# Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $185,831

## Abstract

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

## Key facts

- **NIH application ID:** 10112637
- **Project number:** 1R21CA256390-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Michael Jordan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $185,831
- **Award type:** 1
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112637

## Citation

> US National Institutes of Health, RePORTER application 10112637, Redefining hemophagocytic lymphohistiocytosis in hematologic malignancies (1R21CA256390-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112637. Licensed CC0.

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