Adult Hemophagocytic Lymphohistiocytosis Patients Research Articles

Exploring the Clinical Spectrum and Hematological Patterns of Hemophagocytic Lymphohistiocytosis: A Comprehensive Study

Background: Hemophagocytic Lymphohistiocytosis (HLH) presents a challenging disorder characterized by complex manifestations resulting from dysregulated immune responses. This study aims to enhance our understanding of the clinical and hematological spectrum of HLH, focusing on adult patients. Methods: A retrospective-prospective observational study was conducted involving 64 adult HLH patients meeting HLH-2004 criteria. Comprehensive hematopathological assessments were performed, encompassing clinical parameters, hematological markers, and mortality rates. Data analysis utilized SPSS Version 20.0 for descriptive statistics. Results: The most frequent clinical manifestations were fever (100%), splenomegaly (87.5%), bicytopenia (73.4%), hypertriglyceridemia (60.9%), hyperferritenemia (48.4%), hypofibrinogenemia (32.8%), and pancytopenia (26.6%). We observed that leucopenia was present in majority of patients (62.5%), and leukocytosis was present in 17.2% patients. About 65.6% had mild to moderate thrombocytopenia, followed by 14.1% patients with severe thrombocytopenia, 14.1% had normal platelet count and 6.3% had thrombocytosis. Conclusion: The study revealed a diverse clinical spectrum within adult HLH patients, including universal fever, varied hematological irregularities, and mortality rates of 7.8%. These findings emphasize the complexity of HLH and the importance of early diagnosis and tailored interventions for improved outcomes. This study contributes valuable insights to the understanding of HLH's intricate clinical and hematological aspects, informing more informed diagnostic and therapeutic strategies for this complex disorder. Keywords: Hemophagocytic lymphohistiocytosis (HLH), Clinical characteristics, Laboratory tests, Prognosis

Clinical features and prognostic risk prediction of adult hemophagocytic lymphohistiocytosis: a 9-year retrospective study.

Hemophagocytic lymphohistiocytosis (HLH) has a low incidence and high mortality. In order to improve our understanding of the clinical features and prognostic risk factors of adult HLH, we analyzed the clinical characteristics and prognostic risk factors of adult HLH and developed a prognostic model to predict the overall survival (OS) of adult HLH. The clinical characteristics and survival statistics of adult patients with HLH identified at The Second Affiliated Hospital of Chongqing Medical University between February 2012 and October 2020 were retrospectively analyzed to constitute the primary cohort, while patients between 25 October 2020 and 20 March 2023 were collected at the same institution as a validation cohort for the prospective study. A total of 142 patients met the inclusion criteria, with 72 and 70 in the primary cohort and validation cohort respectively. In the primary cohort, the median OS was 102 days, with 37.5%, 34.5%, and 28.7% 1-, 2-, and 3-year OS, respectively. Univariate analysis showed that age, interleukin-10 (IL-10), interleukin-2 receptor (IL-2R), prothrombin time (PT), and indirect bilirubin (IBiL) were correlated with prognosis. Multivariate analysis showed that IL-10 and PT were independent factors affecting OS in adult patients with HLH. A prognostic model consisting of IL-2R, PT, and IL-10 and a corresponding prognostic nomogram were developed adopting the principle of minimum value of Akaike information criterion(AIC). The model has a high prediction accuracy letter (C-index = 0.708). The AUC values of 1-year, 2-year, and 3-year were 0.826, 0.865, and 0.882, correspondingly. In the validation cohort, all patients were divided into high-risk and low-risk groups, and the risk of death was significantly higher in the high-risk group than in the low-risk group (p < 0.01). The calibration curve for the model shows that the Nomogram constructed in this study is very reliable to predict the OS of HLH patients. IL-10 and PT have significant prognostic value in adult HLH. The prognostic model and the nomogram built in this study can forecast the OS of adult HLH patients.

