Lymphoma-associated hemophagocytic syndrome (LAHS), which is the major subtype of adult-onset secondary hemophagocytic lymphohistiocytosis (HLH), has a poor outcome. Although the early diagnosis and treatment of LAHS contributes to a better outcome, the lack of mass formation and the absence of distinct lymph node enlargement often delay the diagnosis of underlying lymphoma. A recent study, which statistically analyzed HLH cases in the literature, showed that the serum soluble interleukin-2 receptor (sIL-2R)/ferritin ratio could be used as a marker to diagnosis of LAHS. To verify this finding, we retrospectively analyzed the laboratory findings of 21 patients with HLH (10 benign disease-associated HLH and 11 LAHS). No significant differences were observed in the levels of LDH or CRP levels. The mean sIL-2R levels (units per milliliter) were significantly higher in the LAHS group (4,176 vs. 13,451, p = 0.0031), and ferritin levels (nanogram per milliliter) were higher in the benign disease-associated HLH group (20,462 vs. 2,561, p = 0.0031). Consequently, the mean serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease-associated HLH (0.66 vs. 8.56, p = 0.0004). Thus, the results of this study demonstrated that the serum sIL-2R/ferritin ratio is a very useful marker for diagnosing of LAHS, which was further supported by clinical case analysis. Further studies to clarify the pathophysiology of secondary HLH caused by various triggers are needed.

OBJECTIVE:A major cause of hemophagocytic lymphohistiocytosis (HLH) is malignant neoplasms of the blood system, among which NK/T cell lymphoma is one of the most common risk factors. Patients with NK/T cell lymphoma hemophagocytic lymphohistiocytosis (NK/T-LAHS) have a worse prognosis and higher mortality. We aimed to explore the factors that affect the prognosis of NK/T-LAHS. METHODS:Clinical data of 42 patients with NK/T-LAHS diagnosed by Beijing Friendship Hospital from June 2008 to June 2016 were analyzed retrospectively. The survival time was counted until 1 August 2016. RESULTS:For the 42 NK/T-LAHS patients, 1-month survival rate was 48.9%, 2-month survival rate was 36.7%, 3-month survival rate was 28.8%, 6-month survival rate was 23.0%, and 12-month survival rate was 15.4%. NK/T-LAHS patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT) (p = 0.000), exhibited peripheral blood Epstein-Barr virus (EBV)-positivity (p = 0.004), and achieved overall response (OR) remission after initial induction therapy (p = 0.007) had statistical significance. CONCLUSION:NK/T-LAHS is a disease of poor prognosis and high mortality. NK/T-LAHS patients who achieved OR remission after the initial induction therapy had a better prognosis than non-remission patients and Allo-HSCT was an effective way to prolong the survival of NK/T-LAHS patients. However, EBV positivity in peripheral blood was a poor prognostic factor in NK/T-LAHS patients.

Extranodal natural killer (NK)/T cell lymphoma-associated hemophagocytic syndrome (HPS) (NK/T-LAHS) is a heterogeneous and life-threatening disease, which warrants investigation of its risk factors and clinical features. We retrospectively analyzed the clinical records of 202 patients with extranodal NK/T cell lymphoma and compared the characteristics and survival of extranodal NK/T cell lymphoma patients with and without HPS. The cumulative incidence of NK/T-LAHS was 11.4 % (23/202). In a multivariate logistic regression model, younger age (p = 0.012), bone marrow involvement (p = 0.012), and reduced serum albumin (p < 0.001) were independent risk factors for developing HPS in patients with extranodal NK/T cell lymphoma. The survival of extranodal NK/T cell lymphoma patients was aggravated when complicated with HPS, with an overall 2-year survival of 72.1 and 30.4 %, respectively (p < 0.001). Six patients with HPS onset at lymphoma diagnosis tended to have a poor performance status (p = 0.040), while the rate of elevated bilirubin was significantly higher in 17 patients with HPS onset at lymphoma relapse (p = 0.045). After HPS onset, treatment response was poor (response rate, 17.4 %) and survival was dismal with a median of 26 days. Univariate analysis showed that patients with lactate dehydrogenase >1000 U/L (p = 0.048) and disseminated intravascular coagulation (p = 0.004) had shorter survival time. Extranodal NK/T cell lymphoma was frequently complicated with HPS, and survival was discouraging in this circumstance. Intensive chemotherapy regimens including L-asparaginase or pegaspargase and allogeneic stem cell transplantation should be investigated.

