Malignancy-associated Hemophagocytic Lymphohistiocytosis Research Articles

Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

A Retrospective Review of Secondary Hemophagocytic Lymphohistiocytosis (HLH) and Dengue-associated HLH from a Teaching Hospital in Singapore.

Real-world data on the outcome of Asian patients with secondary hemophagocytic lymphohistiocytosis (HLH), especially on dengue-associated HLH, are limited to small case series. This is a retrospective records review of adult patients with secondary HLH between 2015 and 2020. Thirty-two adult patients were followed up for a median of 6.6 months (range 0.1 – 75 months). 15 had underlying lymphomas, and 12 had viral infections. Hemophagocytosis was seen in 28 of 29 patients with a bone marrow biopsy. 100% and 76.5% of patients with and without an underlying malignancy required HLH-directed therapy and blood product transfusion. 12 of 15 patients with lymphomas were treated with additional chemotherapy. Patients with malignancy-associated HLH had poorer survival than non-malignancy-associated HLH (median overall survival (OS) 1.5 months versus not reached, p-value 0.003). The 1-year survival rates of patients with malignancy-associated HLH, HLH with unknown etiologies, and infection-associated HLH were 0.133 (95% CI: 0.036 – 0.484), 0.400 (95% CI: 0.137 – 1.000) and 0.833 (95% CI: 0.647 – 1.000), respectively. Malignancy significantly increased the risk of death compared to infection-associated HLH (HR 9.37, p-value 0.003). Eight patients were diagnosed with dengue-associated HLH with a median HSCORE of 240 (98-99% probability of HLH). Their mean ferritin was 34,740 ng/mL. Three patients required blood product transfusion, 5 required corticosteroids and/or etoposide, with a median duration of treatment of 31 days. Their overall survival rate was 87.5%. Our study highlights the stark contrast in the survival of secondary HLH patients with and without an underlying malignancy. We also present one of the world’s most extensive case series of dengue-associated HLH.

Differing Inflammatory Profiles and Survival Outcomes of Cytokine Storm Arising from CAR T-Cell Therapy, COVID and Malignancy-Associated HLH in Patients with Hematological Malignancies

Background: Cytokine storm is a complex syndrome driven by hyperinflammation leading to multi-organ dysfunction and high mortality rates. Patients with hematological malignancies are susceptible to different types of cytokine storm syndromes (CSS) including those driven by their disease (e.g., malignancy-associated hemophagocytic lymphohistiocytosis (MA-HLH)), treatment toxicities (e.g., cytokine release syndrome (CRS) related to CAR-T) or infections (e.g., COVID associated cytokine storm). The precise nature of the inflammatory mechanisms of different CSS and their impact on clinical outcomes are poorly understood. Methods: We conducted a retrospective study to compare the inflammatory marker profiles and survival outcomes of three CSS: CAR-T CRS, MA-HLH and COVID-CS. The cloud-based Foundry platform was used to aggregate and integrate data from patients with hematological malignancies admitted at the MD Anderson Cancer Center between March 2020 and November 2022. Patients in the CAR-T CRS and MA-HLH cohorts met ASTCT Consensus Grading criteria and HLH-2004 criteria respectively. While there are no well-established diagnostic guidelines for COVID-CS, patients in the COVID-CS cohort had laboratory values higher than the upper limit of normal for at least two of C-reactive protein (CRP), Interleukin 6 (IL-6) or Ferritin within 28 days of COVID diagnosis (Table 1). Biomarker datasets were analyzed through regression models and feature selection to determine inflammation patterns across the three cohorts. Survival outcomes were compared across the cohorts and tested for association with biomarkers to determine their prognostic relevance (Figure 1). Results: A total of 671 in-patients met inclusion criteria across the three patient cohorts: CAR-T CRS (220), MA-HLH (224) and COVID-CS (227). The proportions of different disease types differed among the cohorts (Table 1) with aggressive B-cell lymphomas representing the largest group in the CAR-T CRS cohort (62%) whereas leukemia was the most frequent diagnosis in the COVID-CS (45%) and MA-HLH (38%) cohorts. While fever and fatigue were common presenting symptoms of all 3 CSS, the frequencies of more severe symptoms such as hypotension and capillary leak syndrome were increased in patients with MA-HLH. The median length of hospitalization differed significantly (p < 0.001) across the cohorts: MA-HLH (24 days), CAR-T CRS (15 days) and COVID-CS (6 days). The MA-HLH cohort had the highest proportion of patients requiring ICU admissions and the highest levels of inflammatory markers such as D-dimer, ferritin, IL-6, IL-2 soluble receptor and TNF-alpha and the lowest levels of fibrinogen and albumin. Clustering analysis of laboratory values revealed substantial overlap in patterns between the COVID-CS and CAR-T CRS cohorts, but the MA-HLH cohort was a more distinct cluster. Patients with CAR-T CRS had significantly longer survival (p < 0.0001) than either COVID-CS (hazard ratio 3.7) or MA-HLH (hazard ratio 8.1); MA-HLH patients had the shortest overall survival (Figure 1). These differences were robust after adjusting for differences in baseline demographics. Univariate regression modelling revealed many of the laboratory values to be significantly associated with survival; multivariable analysis found ferritin, LDH and platelet count to be the most significant predictors. Administration of tocilizumab did not improve survival in COVID-CS or MA-HLH. Conclusions: In this retrospective, single-institution study of 3 different types of CSS, we observed that patients with hematological malignancies exhibit different symptom patterns at clinical presentation, have differing inflammatory biomarker profiles and experience variable clinical outcomes depending on the underlying etiology of the CSS. Patients with CAR-T CRS had significantly better survival outcomes compared to those with COVID-CS and with MA-HLH; the latter group had the worst outcomes among the 3 cohorts. This study provides insights into the hyperinflammatory profiles of different CSS in patients with hematological malignancies and highlights the need for developing effective treatments to improve patient outcomes.