Disparity Analysis of Clinical Features and Prognostic Evaluation of Hemophagocytic Lymphohistiocytosis in Pediatric and Adult Patients: A Retrospective Multicenter Study of 525 Cases in HHLWG

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder with rapid progression and high mortality. There have been few large cohort study comparisons of pediatric and adult HLH until now. This study was designed to explore the disparity of clinical presentations and evaluate the prognosis in pediatric and adult HLH patients. Methods: Totally, 525 newly diagnosed HLH patients were included and divided into 4 groups according to age: <6, 6–18, 18–60, and >60 years (geriatric patients). Mann-Whitney U test, Kruskal-Wallis test, χ² test, and Bonferroni’s adjustment were used to explore the difference between age groups. Overall survival (OS) was estimated by using Kaplan-Meier method. The Cox proportional hazard model was used to analyze the univariable and multivariable association between prognostic factors and OS. Results: Geriatric patients had the lowest levels of hemoglobin, platelet, albumin, and the highest level of creatinine, while patients <6 years of age had the lowest values of fibrinogen, IgA, IgM and highest values of triglyceride. The trigger of HLH in patients <18 years of age was mainly EBV infection. However, lymphoma and non-EBV-driven infection were the more frequent drivers in patients aged 18–60 and >60 years, respectively. Geriatric patients were associated with highest mortality (58.8%), and 5-year OS was 43%. By contrast, 5-year OS of patients <6, 6–18, and 18–60 years was 86.1%, 74%, and 58.9%, respectively. Additionally, among patients with different etiologies (EBV, non-EBV-driven infection, and uncertain causes) and treatment regimens (HLH-04, HLH-94, and glucocorticoid regimen), geriatric patients showed lowest 5-year OS. Multivariate analysis revealed that creatinine and alanine aminotransferase were independent risk factors affecting the survival of patients aged 0–6 years, while albumin and IgG were independent factors affecting survival of geriatric patients. Conclusion: Our study showed a wide heterogeneity of clinical presentations, etiology distribution, prognostic factors, and survival outcomes in pediatric and adult HLH patients.

Clinical characteristics and risk factors for 90-day overall survival among 204 adult patients with secondary hemophagocytic lymphohistiocytosis: Experience from a single-center retrospective study.

ObjectivesTo describe the clinical characteristics of secondary hemophagocytic lymphohistiocytosis (HLH) among adult patients, investigate its risk factors for 90-day overall survival (OS) from diagnosis, and establish a new prognostic model applicable to adult patients with secondary HLH.MethodsWe conducted a retrospective cohort study of 204 adult patients with secondary HLH, between January 2010 and December 2020. All patients met at least five HLH-2004 criteria. Clinical features, laboratory results, treatments, and clinical outcomes of the patients were reviewed. Prognostic factors associated with 90-day overall survival from diagnosis were screened using Cox proportional hazard models.ResultsThe most common trigger was malignancy (61.3%). Multivariate analysis showed that age, coagulopathy, levels of hemoglobin, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatinine, ferritin, and prothrombin time (PT) were independent prognostic factors for 90-day OS from the diagnosis of HLH. Based on the above risk factors, the patients were further divided into two groups: low-risk (≤4 risk factors) and high-risk (>4 risk factors), with overall 90-day survival rates of 82.7 and 28.1%, respectively (P < 0.001).ConclusionPatients with older age, coagulopathy, lower hemoglobin, and AST levels, elevated LDH, creatinine and ferritin levels, and prolonged PT tended to have a worse prognosis. Moreover, our prognostic model provides the possibility of forecasting the clinical outcome of adult secondary HLH patients, although a larger sample, multicenter, randomized controlled clinical study is needed to verify the accuracy of the prognostic model.

