An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis

Adi Zoref-Lorenz*, Jun Murakami, Liron Hofstetter, Swaminathan Iyer, Ahmad S. Alotaibi, Shehab Fareed Mohamed, Peter G. Miller, Elad Guber, Shiri Weinstein, Joanne Yacobovich, Sarah Nikiforow, Benjamin L. Ebert, Adam Lane, Oren Pasvolsky, Pia Raanani, Arnon Nagler, Nancy Berliner, Naval Daver, Martin Ellis, Michael B. Jordan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004–defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.

Original languageEnglish
Pages (from-to)1098-1110
Number of pages13
Issue number7
StatePublished - 17 Feb 2022


FundersFunder number
National Institutes of Health
National Heart, Lung, and Blood InstituteR01HL082945
National Cancer InstituteK08CA263183, R21CA256390
American Society of Hematology
Edward E. Ford Foundation
Tel Aviv University


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