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1164 A Predictive Score Based on Cytokines, CD4/CD8 Ratio and Age Predicts Hematological Neoplasm-Associated Hemophagocytic Lymphohistiocytosis (H-HLH)

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Diseases, Immune Disorders, computational biology, Technology and Procedures, Serologic Tests
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Coralie Bloch, MD, PhD1,2*, Nanthara Sritharan3*, Jean-Philippe Jais, MD PhD4,5*, Marine Gil6*, Genevieve de Saint-Basile, MD PhD7,8* and Olivier Hermine, MD, PhD9,10

1Imagine Institut, Imagine Institut INSERM UMR1163, Paris, France
2Clinical Resaerch Unit, University Hospital Paris Seine Saint Denis, Paris, France
3Clinical Resaerch Unit University Hospital Paris Seine Saint Denis, Bobigny, France
4Biostsatistic Unit, Imagine Institut Inserm UMR 11 63, Paris, France
5University Hospital Necker Enfants Malades, PARIS, FRA
6Institut IMAGINE, Paris, FRA
7Imagine Institut UMR 1163, Paris, France
8Hôpital Necker-Enfants Malades, Paris, France
9Department of Hematology, Hospital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France
10INSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, France


Early diagnostic of Hematological neoplasm (H)-associated hemophagocytic lymphohistiocytosis (H-HLH) is a major goal in the management of adult (sporadic) HLH (HLHa) to allow appropriate and early intervention and reduce the risk of fatal outcome. At diagnosis, it is often difficult to distinguish H-HLH from other associated diseases autoimmune/inflammatory (MAS/AID), infectious like leishmaniosis or idiopathic forms. Here we have developed a predictive score for H-HLH that is based on clinical parameters and cytokines levels.


Serum levels of thirty cytokines were analysed by Elisa or by Luminex Technology, in 112 patients (age≥18 years old and “HScore”≥169) of the French HLH cohort data base (clinicaltrials.gov number NCT02113917). Multiple imputation chain equation was performed to account for the missingness in covariates. All following analyses were carried out based on the imputed datasets by combining estimates from each completed dataset using Rubin’s rules. A logistic regression was used to develop and validate the risk score predicting H-HLH. Model calibration and discrimination were assessed using the Hosmer-Lemeshow and receiver operating characteristic (ROC) curves, respectively. A 10-fold cross-validation was carried out to consider overfitting bias. Risk scores were derived using the model parameters and individual covariates values. A threshold on the risk score was determined to maximize the Youden index (sensitivity+specificity-1). H-HLH high-risk and low-risk patients were then delineated according to this score threshold, respectively, defining an high and low risk H-HLH group (score ≥ or < threshold).


The cohort (112 patients) included 45 H-HLH and 67 AID or idiopathic HLHa. Malignancies were distributed as Hodgkin Lymphoma (HL) (n=3), B cell-Non Hodgkin Lymphoma (NHL) (n=22, (EBV+, n=9)), and T cell-NHL (n=13 (EBV+, n=7)). The median [IQR] age of patients in the cohort was 48 years [36-61] old and 64 (57%) were men. From twenty-one potential predictors (including 9 HLH-related cytokines), eight were associated with H-HLH in univariate logistic regression: age > 48y (p<0.004), hemoglobin > 9g/l (p=0.03), platelets > 82G/l (p=0.03), Il-10 > 42 pg/mL (p=0.0003), TNF-α>43 pg/mL (p=0.0006), IL-18>574 pg/mL (p=0.0002), lymphocytes CD4/CD8 >1 (p=0.03), and five, independent in a multivariate analysis, were included in the risk score : age > 48y (OR [95%CI]: 3.0 [1.1 – 8.3], p=0.03), Il-10 > 42 pg/mL (OR [95%CI]: 4.5 [1.4-14.6], p=0.01), TNF-α>43 pg/mL (OR [95%CI]: 0.2 [0.07-0.57] ,p=0.003), IL-18>574 pg/mL (OR [95%CI]: 3.1[1.0-9.5], p=0.04) and lymphocytes CD4/CD8 >1 (OR [95%CI]: 0.3 [0.1-1.0], p=0.04). The score ranged from -28 and 37 with an attribution of points of 11 for age>48, 15 for Il-10 > 42, -16 for TNF-α > 43, 11 for Il-18 > 574 and -12 for CD4/CD8 > 1. The mean AUC in the cohort was 0.87 (95%CI, 0.79-0.92) and the AUC in the internal validation was 0.82 (95%CI, 0.61-1.00). The goodness-of-fit test showed a p-value of 0.30. The logistic model demonstrated that patients with a score ≥ 6 (sensitivity [95%CI]: 0.80 [0.65-0.90] and specificity [95%CI]: 0.75 [0.63-0.85] at the threshold of 6), the risk of having H-HLH increases by a factor of 12 compared to patients with a score < 6. (OR [95% CI] = 12 [4.7-29.7], p < 0.0001).


In this cohort, a risk score based on five parameters (age, IL10, TNF-a, IL-18, lymphocytes CD4/CD8) was developed that may help predict a patient’s risk to have H-HLH.

Disclosures: Hermine: AB Science, BMS/Celgene, Alexion, Novartis, and Inatherys: Research Funding; AB Science: Consultancy, Other: Shareholder.

*signifies non-member of ASH