P1243: RUXOLITINIB COMBINED WITH DEXAMETHASONE IN ADULT PATIENTS WITH NEWLY DIAGNOSED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: INTERIM ANALYSIS OF A PROSPECTIVE, SINGLE-CENTER, SINGLE-ARM, PHASE 2 CLINICAL TRIAL

Background: Hemophagocytic lymphohistiocytosis (HLH) in adults is a major clinical challenge due to its rapid progress and high mortality. The current first-line therapy strategies such as HLH-94 or HLH-2004 regimens are largely extrapolated from paediatric HLH; however, the prognosis of adult HLH is worse than that of children. Ruxolitinib (an oral JAK inhibitor) has shown favorable efficacy and safety in murine models and clinical trials in adult HLH. Moreover, Lauren K. Meyer et al. demonstrate that ruxolitinib can reverse the resistance of CD8 positive T cells to dexamethasone in hypercytokinemia of HLH. We were very interested in these results and preliminarily revealed the high response rate and good short-term survival of ruxolitinib combined with dexamethasone (Ru-D) in a pilot study involving 8 adult HLH patients. On these bases, we conducted this prospective, single-center, single-arm, Phase 2 clinical study. Aims: This phase 2 clinical trial (ChiCTR2100049996) aims to evaluate the efficacy and safety of Ru-D regimen as first-line therapy in adults with newly diagnosed HLH. Methods: This is an interim analysis of an ongoing phase 2 clinical trial of a planned 28 newly diagnosed adult HLH patients. Inclusion criteria were patients who met HLH-2004 diagnostic criteria, older than 18 years old, and had not received HLH first-line therapy. Patients in this study received an 8-week period of treatment. The Ru-D regimen consists of ruxolitinib (15 mg twice daily for 8 weeks) and dexamethasone (initially 10 mg/m2 for 2 weeks followed by 5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks, 1.25 mg/m2 for one week, and one week of tapering). The primary endpoint is the 2-month overall survival rate (OS), and the secondary endpoints are overall response rate (ORR), progression-free survival (PFS), safety and changes in biomarkers. Results: From August 15, 2021 to January 15, 2022, there were 15 patients enrolled in this study with a median follow-up of 78 (31-171) days. The 15 patients included 8 cases of lymphoma-associated HLH (LAHS), five case of Epstein-Barr virus-associated HLH (EBV-HLH), and 2 cases of unknown etiology. It should be mentioned that 4 of 15 patients carried heterozygous HLH-related gene mutations. Patients were followed up until February 15, 2022 or until death, with none lost to follow-up. The primary endpoint, 2-month OS, was 83.3% in 12 evaluable patients, both patients died due to lymphoma progression. The overall mortality rate was 26.7% (4/15), 75% (3/4) deaths occurred in LAHS patients and there was no death directly related to HLH until data cutoff. The ORR to Ru-D regime was 86.7% (13/15), with 13.3% (2/15) in complete response (CR), 73.3% (11/15) in partial response (PR), and 13.3% (2/15) in no response (NR). The treatment was well tolerated, with no toxicities leading to dose reduction or discontinuation of treatment. All LAHS patients were successfully bridged to chemotherapy after Ru-D therapy. Table 1 shows the response outcomes in detail. Image:Summary/Conclusion: In our study, the Ru-D regimen initially demonstrated favorable efficacy in newly diagnosed adult patients with HLH. For patients with LAHS, it is an efficient and safe bridging therapy while waiting for pathological diagnosis. Therefore, Ru-D represents a novel and promising therapeutic option for HLH patients that may provide clinical benefit.

Increased levels of serum interleukin-10 are associated with poor outcome in adult hemophagocytic lymphohistiocytosis patients

