Florid histiocytic hemophagocytosis following therapy with long acting G‐CSF (pegfilgrastim)

Glasser, Leslie; LeGolvan, Mark; Horwitz, Harold M.

doi:10.1002/ajh.20854

Cited by 23 publications

(6 citation statements)

References 14 publications

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“…There are 2 major possibilities as to how IFNγ regulates the expression of GM‐CSF: either GM‐CSF production by CD8+ T cells is a default state in the absence of IFNγ signaling, or other compensatory signaling pathways that promote GM‐CSF production are up‐regulated in the absence of IFNγ. Interestingly, there have been case reports of patients who, while receiving myeloablative chemotherapy, had been administered recombinant GM‐CSF or the related granulocyte colony‐stimulating factor and developed HLH , suggesting a possible causative role of myeloid‐specifying cytokines in the pathogenesis of some subsets of HLH patients.…”

Section: Discussionmentioning

confidence: 99%

Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis

Burn

Weaver

Rood

et al. 2019

Arthritis & Rheumatology

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Objective. Familial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon-γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ-blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH.Methods. IFNγ −/− Prf1 −/− mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell-intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin-33 (IL-33)/ST2 blockade were performed using monoclonal antibodies.Results. LCMV infection of IFNγ −/− Prf1 −/− mice resulted in severe HLH-like disease. CD8+ T cells and the IL-33/ ST2 axis remained essential mediators of disease; however, IFNγ-independent HLH immunopathology correlated with a 10-15-fold increase in neutrophilia (P < 0.001) and an altered cytokine milieu dominated by IL-6, IL-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM-CSF and neutrophil survival.Conclusion. IFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider caseby-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ-dependent and -independent manifestations of HLH/MAS.

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Section: Discussionmentioning

confidence: 99%

Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis

Burn

Weaver

Rood

et al. 2019

Arthritis & Rheumatology

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“…27 G-CSF is postulated to interact with G-CSF receptors on monocytes, providing continuous stimulation with pharmacological rather than lower physiological concentrations of growth factor. 28 A feedback Emerging evidence suggests a role for GM-CSF in HLH, based on admin istration of recombinant G-CSF in patients with this disorder. In clinical practice, there are concerns that administration of G-CSF might worsen HLH; indeed, the observation that administration of recombinant G-CSF (eg, lenograstim) exacerbated syno vitis supported the rationale to target the GM-CSF pathway in rheumatoid arthritis.…”

Section: Gm-csf and Neutrophils In Hyperinflammationmentioning

confidence: 99%

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities

Mehta

Porter

Manson

et al. 2020

The Lancet Respiratory Medicine

126

115

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The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

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“…The subsequent onset of florid HLH was temporally related to G‐CSF, raising the possibility that cytokine stimulation was an exacerbating event. Several case reports suggest that G‐CSF can trigger florid HLH in patients with haematological malignancies, but unlike the current study none of the reported cases were analysed for FHL‐related genes 17–20 . The mechanism by which this occurs is unknown; however, it is plausible that G‐CSF further stimulated activated macrophages through the G‐CSF receptor, leading to hyperactivation and hypersecretion and a self‐perpetuating cycle of inflammation which persisted in the absence of supraphysiological stimulus.…”

Section: Discussionmentioning

confidence: 67%

Dilemmas in the diagnosis and pathogenesis of atypical late‐onset familial haemophagocytic lymphohistiocytosis

2021

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Objectives. A congenital loss of cytotoxic lymphocyte activity leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis. Until recently, this disease was uniformly associated with infants or very young children, but it appears now that the onset may be delayed for decades. As a result, some adults are being mis-or under-diagnosed because of their 'atypical' symptoms that are not recognised as immunodeficiency. The clinical picture and histopathology can overlap with those of haematologic malignancy, further complicating the diagnostic thought process. The spectrum of atypical symptoms is poorly defined, and therefore, it is important to describe these cases and the attendant immunological and cellular changes associated with familial haemophagocytic lymphohistiocytosis, in order to improve diagnosis and prevent unintended consequences of symptomatic therapies. Methods. A 45-year-old patient presented with suspected T-cell lymphoma and was treated with combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone) supplemented with granulocyte-colony stimulating factor (G-CSF). To mobilise stem cells for autologous transplantation, the patient was then treated with high-dose G-CSF and rapidly developed haemophagocytic lymphohistiocytosis. Symptoms resolved temporarily with intensive immunosuppression with alemtuzumab and durably with a subsequent allograft. Results. The patient was found to be a carrier of bi-allelic mutations in the STXBP2 protein that is essential for cytotoxic lymphocyte function, and the initial diagnosis has been revised as familial haemophagocytic lymphohistiocytosis. Conclusion. This case highlights the difficulty in distinguishing atypical/late-onset familial haemophagocytic lymphohistiocytosis from a malignant process as well as a possible exacerbation of the disease with G-CSF therapy.

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Florid histiocytic hemophagocytosis following therapy with long acting G‐CSF (pegfilgrastim)

Cited by 23 publications

References 14 publications

Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis

Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities

Dilemmas in the diagnosis and pathogenesis of atypical late‐onset familial haemophagocytic lymphohistiocytosis

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