Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies

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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that is increasingly recognized in patients with malignancies (M-HLH). However, nearly early everything that is known about its pathophysiology and treatment is derived from clinical and scientific studies related to familial HLH (FHL). Though FHL and M-HLH have clear clinical similarities, it is not known whether they have similar pathophysiol- ogy. Indeed, even though M-HLH has been recognized for decades, we know nearly nothing about its patho- physiology. To remedy this gap, we have assembled an international group of collaborators and a unique set of patient-derived samples that will allow us to compare serum proteomic profiles and immune cellular pheno- types of patients with FHL, M-HLH, uncomplicated malignancies (U-M), and other inflammatory conditions in ways that are likely to yield broad new insights into HLH. Based on the clear clinical similarities between M- HLH and FHL, it is likely that some M-HLH patients will be quite similar to FHL, even though M-HLH patients are diverse enough to encompass multiple distinct mechanisms. Thus, we hypothesize that M-HLH is a com- posite syndrome, including: 1.) patients in which the malignant clone is essentially `mimicking' FHL; 2.) patients with T cell hyperactivation and `hyper-interferonemia' which is recognizably similar to FHL, and; 3.) patients with substantial innate immune dysregulation, which is dissimilar to FHL but not yet classifiable (see Figure 1). Furthermore, we hypothesize that FHL-like T cell hyperactivation represents a new paraneoplastic immune syndrome and may define patients who would benefit from targeted anti-IFN-g therapy developed for FHL, as well as anti-cancer immunotherapies, such as immune checkpoint inhibitors. Aim 1. Define the distinctive serum proteomic profiles of patient groups within M-HLH. We will employ a robust proteomic platform (SomaScan) to assess samples from patients with M-HLH, comparing to the groups listed above. We will develop classifiers to distinguish M-HLH from U-M and define M-HLH subgroups in an exploratory cohort and test the predictive value of these classifiers in a validation cohort. Aim 2. Define the incidence of `FHL-like' T cell activation profiles in M-HLH. We have recently identified a clear CD8+ T cell profile in FHL, which readily distinguishes HLH from another highly inflamed state, bacterial sepsis. We will utilize flow cytometry to analyze the peripheral blood T cell profiles of the patient groups above, focusing on those with proteomic profiles most similar to FHL. We will also compare T cell and monocyte gene expression profiles of these patient groups. These cellular studies will provide valuable cross-validation, com- plementing the proteomic characterization above 1