BackgroundInterleukin-10 (IL-10) is an independent factor for predicting adverse outcomes in pediatric patients with hemophagocytic lymphohistiocytosis (HLH). However, little is known about its prognostic value in adult patients.MethodsThis single center retrospective study was conducted to explore the prognostic value of IL-10 in 101 adults newly diagnosed with HLH. The serum interleukin levels were quantitatively determined by chemiluminescence using cytokine profiling kits.ResultsSerum IL-10 levels were significantly increased in adult HLH patients. Elevated IL-10 levels was correlated with lower concentrations of hemoglobin (r = − 0.279, P = 0.005). IL-10 levels were significantly lower in patients with macrophage activation syndrome (MAS) than in those with infection-associated HLH (IAHS) and malignancy-associated HLH (MAHS) (P = 0.033, P = 0.012). Patients with MAS had relatively longer survival than those with IAHS and MAHS (P < 0.001). Univariate analysis indicated that hemoglobin < 8.2 g/dL, platelets < 40 × 109/L, lactate dehydrogenase ≥ 700 IU/L, albumin < 28 g/L, post-treatment ferritin > 1050 µg/L and IL-10 ≥ 129 pg/mL were poor prognostic factors for survival. However, multivariate analysis revealed that only high serum IL-10 levels (≥ 129 pg/mL) at diagnosis and high post-treatment ferritin levels (> 1050 µg/L) were independent risk factors for poor overall survival in adult HLH patients (HR: 4.087, 95% CI 2.064–8.090, P < 0.001; HR 3.814, 95% CI 2.042–7.126, P < 0.001, respectively).ConclusionsOur results suggest that higher serum IL-10 levels might be a prognostic marker in adult HLH patients.

The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank p = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, p = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.

Increasing ferritin predicts early death in adult hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation. Most studies on adult HLH have evaluated prognostic factors for overall survival; factors predicting early mortality have not been sufficiently investigated. This was a collaborative study between Henry Ford Hospital and Barnes-Jewish Hospital. We identified all adult HLH patients with at least 2 ferritin levels within 30days from admission. One-hundred twenty-four patients were identified. There were 77 males and 47 females; the median age at diagnosis was 48years. Multivariate analysis showed that age (OR=11.41; 95% CI:2.71-48.04; P=.001), hepatomegaly (OR=15.68; 95% CI:3.24-75.96; P=.001), hyponatremia (OR=5.94; 95% CI:1.76-20.1; P=.004), hypoalbuminemia (OR=7.47; 95% CI:2.08-26.85; P=.002), and increasing ferritin levels (OR=19.46; 95% CI:4.69-80.71; P<.001) were significant predictors of 30-day mortality. Patients with declining ferritin by more than 35% from the ferritin peak were more likely to survive the first 30days of admission (OR=4.33; 95% CI:1.04-18.1; P=.033). By risk stratifying our cohort, we identified changes in ferritin levels to be the most significant prognostic factor of 30-day mortality among other risk factors. Further investigating the prognostic utility of ferritin showed that increasing ferritin during the 1st week of admission (data available for 44 patients) was the only significant predictor of 30-day mortality. To the best of our knowledge, this is the first study reporting changes in ferritin to be a predictor for early death in adult HLH. Changes in ferritin might be a useful indicator of adult HLH disease activity and early prognosis.

Hemophagocytic Lymphohistiocytosis for the Internist and Other Primary Care Providers

Hemophagocytic lymphohistiocytosis (HLH) syndrome is a hyperinflammatory state that leads to life-threatening, disproportionate activation of the immune system and may be confused for and concomitantly exist with sepsis. However, its treatment differs from sepsis, requiring early initiation of immunosuppressive treatment. While HLH syndrome is more commonly diagnosed in children, internists and other primary care providers must be familiar with the diagnosis and treatment of adult patients with HLH in the hospital and outpatient setting. In this article, we review the essentials that an internist and other primary care providers managing adult HLH patients should know.

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Ferritin index is a strong prognostic marker in adult hemophagocytic lymphohistiocytosis.

The relationship between ferritin levels and survival in adult hemophagocytic lymphohistiocytosis (HLH) has been evaluated in previous studies. However, Admission-to-discharge percentage ferritin reduction (named as ferritin index) level in adult patients with HLH has never been evaluated to predict 6-month survival. The demographic, laboratory and clinical information of 102 newly diagnosed adult HLH patients were collected. Regression analysis, receiver operating curve and Kaplan-Meier curves were analysed to explore the performance of ferritin levels. Ferritin index and discharge ferritin level were significantly different between survivour and non-survivour group (all P<.001). Ferritin index had the highest area under the curve (AUC) for predicting the survival (AUC=0.802, P<.001) followed by discharge ferritin (AUC=0.746, P<.001). Kaplan-Meier analysis showed a significant difference in survival according to optimum cutoff values of ferritin index≥10.19% (P<.001) or discharge ferritin≤1056.1μg/L (P<.001). Multivariate analysis confirmed that ferritin index and discharge ferritin are independent predictors of 6-month survival (ferritin index: odds ratio (HR) 6.237, 95% confidence interval (CI) 2.075-18.774, P=.001; discharge ferritin: HR 6.024, 95% CI 1.894-19.231, P=.002). In addition, the combination of a ferritin index≥10.19% and discharge ferritin≤1056.1μg/L had a significantly higher 6-month survival (P<.001). Ferritin index is a better predictor of 6-month survival than admission and discharges ferritin levels in adult patients with HLH.

Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment. For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charité - Universitätsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis. Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (P = 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 μg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771-1.000; sensitivity 93.8%, specificity 78.9%). Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring. The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

2212 Hemophagocytic Lymphohistiocytosis Disguised as Acute Liver Injury

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder with unregulated immune activation and inflammation. Primary HLH occurs in infants or young children with or without family history whereas secondary HLH manifests in older children or adults without a family history or gene mutation. Concurrent infection, malignancy or rheumatological disorder usually trigger an uncontrolled immune response in the older age group. Our aim is to raise is awareness among physicians to recognize the early signs and symptoms of this life-threatening condition. CASE DESCRIPTION/METHODS: A 33-year-old female with a history of multiple sclerosis and rheumatoid arthritis presents with elevated LFTs, cholestatic jaundice and intermittent high-grade fever. Imaging studies showed no significant abnormality in the hepatobiliary system. Viral and autoimmune serologies were negative. Lab works revealed low fibrinogen and elevated ferritin and IL-2 receptor levels. Bone marrow biopsy was unremarkable; however, liver biopsy showed features suggestive of HLH. Steroid and etoposide therapy was started but treatment was complicated by pancytopenia and hemodynamic instability despite multiple transfusions and filgrastim administration. With worsening clinical pictures, emapalumab (Interferon gamma blocker) was started. However, the patient developed multiorgan failure with overwhelming sepsis and died within days of emapalumab administration. DISCUSSION: HLH has a wide spectrum of clinical manifestation often masquerading as sepsis or SIRS. Some studies have found that cholestasis and high AST levels are associated with poor outcomes in adult HLH patients. The goal of therapy is to suppress hyper inflammation with agents such as corticosteroids, calcineurin inhibitors, and immunoglobulins. When a patient presents with prolonged fever and liver dysfunction of unknown etiology, HLH should be considered in the differential diagnosis as early recognition and treatment can prevent mortality, which can be high up to 75 % in the adult age group.

Transfusion requirements and 30-day mortality predictors for adult hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an uncontrolled hyper-inflammatory response. We assessed the transfusion requirements and predictors of 30-day mortality for adult HLH patients. We identified all adult patients with a diagnosis of HLH at a large academic hospital from October 2003 through February 2017. We extracted patients' clinical and laboratory data, including transfusion requirements, from their medical records. One-hundred sixteen patients were identified. Their median age was 48years (range 18-82); 72(62%) were male. Median duration of hospital stay was 19days (range 1-89days). At 30days from admission, 81(70%) patients were alive. Death was attributed to sepsis in 21 patients, lymphoma in six, bleeding in four, GVHD in one, liver failure in one, metastatic solid tumor in one, and unknown in one. Transfusion requirements at 30days from admission were as follows: RBC, 86% of patients, median 6 units (range 1-58); platelets, 74% of patients, median 6 units (1-67); plasma, 40% of patients, median 4 units (1-56). Renal failure (OR = 4.39; P = 0.008) and hypofibrinogenemia (OR = 4.07; P = 0.009) correlated with 30-day mortality. The transfusion requirements for adult HLH patients were high. Our study indicated that renal insufficiency and hypofibrinogenemia are predictors of early death in adult HLH.

