Enhancing Diagnostic and Prognostic Strategies in Secondary HLH: Insights from the Weill-Cornell Medicine Experience
Authors: Kaner Justin D. , Luan Danny , Castillo Tokumori Franco , Sidhom John-William , Fernandez-Rengifo Jose , Gerson Samantha , Whitcomb Matthew , Vallon Molly , Ritchie Ellen K. , Samuel Michael , Canaani Jonathan , Bar-Natan Michal , Mulvey Erin , Martin Peter , Desai Pinkal , Allan John N. , Furman Richard R. , Rutherford Sarah C. , Ruan Jia , Roboz Gail J. 
Published: December 2024

Intro: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening condition with diverse triggers. Outcomes for patients (pts) with sHLH are often poor due to delays in diagnosis and/or hesitation in initiating treatment (tx) without a definitive diagnosis. Current diagnostic metrics, including the H-score, HLH-04 criteria and OHI index, are underutilized and lack specificity. Additionally, key components of these scoring systems, and others-such as soluble IL-2 receptor (sIL-2R), NK cell activity, CXCL9, IL-18 and bone marrow biopsy-are not readily available and often result in treatment delays due to long turnaround times. There is an urgent need for improved awareness and identification of convenient surrogate markers to facilitate rapid intervention strategies for pts with suspected sHLH.

Methods: We conducted a single-center retrospective chart review of adult sHLH cases at NYPH/WCM 7/1/2019-7/1/2024. Confirmed sHLH was defined by meeting at least 5 HLH-04 diagnostic criteria, suspected sHLH was defined by 4 criteria combined with sIL-2R &gt;10,000u/mL and possible sHLH by meeting only 3 criteria with sIL-2R &gt;2,500u/mL. Data on pt demographics, laboratory and pathology assessments, tx regimens, and outcomes were analyzed using descriptive statistics and Cox proportional hazards models. Kaplan-Meier method were used to measure overall survival (OS).

Results: Of 42 pts reviewed, 32 pts (76%) met criteria for confirmed sHLH, 7 (17%) were suspected sHLH and 3 (7%) were as possible sHLH.In total, 38 pts (91%) had an underlying trigger:15 (36%) with non-Hodgkin's lymphoma (NHL), 6 (14%) adult-onset Still's disease, 6 (14%) infection, 6 (14%) acute myeloid leukemia (AML), other including Acute Lymphoblastic Leukemia and Hodgkins Lymphoma (n=5). In total, only 4 pts lacked a clear trigger. In all but one patient this was the initial diagnosis of sHLH. The most common treatments for sHLH included HLH-94-based therapies (n=13), malignancy-directed therapies (n=8), and chemotherapy (CTx) free combinations (with or without steroids), including anakinra, emapalumab or ruxolitinib (n=21).

Median follow up time was 5.3 months ([IQR], 1.3-15.1). Median OS was not reached, with 26 pts alive at time of analysis. Two year OS for all sHLH cases was 54.4%: 68.0% and 34.4% in non-malignant and malignant HLH pts respectively. We found a significantly improved 1 yr OS in pts with sIL-2R levels &lt;10,000u/mL compared to higher levels, &gt;10,000u/mL, (66.3% vs 37.0%,). There was no significant difference between high (&gt;169) and low (&lt;169) H-scores (1 yr OS 58.6% vs 40.0%). Emapalumab, 14 (33.3%), anakinra, 13 (31%) and ruxolitinib 4 (10%) were commonly used in our cohort, either alone or in combination with steroids or CTx. Despite this, there were no significant differences in OS between patients who received HLH-94 alone vs HLH-94 with emapalumab/anakinra/ruxolitinib vs CTx free regimens.

Using clinical observations from our cohort, we evaluated readily available laboratory values including ferritin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelet (PLT) counts at the time of presentation and found that high ferritin, low plt and discordant CRP and ESR values (high CRP and low ESR) were correlated with poor survival outcomes. We compared these findings with established metrics, including OHI index, H-score, sIL-2R:ferritin ratio, and sIL-2R threshold &gt;10,000u/mL, and found that they were effective in identifying patients who were critically ill, and those with poor outcomes. These variables correlated with sIL-2R levels &gt;10,000u/mL, which itself correlated with mOS (sIL2R &lt;10,000 mOS NR vs 3 months, p=0.013).

Conclusions: Despite advancements in understanding sHLH, there remains a critical need for effective diagnostic tools to identify pts at high risk for poor outcomes. We present a large single center experience of sHLH with favorable long term outcomes, high utilization of novel therapies and discovery of the poor discriminatory ability of known metrics like the H-score, in predicting long term outcomes. Our findings indicate that readily available laboratory values, correlate with sIL-2R levels, a marker that predicts long term OS. Clinical scores utilizing these variables will be presented at the time of meeting and we plan to expand our cohort to further assess its utility, which could ultimately facilitate timely initiation of appropriate tx.