Myelodysplastic Syndrome Associated Hemophagocytic Lymphohistiocytosis: A Retrospective Study of 15 Cases in a Single Center

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by excessive cytokine secretion, resulting in hyperinflammation and multiorgan dysfunction. It is classified into primary HLH, which is mainly caused by genetic defects, and secondary HLH, triggered by various underlying conditions. Malignancy-associated HLH (M-HLH) is a secondary form commonly observed in patients with hematological malignancies, such as lymphomas, T/NK-cell disorders, acute leukemias, lymphoproliferative diseases, and myelodysplastic syndrome (MDS). M-HLH can occur in up to 1% of patients with hematologic malignancies, with lymphoma being the most frequently associated malignancy. HLH initiated by MDS is a rare entity with only a few cases reported, leading to limited knowledge regarding its pathogenesis, diagnosis and optimal treatment strategies. Methods: In this retrospective study, we analyzed a consecutive series of MDS-HLH patients admitted to our center between March 1, 2019, and March 1, 2023. Bio-clinical data related with MDS and HLH were collected at diagnosis of MDS-HLH. Additional observational indicators encompassed the following: basic clinical characteristics of the patients (age at onset, gender, duration of MDS prior to HLH), correlation between the onset of HLH and MDS, treatment and response, and genetic defects associated with HLH and MDS. MDS risk classification was according to the Revised International Prognosis Scoring System (IPSS-R) and the WHO classification-based Prognosis Scoring System, while patients were categorized into two groups as higher-risk and lower-risk MDS-HLH group. The follow-up period started at the time of MDS-HLH diagnosis and ended at the date of death or last examination. Overall survival (OS) was calculated from the time of HLH diagnosis to the date of death from any cause. Results: A total of 15 patients diagnosed with MDS-HLH were included in the study, with a median age of 66 years (range, 33-83 years). The majority of patients (10/15, 67%) were over 60 years old. All patients exhibited typical features of aggressive HLH: fever, cytopenia and elevated serum ferritin in all patients, hepatomegaly/splenomegaly in 87% (13/15), hypofibrinogenemia/hypertriglyceridemia in 73% (11/15), hemophagocytosis in 73% (11/15), low NK-cell activity in 21% (3/14), and elevated levels of sCD25 in 93% of patients (14/15). Additionally, four patients (27%) had concurrent Epstein-Barr virus (EBV) infection. Further analysis comparing the lower-risk and higher-risk MDS-HLH groups revealed interesting findings. In the lower-risk group, all patients developed HLH concurrently with the diagnosis of MDS. However, in the higher-risk group, the majority of patients (6/8, 62.5%) experienced HLH onset during MDS progression or relapse (p=0.014). Among the 15 patients, 8 patients (53.3%) achieved remission of HLH. During the study period, 8 deaths occurred, all directly attributed to HLH or its complications. The majority of deaths (75%, 6/8) occurred within the first two months after HLH diagnosis. The median overall survival was 12.3 weeks (95%CI, 1.1-23.5). Patients who achieved complete or partial response had significantly prolonged overall survival compared to those who did not respond to treatment (p=0.002). In the multivariate analysis of prognosis, the remission status of HLH was the only factor which was significantly associated with survival (p=0.018, Exp(B)=0.003). Conclusion: This is the first comprehensive study focusing specifically on MDS-HLH, providing valuable insights into the clinical characteristics, treatment outcomes, and prognosis of MDS-HLH. The findings emphasize the need of considering revision of diagnostic criteria specially for MDS-HLH. The pathogenesis of HLH in MDS-HLH differs based on the risk classification of MDS, with higher-risk cases driven by malignancy and lower-risk cases associated with immune dysfunction. The prognosis of MDS-HLH is generally poor. Achieving remission of HLH is crucial for improving the prognosis of MDS-HLH patients. Conventional chemotherapy regimens, including etoposide, have shown limited efficacy and safety in this context. Chemotherapy-free regimens should be preferred considering the features of ineffective hematopoiesis in MDS. The role of EBV infection in MDS-HLH development should be recognized.