Hemophagocytic Lymphohistiocytosis in Adults (aHLH): Results from the German HLH Registry

Introduction:Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by excessive immune activation leading to a life-threatening pro-inflammatory cytokine storm. HLH is not an entity of its own, but a clinical syndrome triggered by various conditions like infections, malignancy or autoimmune disorders. HLH pathogenesis is complex and still not fully understood. Contributing factors include immunosuppression (chemotherapy, long-term immunosuppressive therapy), cytokine release from tumor cells, imbalance between infected and immune effector cells as well as genetic predisposition. Despite improved HLH-specific therapy (adapted components from the pediatric HLH-1994 protocol), prognosis is still poor among adult HLH patients. Due to the lack of data on adult HLH in Germany, a national multicenter registry (http://www.hlh-registry.org/) was initiated.Methods:Patients (pts) with proven or suspected HLH were registered by 35 institutions across Germany from August 2010 to July 2016. Both HLH-2004 diagnostic criteria and the HScore (www.saintantoine.aphp.fr/score/) were used to confirm HLH diagnosis. To characterize adult HLH patients, data referring to underlying disease, treatment, outcome, clinical manifestations and laboratory findings were recorded. Where available, patient samples were tested for mutations of the perforin gene PRF1 by standard Sanger sequencing.Results:A total of 125 pts (48 female) were enrolled in our registry, of whom 105 pts either fulfilled diagnostic criteria according to HLH-2004 diagnostic guidelines (n=96) or met at least 4 out of 8 criteria and reached HLH-probability of over 90 % in the HScore (n=9). Among these 105 pts, n=38 (36 %) were female and n=67 (64 %) male. Median age at diagnosis was 49 years (range 17 - 81). Trigger diseases were in line with the literature, with infections (n=34) and malignancy (n=40) being most frequent (Table 1). Patients show a wide spectrum of underlying conditions, i.e. allogeneic stem cell transplantation (alloSCT) or HLH-mimicking diseases due to cytokine release in response to blinatumomab therapy. Late onset hereditary HLH was found in 3 pts (XLP-1 and -2 respectively in EBV-coinfected pts, one pt with perforin mutation - see below). 22 of 105 patients (21 %) were tested for PRF1 mutations. A compound heterozygous PRF1 A91V/Q405X mutation was identified in one pt presenting with NK/T-cell lymphoma. Heterozygous PRF1 A91V mutations were found in 2 pts with B-cell lymphoma and HLH following alloSCT respectively, in one case with available buccal swab DNA to prove germline origin of the mutation. Table 2 summarizes clinical and laboratory findings in the cohort. A median ferritin value of 32,000 µg/L underlines the importance to evaluate pts with highly elevated ferritin with respect to potential HLH diagnosis. Apart from fever and splenomegaly, clinical presentation frequently comprised hepatomegaly, liver failure, hyperbilirubinemia, renal failure, lung involvement like ARDS, or bleeding. Treatment included steroids in the vast majority of pts (n=89), often combined with i.v. immunoglobulins (n=47) and etoposide (n=49). After a median follow up time of 164 days, 48/97 pts (49.5 %) were alive, 8 pts were lost to follow up. Survival analysis revealed median overall survival of 454 days (Figure 1a). Comparing malignancy-associated HLH and HLH after alloSCT with infection- and autoimmune-associated HLH or HLH due to unknown triggers, survival was significantly poorer in the malignancy/alloSCT group (Figure 1b).Conclusions:HLH trigger conditions in adult patients in Germany are in accordance with published case series. Outcome in adult HLH is still poor, with malignancy-associated and HLH after alloSCT showing the worst prognosis. Diagnostic vigilance and early treatment is a prerequisite for improving outcome of adult HLH. In particular, high ferritin values should raise suspicion of HLH. [Display omitted] [Display omitted] [Display omitted] DisclosuresHochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

Hemophagocytic lymphohistiocytosis : A diagnostic challenge on the ICU

Hemophagocytic lymphohistiocytosis (HLH) has well been studied as agenetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T‑cells and natural killer cells with excessive inflammation based on acytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and asepsis-like disease. Missed or late diagnosis is believed to be amajor cause of the high mortality. To describe the current knowledge on HLH and to raise awareness. Analysis of case reports, current studies, and expert recommendations. Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with aclinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. Apromising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.

