg/kg twice daily) and aIFNg antibody (40 mg/kg; roughly 1mg, every 3-4 days) revealed toxicity and decreased survival of LCMV WE-infected Prf1 −/− animals ( 10 ). In contrast, a separate study incorporating “low” doses of aIFNg antibody (200 μg every 3 days) and ruxolitinib (4 mg/kg twice daily) reported superior suppression of inflammation in LCMV Armstrong-infected Prf1 −/− mice ( 11 ). To date, it has remained unclear whether the opposing outcomes in these studies were due to differences in the viral strains used (with LCMV Armstrong being more neurotropic and LCMV WE more hepatotropic ( 12 )) or rather, to differences in the doses of aIFNg and/or ruxolitinib administered.…”

Section: Introductionmentioning

confidence: 99%

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Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis

et al. 2023

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BackgroundPrimary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (Prf1–/–) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation. Two studies combining ruxolitinib with aIFNg report conflicting results with one demonstrating improvement and the other worsening of disease manifestations. As these studies used differing doses of drugs and varying LCMV strains, it remained unclear whether combination therapy is safe and effective.MethodsWe previously showed that a ruxolitinib dose of 90 mg/kg lessens inflammation in Prf1–/– mice infected with LCMV-Armstrong. To determine whether this dose controls inflammation induced by a different LCMV strain, we administered ruxolitinib at 90mg/kg to Prf1–/– mice infected with LCMV-WE. To elucidate the impacts of single agent versus combination therapy, Prf1–/– animals were infected with LCMV, treated or not with ruxolitinib, aIFNg or both agents, and analyzed for disease features and the transcriptional impacts of therapy within purified CD8 T cells.ResultsRuxolitinib is well-tolerated and controls disease regardless of the viral strain used. aIFNg, administered alone or with ruxolitinib, is most effective at reversing anemia and reducing serum IFNg levels. In contrast, ruxolitinib appears better than aIFNg, and equally or more effective than combination therapy, at lessening immune cell expansion and cytokine production. Each treatment targets distinct gene expression pathways with aIFNg downregulating IFNg, IFNa, and IL-6-STAT3 pathways, and ruxolitinib downregulating IL-6-STAT3, glycolysis, and reactive oxygen species pathways. Unexpectedly, combination therapy is associated with upregulation of genes driving cell survival and proliferation.ConclusionsRuxolitinib is tolerated and curtails inflammation regardless of the inciting viral strain and whether it is given alone or in combination with aIFNg. When administered at the doses used in this study, the combination of ruxolitinb and aIFNg appears no better than treatment with either drug alone in lessening inflammation. Further studies are warranted to elucidate the optimal doses, schedules, and combinations of these agents for the treatment of patients with pHLH.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis

et al. 2023

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“…18,19 The combination of JAK inhibition and interferon-gamma blockade interestingly showed synergistic response in a recent translational mouse study, whereas IL-1 and IL-6 inhibition did not, though validation in human studies is required. 21 Our findings indicate that anakinra usage in adults who experience secondary HLH is well tolerated and yields durable responses.…”

Section: Immune Dysregulation Associated With Hlh Results In Signific...mentioning

confidence: 54%

“…Aside from predominantly monotherapy studies, ruxolitinib has been assessed in combination with etoposide‐containing chemotherapy regimens 18,19 . The combination of JAK inhibition and interferon‐gamma blockade interestingly showed synergistic response in a recent translational mouse study, whereas IL‐1 and IL‐6 inhibition did not, though validation in human studies is required 21 …”

Section: Discussionmentioning

confidence: 99%

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

Lee,

Cao,

Vittayawacharin

et al. 2023

European J of Haematology

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Objective Hemophagocytic lymphohistiocytosis (HLH) is a rare life‐threatening, hyperinflammatory syndrome usually treated with high‐dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH‐94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide‐based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. Methods We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH‐94 protocol, HDS alone, or supportive care. Results Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH‐94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH‐94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH‐94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). Conclusion Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.

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“…Although most patients had HLH secondary to EBV infection, this study demonstrated that ruxolitinib can effectively control inflammation and enable patients to proceed to hematopoietic stem cell transplantation (HSCT). The concept of combining emapalumab and ruxolitinib to obtain even deeper inhibition of IFNg activity was recently reported to be effective in a mouse model [25]. Similarly, Triebwasser et al, described a patient with chronic active EBV-associated HLH who was refractory to HLH-2004 and anakinra, but responded to a combination of emapalumab and ruxolitinib therapy [26].…”

Section: Inhibition Of Cytokine Signalingmentioning

confidence: 99%

Recent advances in the treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome

Jesudas¹,

Nichols

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewThe approach to treating patients with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) has shifted in recent years with the aim to limit exposure to genotoxic agents, such as etoposide, yet dampen hyperinflammation by targeting the activity of specific HLH/MAS-associated cytokines. In this review, we discuss recent efforts to reduce the dose of etoposide and/or incorporate cytokine-targeted therapies for the treatment of HLH/MAS.Recent findingsThere is emerging evidence that reduced-dose etoposide and/or cytokine-targeted therapies, including agents that neutralize or inhibit signaling induced by interferon gamma, interleukin (IL)-1, IL-18, and IL-6, can effectively ameliorate the clinical and laboratory manifestations of HLH/MAS and improve overall outcomes.SummaryThe application of novel regimens containing lower doses of etoposide and/or cytokine-directed agents to treat HLH/MAS holds potential to dampen inflammation while minimizing therapy-associated toxicities. Nevertheless, further research is needed to better understand, which patients represent the most appropriate candidates to receive cytokine-targeted therapies, elucidate the optimal timing and dose of these therapies, and decipher whether they should be administered alone or in combination with conventional HLH-directed therapies, such as dexamethasone and standard-dose or reduced-dose etoposide.

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Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice

Cited by 17 publications

References 83 publications

Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis

Cellular and transcriptional impacts of Janus kinase and/or IFN-gamma inhibition in a mouse model of primary hemophagocytic lymphohistiocytosis

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

Recent advances in the treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome

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