Natural killer (NK)/T cell lymphoma associated with hemophagocytic syndrome (NK/T-LAHS) is a rare and life-threatening disease. The clinical features and overall survival of NK/T cell and other T cell lymphomas associated with hemophagocytic syndrome remain uncertain. We retrospectively reviewed the clinical records of 15 patients with NK/T-LAHS and 14 patients with other T-LAHS from December 2008 to June 2013. Patients with NK/T cell lymphoma had a higher International Prognostic Index (p = 0.045) and were more likely to be positive for Epstein-Barr virus (p = 0.025) than those with T cell lymphoma. The level of aspartate aminotransferase (AST) was significantly higher than that of alanine aminotransferase (ALT) in the NK/T-LAHS group (p = 0.005), as well as in the T-LAHS group (p = 0.019). The level of direct bilirubin (DBIL) was more likely to be elevated than that of indirect bilirubin (IBIL) in patients with NK/ T-LAHS (p = 0.047), while there was no significant difference in the T-LAHS group (p = 0.124). The median survival time for patients with NK/T and T cell lymphoma was 28 and 33 days, respectively (p = 0.726). However, in the NK/T-LAHS group, the median survival time of patients treated with and without pegaspargase was 116 and 15 days, respectively (p = 0.003). Our results suggest that patients with NK/T-LAHS are at higher risk and suffer a worse prognosis. However, the use of pegaspargase could benefit patients and lead to long-term overall survival.

Nasal type, extranodal nature killer (NK)/T cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS) is a rare and fatal disorder with extremely poor prognosis. To investigate its clinical characteristics and risk factors, we retrospectively analyzed 295 patients with nasal type, extranodal nature killer/T cell lymphoma, of which 21 were diagnosed with hemophagocytic syndrome, with a cumulative incidence of 7.1%. The most frequently clinical characteristics were fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, hyperferritinemia, liver dysfunction, hypertriglyceridemia, hypofibrinogenemia and evaluated lactate dehydrogenase (LDH) level. After a median follow-up of 27 months, the 2-year survival for the 295 patients was 74.6%. Significant difference for 2-year survival was found between patients with and without hemophagocytic syndrome (4.8% vs. 80.0%, P<0.001). After developing hemophagocytic syndrome, all patients survived no more than 3 months, with a median survival of 35 days. Risk factors for NK/T-LAHS were bone marrow (BM) involvement (P = 0.019; relative risk, 13.649; 95% confidence interval (CI): 1.538-121.103), hepatosplenomegaly (P = 0.003; relative risk, 9.616; 95%CI: 2.154-42.918), and elevated LDH level (>314U/L) (P = 0.038; relative risk, 6.293; 95%CI: 1.108-35.735). We conducted a risk model for all 295 patients based on the 3 adverse factors as follows: low risk (233 cases, 79.0%), no factor; intermediate risk (43 cases, 14.6%), one factor; high risk (19 cases, 6.4%), 2 or 3 factors. The probabilities for developing LAHS were 0.9% for low-, 14.0% for intermediate-, and 68.4% for high-risk group. Significant differences in the 3 risk groups were observed (P<0.001).

BACKGROUND:Lymphoma associated hemophagocytic syndrome (LAHS) is one of the major adult secondary hemophagocytic lymphohistiocytosis (HLH). Early diagnosis and treatment contribute to improved outcome. No enlarge lymph nodes can often delay the diagnosis of underlying lymphoma. OBJECTIVE:To find out criteria distinguishing LAHS from HLH induced by benign diseases. METHODS:clinical characteristic and laboratory feature of 31 patients with HLH (10 benign disease-associated HLH and 21 LAHS) were analyzed retrospectively. RESULTS:No significantly differences were observed in the levels of LDH, IL-6, IL-10, TNF-α; however, the level of CRP (C reactive protein) and the mean level of sIL-R (soluble interleukin-2 receptor) were higher in patients with LAHS than those with benign disease associated disease associated HLH while ferritin levels were higher in benign disease associated HLH than in LAHS. Consequently, the serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease associated HLH (0.33 ± 0.23 vs 5.82 ± 3.26, P= 0.0001). In addition, we found out that the mean level of miR-133 (microRNA-133) was significant higher in LAHS than in benign disease associated HLH (18.83 ± 10.44 vs 5.82 ± 3.26, P⩽ 0.0001). CONCLUSION:Serum miR-133 is a new very useful marker for diagnosing of LAHS, but it need further confirmation by further clinical studies.

Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome, which can manifest either secondary to a variety of underlying causes, or due to a primary genetic defect. Malignancy is the most common underlying disease in adults with HLH, with lymphomas being the most common malignancy. Lymphoma-associated hemophagocytic syndrome (LAHS) typically follows a rapidly progressive clinical course and is associated with poor prognosis. We herein present four patients with HLH associated with aggressive lymphoma. At initial presentation, the underlying etiology of the HLH was unclear. Two patients were eventually diagnosed with anaplastic large cell lymphoma, while the other two had diffuse large B cell lymphoma. Two of the patients experienced rapid clinical deterioration, one at diagnosis and the other at relapse, and both died prior to diagnosis of lymphoma despite HLH-directed therapy. These cases highlight the need for intensive management in adults with HLH without a clear etiology, especially in cases when lymphoma-associated HLH is suspected. We describe the current pitfalls in diagnosis and treatment of LAHS and discuss possible ways to improve patient management.

PURPOSE:Case reports suggest that ruxolitinib-containing treatment could increase the clinical response rate of patients with hemophagocytic syndrome (HPS). This study aimed to explore the effect of ruxolitinib-containing treatment for patients with lymphoma-associated hemophagocytic syndrome (LAHS). METHODS:This was a retrospective study of patients with LAHS hospitalized at the First Affiliated Hospital of Guangdong Pharmaceutical University between October 2017 and September 2019. Patients were treated with HLH-94 (etoposide and dexamethasone) or R-DED regimen (ruxolitinib, doxorubicin, etoposide, and dexamethasone). The clinical characteristics, treatment responses, and overall survival (OS) were compared. The patients were divided into the HLH-94 group (n = 34) and the R-DED group (n = 36). RESULTS:Compared with HLH-94, R-DED might effectively improve the clinical manifestations, including fever and splenomegaly in patients with LAHS, and control the systemic cytokine storm. The response rate at 2 weeks was 54.8% in the HLH-94 group, which was lower than in the R-DED group (83.3%) (p = 0.011). The OS was significantly prolonged in the R-DED group compared with the HLH-94 group (median, 5 vs. 1.5 months, p = 0.003). The multivariable analysis showed that lower IL-10 levels [hazard ratio (HR)] = 1.000, [95% confidence interval (CI)] 1.000-1.000, p = 0.012), R-DED regimen (HR = 0.196, 95% CI 0.084-0.457, p < 0.001), and non-NK/T-cell lymphoma (HR = 0.254, 95% CI 0.102-0.628, p = 0.003) were associated with better OS. The prognosis of patients with LAHS was generally poor. CONCLUSION:Ruxolitinib can be combined with chemotherapy in HPS. It is feasible, with no early signals of increased toxicity.

Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly life-threatening disease characterized by an uncontrolled immune disorder. Both under-recognition and delayed diagnosis may contribute to aggressive diseases, and a poorer prognosis. Identification of laboratory features specific for LAHS patients may allow for early detection and intervention with improved outcomes. In the present study, 120 lymphoma patients at first diagnosis were recruited and the function of lymphocytes was evaluated by IFN-γ secretion assay at first diagnosis and follow up. During the surveillance period, 20 patients who complicated with hemophagocytic lymphohistiocytosis (HLH) were classified as LAHS group, and 30 patients without infectious diseases during the course of treatment were classified as lymphoma control group. In addition, 20 non-malignant associated HLH patients recruited as HLH control group and 50 healthy control (HC) subjects were also included. The IFN-γ secretion capability of lymphocytes was compared between first diagnosis of lymphoma patients who was complicate with HLH or not in the disease progression. Our results showed that only NK cell activity was decreased in lymphoma control group, but the activities of NK, CD4+ and CD8+ T cells were all significantly decreased at the time of lymphoma diagnosis in those who would progress with HLH. During the course of treatment, lymphocyte function was relatively stable in lymphoma patients but became further decreased when suffering from complication of LAHS. The IFN-γ secretion capability of lymphocytes in LAHS and non-malignant associated HLH patients were all significantly decreased compared with HCs. So the occurrence of HLH was the key factor leading to the impaired activity of lymphocytes. These data suggest that decreased lymphocyte function might be used as a predictor of LAHS, which has critical clinical significance in diagnosis and further understanding the pathogenesis of the disease.