Hemophagocytic Lymphohistiocytosis (HLH) in 44 Adults: Results from the Retrospective Polish Registry

▪IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of extreme hyperinflammation. It does not self-limit and needs to be stopped by effective treatment. This reaction can be triggered by numerous factors, including infection, malignancy and autoimmune disease. HLH used to be diagnosed in children, but in last few years more and more adults with this syndrome are treated. This raising awareness enabled creating retrospective registry of adult HLH patients in Poland.MethodsA multicenter retrospective analysis of adult (≥18 years) patients was performed. Inclusion criteria were based on the HLH-2004 protocol.ResultsForty four adult (median age 34, range 18-80) patients from 13 clinical centers were reported. The gender ratio was balanced (M/F: 23/21). Patients fulfilled on the average 5.2 of HLH-2004 criteria. Due to the lack of possibility of sCD25 and NK activity testing in majority of centers only 6 criteria were actually evaluated. Also 6 patients with strong clinical suspicion (e.g. recurrent HLH) fulfilling 4 out of 6 available criteria were included. The most frequent triggering factor was malignancy (14/44) with lymphoma (T-cell 6/14, B-cell 4/14) being the most common. Infection-associated HLH was present in 13 patients, most of which was attributed to EBV (11/13; additionally CMV and B19 occurred). One patient suffered from both T-lymphoma and EBV infection. The most frequent autoimmune diseases identified were Still's disease (n=3) and systemic lupus erythematosus (n=2). In 11 patients clear triggering factor could not be identified. Three patients underwent liver transplantation.Baseline characteristics of all patients are shown in Table 1. Briefly, almost all patients presented with extreme hyperferritinemia, fever, splenomegaly. Other Important features are liver involvement and coagulopathy.Majority of patients were treated according to HLH-2004 protocol, except of patients with malignancy treated with disease-specific chemotherapy regimens (with emphasis on inclusion of etoposide if appropriate). None of the patients underwent stem cell transplantation (SCT) as HLH therapy; one patient had HLH triggered by EBV reactivation after alloSCT.Median survival was 66 days (Fig.1), 39% of patients survived with median observation of 21 months (3-98).ConclusionsHeterogeneity of HLH syndrome was confirmed in Polish population, with malignancy and EBV infection being the most frequent triggering factors.Awareness of HLH in adults is raising, but it should be fostered as HLH is still underdiagnosed. Further studies are needed to deepen our knowledge about HLH in adults.Analysis of additional, newly diagnosed cases is ongoing and will be presented at the meeting.Table 1Baseline patient characteristicsCharacteristic[unit](n)%MedianRangeFever(n=44)97.7Splenomegaly(n=44)90.9Hemophagocytosis(n=41)70.7Hyperferitinemia[µg/l](n=44)10014280846-126680Hemoglobin[g/dl](n=44)8.36.1-13.9Neutrophil count[G/l](n=41)1.10-173Platelet count[G/l](n=44)434-349Triglycerides[mg/dl](n=38)31674-1559Fibrinogen[mg/dl](n=43)16630-901PT[s](n=30)15.99-46.6APTT[s](n=39)3622-86.8CRP[mg/l](n=40)40.10.4-373LDH[U/l](n=39)970195-13160AST[U/l](n=39)15016-16280ALT[U/l](n=40)10018-12390Total Bilirubin[mg/dl](n=37)3.70.34-25.6PT indicates Prothrombin Time; APTT, Activated Partial Thromboplastin Time; CRP, C-Reactive Protein; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase [Display omitted] DisclosuresKnopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Wiktor-Jedrzejczak:Amgen, Inc.: Research Funding; Onconova: Other: Advisory Board; Novartis: Research Funding; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board, Research Funding; Jansen: Other: Advisory Board; Celgene: Other: Advisory Board.

Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study.

