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J.H. Yoon et al.
important for survival.4-6 However, even when specific therapies are administered promptly, treatment response and overall survival rates remain poor, especially when the condition is associated with malignancies.7,8 Poor survival and frequent relapse are common not only in patients with malignancy-associated HLH, but also in those with active Epstein-Barr virus (EBV) infection and in some high- risk patients with HLH of unknown cause.9-11 For relapsed or refractory HLH patients, several salvage treatments12-18 followed by allogeneic hematopoietic cell transplantation (HCT) are now considered,19-21 but many of these patients die of rapid deterioration due to severe sepsis and multi- organ failure. It is, therefore, important for physicians to identify high-risk patients earlier in the course of treat- ment, and to apply second-line therapy and prepare the patient immediately for allogeneic HCT. However, there are few data identifying relevant prognostic factors and enabling risk-stratification for adult patients with second- ary HLH.8,11
In this study, we initially analyzed treatment response and survival outcomes among 126 adult patients with non-malignancy-associated secondary HLH according to the underlying causes of the disease. We then assessed factors predictive of treatment response and survival out- come. Finally, we constructed a prognostic model using risk-stratification according to predictive factors in order to identify high-risk patients who should be considered for early second-line therapies, including salvage regimens and allogeneic HCT.
Methods
Patients
We retrospectively reviewed records for 165 adult patients who were diagnosed with HLH from 2001 to 2017. All patients pre-
sented with fever, some criteria of HLH2004,5,22 and increased his- tiocytosis with active hemophagocytosis in bone marrow. Of these 165 patients, we excluded 12 who did not satisfy the full diagnostic criteria and 27 with malignancy-associated HLH (Figure 1 and Online Supplementary Methods for Identification of the causes of HLH). Ultimately, we analyzed 126 patients (median age 45 years, range 15-85 years) with non-malignancy-associated second- ary HLH due to several causes. This research was conducted in accordance with Institutional Review Board and Ethics Committee guidelines of the Catholic Medical Center (KC15RISI0863) and the principles of the Declaration of Helsinki.
Parameters associated with hemophagocytic lymphohistiocytosis
All parameters included in the diagnostic guidelines for HLH were reviewed: fever, splenomegaly, cytopenia affecting at least two lineages, triglycerides, fibrinogen, ferritin, and natural killer (NK)-cell cytotoxic activity. Laboratory findings were serially accessed and the lowest levels were captured for complete blood cell counts, fibrinogen, albumin, and prothrombin time before treatment. The highest levels within 4 weeks after initial treat- ment were used for ferritin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, lactate dehydrogenase, and triglycerides in order to assess clinical outcomes. We have ana- lyzed NK-cell cytotoxicity by a flow cytometry-based assay since 2012.23 We did not check levels of soluble CD25. Thus, the major- ity of patients enrolled in the current study satisfied at least five out of six criteria for the diagnosis of HLH, excluding the soluble CD25 and NK cytotoxicity criteria. An association with EBV was evaluated by both serology and EBV DNA real-time quantitative polymerase chain reaction (RQ-PCR) analysis (See the Online Supplementary Methods for Identification of the causes of HLH).
Treatments
Treatment strategies were based on HLH-94 protocols, which consisted mainly of dexamethasone, etoposide, and additional
Figure 1. Consort diagram of enrolled patients. A total of 126 patients with secondary hemophagocytic lymphohistio- cytosis without malignancy were enrolled. HLH: hemophago- cytic lymphohistiocytosis; EBV: Epstein-Barr virus.
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haematologica | 2019; 104(2)