Differences in Diagnostic Characteristics and Outcomes in Adults with Malignancy-Associated and Non-Malignancy-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by life-threatening inflammation. In adults, roughly 50% of HLH manifests in association with an underlying malignancy (most commonly lymphoma), and the remaining cases are due to infection, autoimmune disease, late presentations of genetically-driven HLH, and sometimes multifactorial or idiopathic causes. Although the majority of prospective data for HLH are derived from children, survival outcomes for non-malignant causes of adult HLH (nmHLH) are thought to rival pediatric HLH; however, outcomes for malignancy-associated HLH (mHLH) appear to be substantially worse (~10-30% 5-year overall survival) in the literature. As diagnostic and prognostic models for HLH outcomes have primarily been constructed using pediatric data, attempts have been made to develop diagnostic indices applicable to adult HLH (particularly mHLH). Here, we summarize the clinical and laboratory characteristics of mHLH and nmHLH in a retrospective observational study, and evaluate the role for common diagnostic tools for adult HLH. Methods: Patients >18 years old, fulfilling at least five of the HLH-2004 diagnostic criteria with at least 3 months of follow-up (among survivors) were enrolled. All included patients received definitive HLH therapy, including cancer-directed therapy when appropriate, but those receiving only systemic steroids were excluded. Treatment-related HLH, such as HLH occurring with immune effector cell therapy or hematopoietic cell transplantation, was excluded. Clinical and laboratory parameters reflect the most recent values on or prior to diagnosis and treatment initiation. Differences between mHLH and nmHLH were assessed with two-tailed t-test or Wilcoxon test. Survival outcomes are estimated by Kaplan-Meier. Multivariate analysis was performed using Cox proportional hazards and compared using logrank test. Results: 42 adults were diagnosed with HLH requiring HLH-specific therapy (23 mHLH, 19 nmHLH) between 3/2016 and 3/2023 with a median age of 50 (range 21-75). Of the mHLH cases, 44% were due to T/NK cell lymphomas; 52% were B cell lymphomas including 26% Hodgkin. Of the nmHLH cases, most were due to infection (47%); while others were deemed to be idiopathic (26%) or genetic (16%). All patients with mHLH had fever (v 84% in nmHLH); 91% met cytopenia criteria (v 68%), and absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet count (plt) were all statistically lower than in nmHLH (mean ANC 3.2 v 11.3; Hgb 7.8 v 8.5; plt 43 v 88; p<0.05). Mean soluble interleukin-2 (sIL2) level was significantly higher in mHLH (39,579 pg/mL v 18,484) after adjusting for a single outlier. All other HLH-2004 diagnostic parameters were not statistically different between mHLH and nmHLH, including ferritin and sIL2/ferritin index. All mHLH patients had an underlying lymphoma and met the optimized HLH inflammatory (OHI) index except a single patient with leukemia; 4 patients with nmHLH did not meet the OHI index. In 79% of patients, the HLH94 regimen was incorporated in the induction regimen; the remaining utilized chemotherapy or antibiotics, with and without adjunctive steroids. 4 cases proceeded to allogeneic transplantation. Relapse rates were high, with median relapse-free survival (RFS) being 37 days (23 v 47 days for mHLH and nmHLH, respectively); median overall survival (OS) was 96 days (86 v 149 days). RFS/OS was not statistically different between mHLH and nmHLH. Age was a significant predictor of OS but not RFS; no other diagnostic parameter was predictive, including degree of ferritin or sIL2 elevation. 13 patients were alive at the time of last follow-up (6 mHLH, 7 nmHLH). Conclusions: In this single center retrospective study, both mHLH and nmHLH requiring HLH-directed therapy demonstrated poor survival outcomes in adults. The degree of cytopenias and sIL2 elevation were more significant in mHLH in comparison with nmHLH. The OHI index identified all cases of lymphoma-associated HLH but neither ferritin nor sIL2 levels were predictive of survival. These data emphasize the need for therapeutic advances for management of adults with mHLH and nmHLH and continued optimization of diagnostic criteria for adult HLH.

A Phase 1b Study of ELA026, a Monoclonal Antibody Targeting Signal Regulatory Protein-α/β1/γ, in Patients with Newly Diagnosed and Previously Treated Secondary Hemophagocytic Lymphohistiocytosis

Introduction: ELA026 is under investigation in secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening, hyperinflammatory condition that is most often triggered by malignancies, autoimmune disorders, and infectious diseases. There are no approved therapies for sHLH, and current treatment approaches, particularly for malignancy-associated HLH (mHLH), are suboptimal. For example, in adult patients with mHLH, median overall survival (mOS) is approximately 2 months (Lee et al. 2023). ELA026 is a monoclonal antibody directed against signal regulatory protein-α/β1/γ and is intended to target the activated myeloid and T cells that drive sHLH. Methods: This is an open-label, single-arm, Phase 1b global multicenter study (NCT05416307) to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of ELA026 in newly diagnosed and previously treated sHLH patients, aged 12 years or older (6 years or older in select countries including the US). In Cohort 1, an intra-patient dose escalation of ELA026 occurs in the absence of a dose limiting toxicity (DLT) and optimal biomarker response. Response is evaluated as described in Locatelli et al. 2020. Results: Six mHLH patients enrolled in Cohort 1 with median age of 50 years (range 21-67). Three patients were refractory to etoposide-based therapies and/or anti-cytokine therapies. No DLTs or study drug-related serious adverse events occurred. Five patients were deemed evaluable for efficacy based on >1 week of ELA026 exposure (efficacy assessment is pending). All 5 patients received concurrent chemotherapy for their malignancies. As of July 31, 2023, 3 patients are alive and 2 patients have died from complications of malignancy (mOS has not been reached but has exceeded 3 months). Three patients who had periods of ELA026 monotherapy displayed early, progressive monocyte and lymphocyte reductions with associated improvements in C-reactive protein and other sHLH-associated biomarkers. Updated study results and progress will be provided at the meeting. Conclusion: Preliminary data suggest ELA026 is well tolerated in sHLH patients and induces early biomarker changes that warrant further clinical investigation.

Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival

AbstractWe evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P < .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P < .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P < .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.