Hemophagocytic lymphohistiocytosis (HLH) is a critical condition that may lead to organ failure and early death. The aim of this retrospective observational study was to describe a cohort of HLH patients admitted to intensive care unit (ICU) and investigate the risk factors of early death.A positive HLH diagnosis was defined by an HScore ≥169. Univariate and multivariate analyses were carried out to investigate hospital and 28-day mortality risk factors. Between January 2002 and July 2014, 71 HLH cases were seen at our institution.The overall 28-day mortality (start at ICU admission) and hospital mortality were 38% and 68%, respectively. The factors associated with increased 28-day mortality were the sequential organ failure assessment score at ICU admission (P < .001) and advance in age (P = 0.03). The factors associated with increased hospital mortality were a high sequential organ failure assessment score at ICU admission (P < 0.01), advance in age (P = 0.04), and the presence of lymphoma-related HLH or HLH of unknown origin (P < 0.01).Organ failure overtops the classical early-death risk factors in adult ICU-admitted HLH patients. This failure and the subsequent early death may be prevented by timely specific cytotoxic therapies and the control of the underlying disease.

Hemophagocytic Lymphohistiocytosis

To investigate the clinical features of adult patients with hemophagocytic lymphohistiocytosis (HLH) and to explore possible risk factors for death, we retrospectively reviewed the medical records of 103 adult HLH patients hospitalized from 1997 to 2012. We analyzed the underlying diseases, clinical characteristics, 1aboratory findings, outcomes, and prognostic factors. The most common cause of HLH was hematologic malignancies (n = 49), followed by infectious diseases (n = 24) and autoimmune disorders (n = 14); 24 cases were of unknown etiology. Eight patients had a combination of underlying diseases. HLH was clinically characterized by high fever (96.1%), splenomegaly (79.6%), hepatomegaly (65.0%), lymphadenopathy (53.4%), proteinuria (31.1%), skin rash (25.2%), gastrointestinal hemorrhage (14.6%), disseminated intravascular coagulation (13.6%), increased creatinine (7.8%), and central nervous system involvement (12.6%) including altered mental status (9.7%) and cranial hemorrhage (2.9%). Laboratory abnormalities included cytopenia (99.0%), serum ferritin >500 ug/L (98.4%), liver dysfunction (98.1%), hypertriglyceridemia (88.5%), hemophagocytosis in bone marrow smear (87.4%), and hypofibrinogenemia (60.9%).In addition to the treatment they received for the underlying causes, patients received therapy for HLH consisting of corticosteroids, immunosuppressive drugs, and intravenous immunoglobulin. Twenty-six patients (25.2%) recovered after treatment, and 19 of them achieved long-term remission during follow-up. Seventy-seven patients (74.8%) died because of tumor, sepsis, multiple organ failure, or HLH-related organ hemorrhage and coagulopathy. The deceased patients were more likely to be older at disease onset, male, and to present with splenomegaly and thrombocytopenia, compared to the survivors. Treatment for the underlying diseases combined with corticosteroids, immunosuppressive agents, and immunoglobulin therapy may improve the prognosis of HLH. More attention should be paid to high-risk patients to prevent the development of serious complications associated with HLH.

Primary Splenic Lymphoma Associated with Hemophagocytic Lymphohistiocytosis Complicated with Splenic Rupture

Primary splenic lymphoma (PSL) is a rare disease with ambiguous definition, comprising less than 1% of non-Hodgkin's lymphoma. Even rarer is PSL combined with hemophagocytic lymphohistiocytosis (HLH), which has presentations of fever, cytopenia, hepatosplenomegaly, hyperferritinemia, and phagocytosis of hematopoietic cells in the reticuloendothelial system. We report the case of a 77-year-old man who presented with HLH initially. Refusing diagnostic splenectomy, he received chemotherapy. Spontaneous splenic rupture occurred after chemotherapy. In the following emergency operation, PSL was diagnosed. He received another 5 courses of chemotherapy with the R-CNOP regimen (rituximab, cyclophosphamide, mitoxantrone, vincristine, prednisolone). Now he has no residual or relapsed disease. Diagnostic splenectomy for adult HLH patients without definite etiologies may play an important role.