Authors: Brenda S. Castillo, MD, Stephen Njau, MD, Sarah Monsell, Aaron Boothby, MD, Paul C. Hendrie, MD, PhD, Prakash Vishnu, MD, FACP.

Introduction Despite advances in diagnosis and treatment of hemophagocytic lymphohistiocytosis (HLH), the early mortality rate remains high with 20% of adults patients dying within 30 days. (Arca et al Br J Haematol 2015;168:63-68) Because the clinical presentation of HLH often overlaps with other inflammatory syndromes, prompt diagnosis and initiation of treatment remain a challenge. Diagnostic delays are common and may impact outcomes in over 20% of cases. (Brindt et al J Cancer Res Clin Onc 2020; 146(4):1065-1077) Our objective was to examine the characteristics of adult patients with HLH treated at our center to provide a foundation for future quality improvement initiatives.

Methods We conducted an IRB approved retrospective review of adult (age ≥18 years) patients who were diagnosed with HLH between January 2023 to December 2024. Epic's SlicerDicer tool plus manual chart reviews were used to obtain demographic information, HLH-2024 clinical and laboratory diagnostic criteria (included fever, splenomegaly, cytopenia, hypertriglyceridemia, hemophagocytosis, hyperferritinemia and elevated soluble CD25), underlying condition(s), HLH treatment(s), and clinical outcomes. Data collected was analyzed to determine time to diagnosis and treatment and the 30-day mortality rate from time of presentation at our institution.

Results We identified 43 unique patients with confirmed secondary HLH (sHLH) (no patients with familial HLH were identified). Median age was 50 years and 2/3 were male. Demographics included self-reported 54% white, 23% Asian, 17% Hispanic, 13% black, 3% native Hawaiian. The time-to-diagnosis was 20 days for 95% of patients while time-to-treatment was 5 days for 73% and 10 days for 17%. The presence of HLH criteria was as follows: fever 88%, splenomegaly 63%, cytopenia (>1) 93%, hypertriglyceridemia or hypofibrinogenemia 53%, hemophagocytosis in the bone marrow 84%, low or absent NK activity 84%, and ferritin >500 mcg/L (100%), Soluble CD25 (86%). The most common underlying condition was malignancy (72%), with lymphoid malignancies the most prevalent (78%) followed by myeloid (12.5%), and solid tumors 9%. Additional etiologies included infection (9%), unknown etiology (9%), autoimmune (7%), and both malignancy and infection (2%). 95% of patients were diagnosed in the first 20 days from presentation, and 83% of patients received treatment within the first 5 days.

Initial therapy was malignancy-specific chemotherapy (39%), HLH-94 protocol based therapy (30%), steroids alone (23%), and anakinra (2%) while others were not treated (6%). For malignancy-associated HLH, 37% of patients received HLH directed therapy (HLH-94 protocol guided), 30% received malignancy directed therapy, and 33% received other treatments such as steroids as first line. Overall, 46% of patients required several lines of treatment and were subsequently treated with several additional agents in the second line setting including malignancy directed therapy, ruxolitinib, alemtuzumab, eculizumab, IVIG, cyclosporine, tacrolimus and rituximab. For all patients, the 30-day mortality rate from time of presentation was 26%.

Conclusion In this retrospective cohort of adults with confirmed sHLH, most cases were driven by an underlying malignancy. Despite timely diagnosis and intervention, the condition remained associated with a high short-term mortality (26% at 30 days). Treatment strategies varied, although most patients received lymphoid malignancy directed therapy, reflecting the predominance of lymphoid malignancy associated sHLH in our cohort. These findings underscore the aggressive nature of sHLH in adults and the need to improve timely diagnosis and selection of effective treatments. Clinical trials focused on sHLH and especially in the setting of lymphoid malignancies are needed. To improve timely diagnosis and treatment decisions, we, like other centers, are implementing electronic medical record order sets for HLH diagnosis and management and organizing an HLH expert panel to provide timely case reviews and treatment recommendations.

In memory of our esteemed colleague and co-author Stephen Njau, MD

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2025
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