Hemophagocytic lymphohistiocytosis associated with hepatocellular carcinoma.

A man in his 60s was admitted because of abdominal pain and fatigue. Contrast enhanced computed tomography (CECT) showed a hypovascular tumor, 7cm in size, in the left lobe of liver. He had no history of alcohol consumption. HBs antigen and HCV antibody were negative. For definitive diagnosis, biopsy of the hepatic tumor was performed. After the biopsy, the patient suddenly got high fever, and blood tests showed WBC 22,000/L, Hb 8.9g/dL, Plts 11.6 × 104/L, AST 140IU/L, ALT 93IU/L, LDH 635U/L. He died on the following day despite of supportive therapy. Autopsy revealed that the hepatic tumor was poorly differentiated hepatocellular carcinoma (HCC) and that hemophagocytic macrophages were found in the bone marrow and spleen. Based on the pathological findings of autopsy, he was finally diagnosed with hemophagocytic lymphohistiocytosis (HLH) associated with HCC. HLH is a rare and life-threaded disorder of immune overactivation. Malignancy-associated HLH is well-known; however, it is usually associated with malignant lymphoma. To our knowledge, this is the first reported case of HLH associated with HCC, which was diagnosed by autopsy. Although extremely rare, our case highlights that HLH should be considered as a differential diagnosis of unknown high fever and bicytopenia in patients with solid tumors, including HCC.

E035 An evaluation of the causes and outcomes of haemophagocytic lymphohistiocytosis in Sheffield Teaching Hospitals: 2016 to 2021

Abstract Background/Aims Haemophagocytic lymphiohistiocytosis (HLH) is a rare, underrecognised hyperinflammatory syndrome, characterised by immune dysregulation. Without treatment, the ensuing cytokine storm leads to high mortality. Secondary HLH (sHLH) is triggered by malignancy, infection, autoimmunity and medicines; treatment with immunosuppression is consensus- rather than evidence-based and extrapolated from primary HLH. Sheffield hosts a mature HLH multidisciplinary advisory group (MDAG). Here we evaluate the cause, treatment, requirement for critical care and mortality of people with HLH managed through the MDAG in a period including the coronavirus pandemic but prior to NHS England approval of anakinra (IL-1 antagonist) for HLH. Methods This retrospective evaluation (approved locally STH 10850) identified patients from MDAG records 1st October 2016 to 30th September 2021. Data from electronic/paper records was analysed using Microsoft Excel. Results HLH triggers were infection (viral 34%, bacterial 10%), haematological (35%), rheumatological (13%) and other (8%). Rheumatological causes were Still’s disease (n = 5); antiphospholipid syndrome (n = 2); JO1 dermatomyositis (n = 1); SLE (n = 1); and rheumatoid arthritis (n = 1). Other causes included unknown (n = 3); combined systemic JIA and sickle cell crisis (n = 1); medication (alemtuzumab) (n = 1); and primary HLH (n = 1). Overall mortality was 53% and highest in HLH with a haematological malignancy trigger (82%) Prior to the COVID19 pandemic (pre-March 2020), the commonest trigger of HLH was haematological malignancy (47%); after March 2020, the commonest trigger was infection (64%); COVID-19 explained 42% of cases. Mortality fell from 72% to 31%. Conclusion In this real-world series of people with HLH, mortality and critical care requirement was high. HLH triggers reflect published evidence as does poor prognosis in haematological malignancy-associated HLH. No-HLH associated with non-haematological malignancy was identified; we may need to improve MDAG reach into oncology. Seeming reduction in mortality following the COVID-19 pandemic may reflect increased recognition of COVID-19 induced hyperinflammation along with locally-agreed access to anakinra for COVID-19-induced HLH. The increase in infection related HLH cases since March 2020 is explained largely by COVID-19 cases. This has led to a relative reduction in cases related to haematological malignancy. HLH requires multidisciplinary management and better research to improve treatment. Disclosure B. Awdas: None. T. Nadin: None. R. Tattersall: None.

Extensive histiocytosis masking anaplastic large-cell lymphoma (ALCL).

HLH represents a severely uncontrolled hyperinflammatory reaction with numerous aetiologies including genetics, infection, autoimmune and malignancy. HLH is not itself a standalone pathological diagnosis, but rather a diagnosis based on integration of clinical and histological examination. Although malignancy-associated HLH (M-HLH) is seen commonly with lymphomas, HLH associated with ALCL is extremely rare. Diligent assessment of the histological tissue should be performed to identify the aetiology and not be distracted by the histiocytosis, likely caused by cytokines released from tumour cells.

Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe, dysregulated inflammation driven by the inability of T cells to clear an antigenic target. When associated with malignancy (mHLH), the HLH syndrome is typically associated with extremely poor survival. Here, we review the diagnosis of secondary HLH (sHLH) syndromes in adults, with emphasis on the appropriate workup and treatment of mHLH. At present, the management of HLH in adults, including most forms of mHLH, is based on the use of corticosteroids and etoposide following the HLH-94 regimen. In some cases, this therapeutic approach may be cohesively incorporated into malignancy-directed therapy, while in other cases, the decision about whether to treat HLH prior to initiating other therapies may be more complicated. Recent studies exploring the efficacy of other agents in HLH, in particular ruxolitinib, offer hope for better outcomes in the management of mHLH. Considerations for the management of lymphoma-associated mHLH, as well as other forms of mHLH and immunotherapy treatment-related HLH, are discussed.