INTRODUCTION:Hemophagocytic lymphohistiocytosis (HLH) is a disorder caused by severe immune activation. There are no specific criteria to establish the diagnosis in adults; however, the HLH-04 criteria are among the most commonly used. The HScore is a non-validated tool that can also be useful for HLH diagnosis. PATIENTS AND METHODS:We describe the prognostic factors and outcomes of 64 adults diagnosed with HLH in a reference medical center in Mexico City. We included patients ≥ 18 years with HLH, diagnosed and treated at our institution from 1998 to 2016. RESULTS:The median age was 35 years (range, 18-77 years). The underlying cause of HLH was lymphoma in 33 (51.56%) patients (MA-HLH). Cutaneous involvement was more frequent in MA-HLH (33.33%), when compared with patients with non-malignancy associated HLH (NM-HLH) (9.68%) (P = .022). Neurologic symptoms were more frequent in NM-HLH (25.81%) versus MA-HLH (6.06%) (P = .032). After a median follow-up of 14 months (range, 0-216 months), 30-day mortality was 26.56%. Three-year overall survival (OS) was higher for patients with MA-HLH compared with patients with NM-HLH (41% vs. 22.5%; P = .046). Multivariate analysis showed that the presence of nosocomial infection and neurologic symptoms were statistically significant predictors of inferior OS (P = .034 and P = .033, respectively). CONCLUSION:In this series of adults with HLH, patients with nosocomial infections and neurologic symptoms had a statistically significant worse OS. In the largest series in Latin America, the most common cause of HLH was T-cell lymphoma. In our population, NM-HLH presented a higher mortality.

BACKGROUND:Lymphoma-associated hemophagocytic syndrome (LAHS) is a highly fatal immune disorder. Poor prognosis is partly attributed to under diagnosis or delayed diagnosis. AIM:Early identification of LAHS patients based on the laboratory findings could improve the outcomes. DESIGN:Retrospective observational cross-sectional study. METHODS:From January 2011 to June 2016, 282 adult patients with hemophagocytosis in bone marrow were enrolled, and 114 hemophagocytic lymphohistiocytosis (HLH) patients with definite underlying cause were finally included for analysis. The HLH patients were further divided into LAHS (76 out of 114) and non-malignancy-associated HLH (38 out of 114) groups. RESULTS:Compared to non-malignancy-associated HLH, LAHS patients had significantly elevated lactate dehydrogenase (LDH) levels, increased thickness of spleen, higher proportion of patients with lymphadenopathy and significantly decreased peripheral blood cell count. In multivariate logistic regression model analysis, thickness of spleen ≥5 cm (OR = 17.9, 95%CI 1.35-236.6; P = 0.028), IL-6 level ≥55.1 pg/ml (OR = 12.01, 95%CI 1.03-138.9; P = 0.047) and IL-10 level ≥425.9 pg/ml (OR = 51.18, 95%CI 2.53-1035.1; P = 0.010) were independent predictors of LAHS diagnosis. Based on the regression parameters, we established a diagnostic index with weighted risk scores of 1 assigned to thickness of spleen and IL-6 level respectively, and a score of 3 assigned to IL-10 level. A diagnostic index ≥ 2 points had the best AUC value (0.889) with 84.2% of sensitivity and 93.7% of specificity for predicting LAHS. CONCLUSIONS:LAHS can be considered when HLH patients have a diagnostic index ≥2 points, so actively looking for evidence of lymphoma and effective chemotherapy may be necessary.