The predictive value of the interleukin 2 receptor (IL2)/ferritin ratio in the diagnosis of lymphoma associated hemophagocytic lymphohistiocytosis (LAHS): A United States, multi center experience

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome that can occur de novo or due to the presence of an underlying malignancy. Prior studies have shown the IL2/ferritin ratio is a simple predictive tool in determining HLH associated with lymphoma. Two studies from Japan demonstrated a ratio >2 has 95.6% positive predictive value for an underlying lymphoma diagnosis. We aimed to validate the ratio as a diagnostic tool for lymphoma associated HLH across a heterogenous, Western population as well as investigate for other novel laboratory predictors of LAHS. Methods This was a multi-institutional retrospective chart review of patients with an ICD-10 code diagnosis of HLH from 2008-2024. Data obtained included patient demographics, lab values, presumed etiology of HLH and presence of macrophages in the bone marrow. HLH was diagnosed according to the HLH-2004 diagnostic guidelines. The diagnosis of malignant lymphoma was made according to the 2008 WHO classification as data was pulled from 2008-2024. We compared the laboratory findings of the non lymphoma-associated HLH (N-LAHS) group with those of the LAHS group. Patient characteristics were compared using Fisher's exact test, chi-square test, and Mann-Whitney test. Bivariate and multivariate logistic regression models with log transformed ratios were developed. Results In total, 126 cases of HLH were identified, with 82 classified as N-LAHS and 44 LAHS. The median age was 55 and 45% were female. Overall, 55.2% were White, 36.8% Black, 2.4% Asian and 5.6 % Hispanic. Black patients were more likely to have N-LAHS (p=0.021). Causes of N-LAHS were primary HLH (1), HLH due to a rheumatologic cause (14), Infectious etiologies (31) and 36 were classified as “other” which included unknown causes for HLH, other hematolymphoid causes for HLH and cellular therapy/immune checkpoint inhibitor associated HLH. Lymphoma subtypes included Aggressive B-cell lymphomas (15), Aggressive T-cell lymphomas (9), Indolent B-cell lymphomas (3) and Unspecified (17). Patients with LAHS had a median IL2 level of 25,620 (range 1,394 – 266,968) compared to N-LAHS of 8061 (859 – 85840) (p=<0.001). The median ferritin values were 11,704 (695 – 152,384) for LAHS and 15,000 (1,139 – 320,000) for N-LAHS (p=0.147). The IL2/ferritin ratio median for LAHS was 2.2 (0.1 – 36.4) and 0.4 (0.0 – 56.6) for N-LAHS (p=<0.001). The IL-2/(ALT/AST) ratio for LAHS was 10,255.9 (265.4 – 174,263.9) and 5,277.9 (319.0 – 133,760.8) for N-LAHS (p=<0.001). Bivariate logistic regression models for log transformed sIL2R/ferritin and sIL-2R/(ALT/AST) ratios were developed. The model revealed that 1-unit increase in the log(sIL2R/ferritin ratio) was associated with a 74% increase in the odds of having lymphoma (OR: 1.74, 95% CI: 1.33–2.29). Therefore, a doubling in the sIL2R/ferritin ratio increased the odds of lymphoma by 47%. When the predictor was categorized as > or < 2, the OR showed that patients with an IL2/ferritin ratio >2 had a nearly 7 times greater odds of having lymphoma compared to those with a ratio <2. Each 1-unit increase in the log(sIL-2R/(ALT/AST) ratio) was associated with a 90% increase in the odds of having lymphoma (OR: 1.90, 95% CI: 1.38–2.61). Therefore, a doubling in the sIL-2R/(ALT/AST) ratio increased the odds of lymphoma by 56%. Conclusions Our study validated the significance of IL2/ferritin ratio as a differentiator for the diagnosis of LAHS and N-LAHS within a Western population with different disease and population demographics. Our group utilized a logistic regression model to predict the outcome of lymphoma based on the value of the Il2/ferritin ratio, rather than the described distribution of the outcome across the >2 / <2 groups in our sample. This was done intentionally to predict the risk in an individual rather than a population. Taken together, these findings suggest that the IL2/ferritin ratio has sufficient diagnostic accuracy in predicting LAHS in a Western population. Validation of the IL2/ferritin ratio suggests integrating it into the diagnostic algorithm for LAHS. Notably, our findings also suggest that the IL2/ (ALT/AST) ratio is potentially a new biomarker that may assist in predicting LAHS.