Clinicomorphological spectrum of hemophagocytic syndrome in a tertiary care hospital

Introduction: The HLH-2004 trial established the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH), a severe hyperinflammatory condition. It typically develops due to inappropriate macrophage activation. Our objective was to assess the spectrum of hemophagocytic syndrome presentations by identifying hemophagocytic activity in the bone marrow, and to unravel the etiopathogenesis of this condition. Material and methods: A retrospective study was carried out in the Department of Pathology in a tertiary care hospital reporting the clinical and laboratory findings of patients who had been previously diagnozed with hemophagocytosis in the bone marrow. The parameters in the diagnostic criteria of HLH of the same patients were documented and analyzed. Results: The characteristics of the 32 patients who presented with hemophagocytosis in the bone marrow were documented. Persistent fever was the most frequent presentation. Mild to moderate anemia (69%), severe leucopenia (59%), and mild to moderate thrombocytopenia (63%) were other frequent findings. The incidence of primary HLH was found to be only 3%; 87% had hyperferritinemia, 78% had bicytopenia, 59% had hypertriglyceridemia, and 53% had splenomegaly. Infections followed by malignancies were shown to be the most frequent cause of secondary HLH, while the prognosis for malignancy-associated HLH appeared to be poor. Conclusions: Based on the findings of this study, conclusions about the clinical symptoms and etiologies of HLH may be drawn, which will assist in early identification. Hence, all subjects with a clinical suspicion of HLH should be thoroughly investigated for a possible etiology.

Elevated Interleukin-10 Levels Are Associated with Low Platelet Count and Poor Prognosis in 90 Adult Patients with Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive inflammatory responses. This study explored the association between laboratory characteristics and outcomes in adult patients with HLH. Methods: The adult patients diagnosed with HLH at the Second Hospital of Shanxi Medical University from September 2016 to September 2021 were retrospectively analyzed in this study. Results: A total of 90 HLH patients were included. Among them, 60% were males, with a median age at diagnosis of 54 years. More than 85% of HLH patients presented with fever, splenomegaly, and cytopenias. IL-10 and IL-6 were elevated in 93.3% and 91.1% of patients, respectively. Elevated IL-10 levels were associated with lower platelet counts (r = −0.37, p < 0.001). Infections were seen in 46.7% (42/90) of cases. 29 patients with malignancy-associated HLH had T- or NK-cell (n = 16) or B-cell (n = 12) lymphoma. Autoimmune diseases accounted for 21.1% (19/90). Treatment was variable. In total, 36 patients survived (40%). The median overall survival (OS) was 1.5 months (95% confidence intervals [CI]: 0.2–2.8 months), with a 1-year OS of 40.9%. Patients with autoimmune diseases had markedly longer survival than those triggered by infection and malignancy (p < 0.001). Multivariate Cox regression analysis indicated that treatment delays (hazard ratios 0.36, 95% CI: 0.14–0.94, p = 0.036), platelet count (2.33, 1.30–4.18, p = 0.005), and IL-10 (2.07, 1.16–3.68, p = 0.014) were independent risk factors for poor outcome. Conclusion: Infection and lymphoma are the leading causes of HLH in adult patients with heterogeneous clinical manifestations. Survival of adult HLH is frustrating, especially those associated with malignancies. Besides, elevated IL-10 levels were associated with lower platelet counts, and these two markers were independent risk factors for poor prognosis. Earlier treatment led to better outcomes.

Hemophagocytic Lymphohistiocytosis Appearing During Blast Phase of Chronic Myeloid Leukemia

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening illness with rapid progression and high mortality and is associated with genetic defects or can be induced by malignancies or severe infections. Most of the hematological malignancy-related HLH reported was accompanied by lymphoid neoplasms. Here, we present an unusual case of HLH with co-existing blast phase of chronic myeloid leukemia (CML-BP). A diagnosis of AML-M5 with most likely concomitant HLH was made based on the clinical features, morphology, flow cytometry immunophenotyping, and genetics. Moreover, clinical characteristics were more suggestive of myeloid blast phase CML than de novo AML with the positive p210 BCR-ABL1. However, disease-causing mutations of HLH were not available, the patient probably had secondary malignancy-associated HLH induced by an acute infection. The case focuses on the contribution of bone marrow morphological examination in getting the first diagnostic clue of CML-BP concomitant with HLH.

Acute Clinical Syndrome of HLH in Patients with Hematologic Malignancy and EBV Infection

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by dysregulation of the reticuloendothelial system, overactivation of macrophages and lymphocytes, hemophagocytosis, and cytokine storm collectively causing systemic inflammation and organ damage. Malignancy-associated HLH (M-HLH) is associated with poor prognosis and survival of 1-2 months (Daver N, et.al., Cancer. 2017). Viral infections such as Epstein-Barr Virus (EBV) can independently contribute to development of lymphoproliferative neoplasms and non-malignancy associated HLH. While both malignancy and EBV are recognized as independent risk factors for HLH, a syndrome of overlapping M-HLH and EBV-HLH remains underreported. The optimal long-term treatment strategy for M-HLH in EBV positive patients is unknown, with combinations of HLH and malignancy directed therapy reported in the literature without significant improvement in survival (Zhao A, et.al., Front Immunol. 2022). We report a case series of patients with EBV infection and newly diagnosed hematologic malignancies complicated by HLH demonstrating poor prognosis despite initial control of disease. Methods: Between July 2020 and July 2021, 8 patients >18 years of age hospitalized at Montefiore Medical Center were identified meeting diagnostic criteria of HLH with associated primary hematologic malignancy, and concomitant EBV infection. Data on demographics and clinical characteristics, laboratory studies, malignancy diagnosis, treatments received, and disease course were collected. HLH-04, H-Score were recorded for all patients. Data were analyzed using descriptive statistics. Results: The median age was 53.6 years old (range 29-75). Five out of 8 patients met systemic inflammatory response syndrome (SIRS) criteria on presentation. The median H-Score was 217.1 (range 183-247). All but one patient exceeded CD25 and ferritin parameters of optimized HLH inflammatory (OHI) index suggestive of high mortality risk. Classical Hodgkin Lymphoma (cHL) was seen in 4/8 patients; other diagnoses included large B cell lymphoma, angioimmunoblastic T cell lymphoma, intravascular large B cell lymphoma, and anaplastic large cell lymphoma. Dexamethasone was the backbone of treatment and the initial HLH directed therapy in all patients, starting on average 9 days after presentation (range 2-17) and preceding treatment with other HLH directed therapies by median of 7.2 days (range 0-33). Four out of 8 patients received dexamethasone, etoposide, and rituximab; 2 patients received dexamethasone with etoposide and 2 received dexamethasone alone. The administration schedule and cumulative doses of both rituximab and etoposide varied significantly between the patients. Initiation of malignancy directed chemotherapy lagged the initiation of dexamethasone by median of 16.5 days (range 0-53). Delays were due to patients' clinical condition, organ function, and pending diagnosis of malignancy. Median overall survival from the initial presentation was 102.5 days (range 33-219). Two out of 8 patients in our case series survived. One received dexamethasone and etoposide, followed by 6 cycles of malignancy-directed chemotherapy and autologous stem cell transplant. The second patient was treated with dexamethasone, rituximab, etoposide with addition of anakinra, followed by malignancy directed therapy without rituximab or etoposide. At the time of death, 4 out of 6 patients had active HLH and 3 out of 6 patients were treated for an overwhelming polymicrobial infection. Conclusion: HLH is the setting of EBV-positive malignancy results in a syndrome with an aggressive clinical course and high early mortality rate. Here we demonstrate that HLH-directed therapy prior to or incorporated into malignancy-directed therapy extended patients' survival to median 3 months, as compared to 1-2 months reported in the literature. Nevertheless, most patients suffered HLH relapse and succumbed to infectious complications of prolonged hospitalization and immunosuppression. Long term HLH therapy with immunomodulatory agents and EBV-directed therapies is needed to achieve sustained control of systemic inflammation. Patients who survive initial HLH episode need to be closely monitored for recurrence. Preemptive strategies such as autologous stem cell transplant should be considered in eligible patients to further reduce the risk of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Optimized HLH Inflammatory Index Is Associated with a Higher Stage of Lymphoma, but an Unexpected High Mortality Associated with Inflammation

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the 'optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 (>3,900 U/mL) and ferritin (>1,000 ng/mL) in this context (Zoref-Lorenz A, Murakami J, Hofstetter L, et al. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis. Blood. 2022;139(7):1098-1110). In this study, we assessed whether OHI-positive lymphoma patients have more advanced lymphoma and whether mortality among these patients is related to lymphoma or other causes. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed lymphoma in whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH and classified patients by their OHI status. Age at lymphoma diagnosis, complete blood counts, albumin, lactate dehydrogenase, Ann Arbor stage, extranodal site involvement, and ECOG performance status were documented. Overall survival at five years/last follow-up was recorded, as was the cause of death. OHI- and OHI+ patients were compared by international prognostic index (IPI), International Prognostic Score, and Follicular Lymphoma International Prognostic Index for T/B cell non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, and follicular lymphoma, respectively. Predicted five-year overall survival was calculated based on the relevant prognostic index and was compared between OHI- and OHI+ patients. The odds ratios (ORs) for observed vs. predicted mortality was calculated using the Chi-square test. In addition, time to death by mortality cause analysis was performed. Results: 100 lymphoma patients were studied: 63 were OHI-, and 37 were OHI+, 65% of the patients had B cell NHL, 18% had natural killer/ T cell lymphoma, and 17% had Hodgkin's lymphoma. More than half of the patients had sCD25 and ferritin measured as routine surveillance at the time of malignancy diagnosis (57%). The disease-relevant prognostic index-predicted five-year survival did not differ between OHI- and OHI+ patients (a mean of 57% in OHI- and 58% in OHI+ p=0.62). Compared to OHI- patients, OHI+ patients had a more advanced Ann Arbor stage (p=0.014) but did not differ in the number of extranodal sites, ECOG performance, or disease-relevant IPI. The disease-relevant prognostic index-predicted 5 - year survival did not differ between OHI- and OHI+ patients (Figure 1). However, the actual 5-year survival in OHI+ patients was substantially lower than predicted (12%), reflecting a mortality incidence four times higher than predicted by standard prognostic scoring (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted (Figure 1) by their prognostic scores (OR 0.15; CI 0.07-0.34). In addition, more than half of the OHI+ patients died from non-malignant causes, while most deaths among OHI- patients (92%) were from progressive malignancy. Mortality related to multi-organ failure occurred early in OHI+ patients (Figure 2). Conclusion: OHI+ patients had a slightly more advanced lymphoma but were generally similar to OHI- patients according to their lymphoma-relevant prognostic index. However, OHI+ patients had a higher mortality rate due to infections and multi-organ failure, suggesting that the OHI index identifies a clinically important inflammatory state in lymphoma patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA-DR+ CD38high Expression in T Cells Is Excellent in Quantifying the Amplitude of T-Cell Activation in a Spectrum of Hyperinflammatory Disorders Including HLH

Introduction: T cell activation is the hallmark of several hyperinflammatory states such as HLH and immune dysregulation disorders like LRBA deficiency. Identifying T-cell activation and quantifying the amplitude of T-cell activation is critical for diagnosis, management, and monitoring treatment response in patients with hyperinflammatory and immune regulatory disorders. Soluble Interleukin 2 Receptor (sIL2R) is one of the established systemic T-cell activation markers for diagnosing and monitoring HLH and other hyperinflammatory disorders. However, the clinical availability of sIL2R testing is limited, and it may not be a reliable marker of T-cell activation in patients with eosinophilia and T-cell lymphoma. A recent study by Chaturvedi et.al has demonstrated the utility of flow-based T-cell activation assessment in differentiating HLH from sepsis. However, its utility in defining and quantifying T-cell activation across the hyperinflammatory spectrum and its correlation with sIL2R has not yet been established. Methods: A total of 125 samples were collected either at disease onset (n = 81) or at follow-up (n = 44) from 85 human subjects. Paired plasma sIL2R and T-cell activation markers were prospectively evaluated in patients with suspected HLH (n = 79) or immune dysregulation disorders (n = 46). Out of 85 patients, 21 patients were diagnosed with either primary HLH (p-HLH), Epstein-Barr virus infection-associated HLH (EBV-HLH), malignancy-associated HLH (m-HLH), or macrophage activation syndrome (MAS). The rest of the patients were diagnosed with either sepsis, multisystem inflammatory syndrome in children (MIS-C), hyperinflammatory conditions, hepatitis, or acute liver failure. Flow cytometry-based T-cell activation was evaluated in different T-cell sub-compartments by the co-expression of HLA-DR and CD38 surface markers. Plasma sIL2R levels and CXCL9 (a chemokine driven by IFN-g) were determined independently in CLIA certified clinical diagnostic laboratory. Research personnel who analyzed the flow cytometry data were blinded to the corresponding sIL2R test results and clinical diagnosis. Longitudinal follow-up was performed for a subset of patients with HLH or immune dysregulation with evidence of T-cell activation. We also evaluated T-cell activation in 30 healthy controls (HC) to establish a reference range. In addition, the correlation between T-cell activation markers with plasma levels of sIL2R and CXCL9 was also investigated. Results: Evaluation of T-cell activation measured by HLADR+CD38high in HCs and different hyperinflammatory/ immune regulatory disorders revealed that HCs have less than 8% of T-cell activation in CD8+ T effector memory (TEM) and less than 4% for activation in the CD4+ TEM compartments. In patients with suspected hyperinflammatory/ immune regulatory disorders, we identified significant correlation of direct T-cell activation with plasma sIL2R level in different T-cell subsets, CD3 (r = 0.44, p < 0.0001), CD4 (r = 0.41, p < 0.0001), CD8 (r = 0.45, p <0.001), CD4 TEM (T effector memory) (r =0.53, p < 0.001), and CD8 TEM (r =0.53, p < 0.0001). The strongest correlation between HLADR+CD38high with sIL2R level was noted in CD4+ TEM and CD8+ TEM compartments (Figure 1). The correlation is even more robust at disease onset (r = 0.69, p <0.0001 for CD4+ TEM and r = 0.64, p < 0.0001 for CD8+ TEM). However, at follow up, only activation in CD8+ TEM correlated with sIL2R levels (r = 0.4, p = 0.0069). Moreover, T-cell activation in CD8+ TEM correlated well with CXCL9 and ferritin levels. Among the cohort of patients with the confirmed final diagnosis, we found that both p-HLH and EBV-HLH have CD8+ TEM activation > 70%, whereas MAS and m-HLH have a median T cell activation of 37.8% (10.5-67) and 48.1% (4.9-80.6) respectively. Immune dysregulation patients had T-cell activation range from 8.0 to 46.0 % and sepsis group has 0% to 10.8% (Figure 2). A similar trend was also validated using corresponding plasma sIL2R levels in different hyperinflammatory states. Conclusions: Flow cytometry-based direct assessment of HLADR+CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulations disorders. If validated, this could be used as a real-time assessment of T-cell activation at disease onset and monitoring response to therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Good Prognosis of Adult Hemophagocytic Lymphohistiocytosis (HLH) Associated with the HAVCR2 germline Mutation

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition caused by excessive immune activation. Known etiologies are malignancies, infections, and autoimmune diseases. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is associated with HLH in approximately 15-20% of cases. Recent studies identified germline HAVCR2 (Hepatitis A Virus-Cellular Receptor 2) mutations in SPTCL and/or HLH. The most commonly reported mutation is HAVCR2 p.Y82C. We aimed to explore the incidence of germline HAVCR2Y82C mutation in SPTCL-associated and idiopathic HLH and compare clinical outcomes with HLH from other causes. We collected patients, aged 15 or older, with HLH or HLH-like systemic illness from January 2011 to June 2022. HLH was defined according to the HLH-2004 criteria. The term HLH-like systemic illness was applied to those with incomplete HLH-2004 criteria, but clinically consistent with HLH. Causes of HLH were comprehensively reviewed and documented for baseline characteristics. Direct sequencing to detect germline HAVCR2 p.Y82C (c.245A>G) was done in idiopathic and SPTCTL-associated HLH. DNA was extracted from formalin-fixed paraffin-embedded specimens or blood samples. Of the 56 HLH or HLH-liked patients, 64% were male with the median age of 46 years old. The median HLH-2004 diagnostic score was 5 (26/56; 46.4%), ranging from 3 - 6 points. We detected germline HAVCR2Y82C mutations in 9 out of 56 cases (16%), of which 5 cases diagnosed with SPTCL, while 4 cases were idiopathic HLH. Six of 9 mutated cases carried homozygous HAVCR2Y82C mutation. The other causes of HLH were hematologic malignancies excluding SPTCL (17/56; 30%), idiopathic HLH without HAVCR2 mutation (17/56; 30%), infections (8/56, 14.3%) and autoimmune diseases (5/56; 8.9%). The hematologic malignancy subgroup comprised NK/T cell lymphoma (5/17; 30% ), diffuse large B-cell lymphoma (3/17; 17%), peripheral T-cell lymphoma, not otherwise specified (3/17; 17%), pure erythroid leukemia (2/17; 12%), non-Hodgkin's lymphoma unknown type (2/17; 12%), Hodgkin's lymphoma (1/17; 6%) and myelodysplastic neoplasms (1/17; 6%). Patients with germline HAVCR2Y82C mutations showed superior survival than the others (Figure 1). Idiopathic and malignancy-associated HLH showed significant inferior outcomes compared to patients with germline HAVCR2 mutations with hazard ratios (HR) of 5.39 (95% Confidence interval [CI] 1.21-23.99; p=0.027) and 6.53 (95%CI 1.48-28.79; p=0.013), respectively. HLH with germline HAVCR2Y82C mutation were younger than HLH from other causes (30 vs. 47 years old; p=0.043). Patients with germline HAVCR2Y82C mutations showed significantly higher hemoglobin levels but lower absolute neutrophil count than HLH with other causes (Table 1). In conclusion, germline HAVCR2 mutations define a subgroup of HLH with better survival than the others. The mutation test is helpful to determine the prognosis of HLH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Temporal Trends in the Incidence of Hemophagocytic Lymphohistiocytosis: A Nationwide Cohort Study From England 2003-2018.

Hemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality, and is increasingly being diagnosed. We aimed to quantify the incidence of diagnosed HLH and examine temporal trends in relation to age and associated diseases. Using national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between January 1, 2003, and December 31, 2018. We calculated incidence rates of diagnosed HLH per million population by calendar year, age group, sex, and associated comorbidity (hematological malignancy, inflammatory rheumatological or bowel diseases [IBD]). We modeled trends in incidence and the interactions between calendar year, age, and associated comorbidity using Poisson regression. There were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (incidence rate ratio [IRR] 2018 compared to 2003: 3.88, 95% confidence interval [CI] 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11, 95% CI 1.09 to 1.12). There was a transition across age groups with greater increases in those aged 5-14 years of HLH associated with rheumatological disease/IBD compared with hematological malignancy, with similar increases in HLH associated with both comorbidities for those 15-54, and greater increases in HLH associated with hematological malignancies for those 55 years and older. The incidence of HLH in England has quadrupled between 2003 and 2018. Substantial variation in the incidence occurred with inflammatory rheumatological diseases/IBD-associated HLH increasing more among the younger age groups, whereas in older age groups, the largest increase was seen with hematological malignancy-associated HLH.

Comparison of Hemophagocytic Lymphohistiocytosis Diagnostic Criteria in Malignancy-Associated Hemophagocytic Lymphohistiocytosis Patients

Background Fulfilling diagnostic criteria of hemophagocytic lymphohistiocytosis (HLH) is challenging due to unavailable laboratory tests. Hence, we aimed to reveal malignancy-associated-HLH (M-HLH) patients in our center, which can not be reached in all tests.&#x0D; Material and Methods Nine patients with M-HLH were analyzed retrospectively.&#x0D; Results The median age was 59 years. The distribution of the underlying diseases was like diffuse large B cell lymphoma in 3 patients, acute myeloid leukemia in 2 patients, Hodgkin lymphoma in 2 patients, T cell non-Hodgkin lymphoma in 1 patient, and small cell lung cancer in 1 patient. According to HLH-2004 diagnostic criteria except for soluble CD25 and natural killer activity tests; one patient had 3/6, six patients had 5/6, two patients had 6/6 criteria while the median H-score was 258 at diagnosis. According to Tamamyan et al’s criteria; at the diagnosis, all patients had ≥7 (between 7-12) of 18 parameters. Patients fulfilled ≥5 parameters a median of 15 days (3-52 days) before the diagnosis and on that time six patients had 3/6 criteria of HLH-2004. 88.8% of the patients died. The median duration of survival was 8.5 days (1-18 days).&#x0D; Conclusions Unavailability of the tests in some countries and centers as in ours results in complications to fulfill 5 of 8 criteria and being delayed in diagnosis and treatment. We need to develop more specific and accessible criteria, and grading systems for M-HLH diagnose.